|
1
|
Hylton-McComas HM, Cordes A, Floros KV, Faber A, Drapkin BJ, Miles WO. Myc family proteins: Molecular drivers of tumorigenesis and resistance in neuroendocrine tumors. Biochim Biophys Acta Rev Cancer 2025; 1880:189332. [PMID: 40280500 DOI: 10.1016/j.bbcan.2025.189332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 04/18/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
Neuroendocrine cancers are a diverse and poorly understood collection of malignancies derived from neuroendocrine cells throughout the body. These cancers uniquely exhibit properties of both the nervous and endocrine systems. Only a limited number of genetic driver mutations have been identified in neuroendocrine cancers, however the mechanisms of how these genetic aberrations alter tumor biology remain elusive. Recent studies have implicated the MYC family of transcription factors as important oncogenic factors in neuroendocrine tumors. We take a systematic approach to understand the roles of the MYC family (c-MYC, n-MYC, l-MYC) in the tumorigenesis of neuroendocrine cancers of the lung, GI tract, pancreas, kidney, prostate, pediatric neuroblastoma, and adrenal glands. Reflecting the complexity of neuroendocrine cancers, we highlight the roles of the MYC family in deregulating the cell cycle and transcriptional networks, invoking cellular plasticity, affecting proliferation capacity, aiding in chromatin remodeling, angiogenesis, metabolic changes, and resistance mechanisms. Depicting the diversity of neuroendocrine cancers, we suggest new approaches in understanding the underlying tumorigenic processes of neuroendocrine cancers from the perspective of MYC.
Collapse
Affiliation(s)
- Hannah M Hylton-McComas
- Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12(th) Avenue, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, The Ohio State University, 460 West 12(th) Avenue, Columbus, OH 43210, USA
| | - Alyssa Cordes
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Konstantinos V Floros
- VCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA 23298, USA; Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
| | - Anthony Faber
- VCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA 23298, USA; Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
| | - Benjamin J Drapkin
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Wayne O Miles
- Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12(th) Avenue, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, The Ohio State University, 460 West 12(th) Avenue, Columbus, OH 43210, USA.
| |
Collapse
|
|
2
|
Jeong M, Kim KB. Recent Research on Role of p53 Family in Small-Cell Lung Cancer. Cancers (Basel) 2025; 17:1110. [PMID: 40227619 PMCID: PMC11988120 DOI: 10.3390/cancers17071110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/20/2025] [Accepted: 03/25/2025] [Indexed: 04/15/2025] Open
Abstract
Small-cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid proliferation, early metastasis, and frequent recurrence, which contribute to a poor prognosis. SCLC is defined by the near-universal inactivation of key tumor suppressor genes, notably TP53 and RB1, which play central roles in its pathogenesis and resistance to therapy. The p53 family of proteins, including p53, p63, and p73, is essential to maintaining cellular homeostasis and tumor suppression. TP53 mutations are almost ubiquitous in SCLC, leading to dysregulated apoptosis and cell cycle control. Moreover, p73 shows potential as a compensatory mechanism for p53 loss, while p63 has a minimal role in this cancer type. In this review, we explore the molecular and functional interplay of the p53 family in SCLC, emphasizing its members' distinct yet interconnected roles in tumor suppression, immune modulation, and therapy resistance. We highlight emerging therapeutic strategies targeting these pathways, including reactivating mutant p53, exploiting synthetic lethality, and addressing immune evasion mechanisms. Furthermore, this review underscores the urgent need for novel, isoform-specific interventions to enhance treatment efficacy and improve patient outcomes in this challenging disease.
Collapse
Affiliation(s)
- Minho Jeong
- School of Life Science and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
- KNU-G LAMP Project Group, KNU-Institute of Basic Sciences, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Kee-Beom Kim
- School of Life Science and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
- KNU-G LAMP Project Group, KNU-Institute of Basic Sciences, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| |
Collapse
|
|
3
|
Hao Y, Li M, Liu W, Ma Z, Liu Z. Autophagic flux modulates tumor heterogeneity and lineage plasticity in SCLC. Front Oncol 2025; 14:1509183. [PMID: 39850810 PMCID: PMC11754400 DOI: 10.3389/fonc.2024.1509183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 12/12/2024] [Indexed: 01/25/2025] Open
Abstract
Introduction Small cell lung cancer (SCLC) is characterized by significant heterogeneity and plasticity, contributing to its aggressive progression and therapy resistance. Autophagy, a conserved cellular process, is implicated in many cancers, but its role in SCLC remains unclear. Methods Using a genetically engineered mouse model (Rb1fl/fl ; Trp53fl/fl ; GFP-LC3-RFP-LC3△G), we tracked autophagic flux in vivo to investigate its effects on SCLC biology. Additional in vitro experiments were conducted to modulate autophagic flux in NE and non-NE SCLC cell lines. Results Tumor subpopulations with high autophagic flux displayed increased proliferation, enhanced metastatic potential, and neuroendocrine (NE) characteristics. Conversely, low-autophagic flux subpopulations exhibited immune-related signals and non-NE traits. In vitro, increasing autophagy induced NE features in non-NE cell lines, while autophagy inhibition in NE cell lines promoted non-NE characteristics. Discussion This study provides a novel model for investigating autophagy in vivo and underscores its critical role in driving SCLC heterogeneity and plasticity, offering potential therapeutic insights.
Collapse
Affiliation(s)
- Yujie Hao
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Mingchen Li
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Wenxu Liu
- Zhejiang Key Laboratory of Medical Epigenetics, Department of Cell Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Zhenyi Ma
- Zhejiang Key Laboratory of Medical Epigenetics, Department of Cell Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Zhe Liu
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Zhejiang Key Laboratory of Medical Epigenetics, Department of Cell Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
4
|
Masuda K, Yoshida T, Motoi N, Shinno Y, Matsumoto Y, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Watanabe S, Hoshino T, Yatabe Y, Ohe Y. Schlafen 11 Expression in Patients With Small Cell Lung Cancer and Its Association With Clinical Outcomes. Thorac Cancer 2025; 16:e15529. [PMID: 39809728 PMCID: PMC11732703 DOI: 10.1111/1759-7714.15529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 12/25/2024] [Accepted: 01/01/2025] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Schlafen 11 (SLFN-11) has been identified as a sensitizer of tumor cells to DNA-damaging agents. However, the relationship between SLFN-11 expression and clinical outcomes in patients with small cell lung cancer (SCLC) remains unexplored. Thus, we aimed to evaluate the impact of SLFN-11 expression on survival in patients with limited-stage (LS) SCLC. METHODS We conducted a retrospective review of data from patients pathologically diagnosed with LS-SCLC post-surgery between January 2008 and December 2018. SLFN-11 expression was assessed using immunohistochemistry in tissue microarrays and scored using a histology (H)-score (range: 0-300). RESULTS Overall, 86 patients were included in the analysis with a median H-score of 43 for SLFN-11 expression. Among the patients, 44 had high SLFN-11 expression (provisionally defined as H-score ≥ 43). No significant differences in clinical profiles were observed between the two groups (high and low SLFN expression). The median survival durations were not reached (NR; 95% confidence interval [CI]: 65.1 months to NR) and 33.5 months (95% CI: 24.2 months to NR) for patients with high and low SLFN-11 expression, respectively (hazard ratio [HR]: 0.40, 95% CI: 0.19-0.81; p = 0.012). Among patients who relapsed post-surgery (n = 21), the median survival durations were 22.0 (95% CI: 7.6-44.9 months) and 8.1 (95% CI: 1.8-24.6 months) months in patients with high and low SLFN-11 expression, respectively (HR: 0.22, 95% CI: 0.06-0.84; p = 0.026). CONCLUSIONS High SLFN-11 expression is associated with relatively longer survival in patients with LS-SCLC in both those undergoing surgery and those who have relapsed.
Collapse
Affiliation(s)
- Ken Masuda
- Department of Thoracic OncologyNational Cancer Center HospitalTokyoJapan
| | - Tatsuya Yoshida
- Department of Thoracic OncologyNational Cancer Center HospitalTokyoJapan
- Department of Experimental TherapeuticsNational Cancer Center HospitalTokyoJapan
| | - Noriko Motoi
- Department of Diagnostic PathologyNational Cancer Center HospitalTokyoJapan
- Division of Genome BiologyNational Cancer Center Research InstituteTokyoJapan
- Department of PathologySaitama Cancer CenterSaitamaJapan
| | - Yuki Shinno
- Department of Thoracic OncologyNational Cancer Center HospitalTokyoJapan
| | - Yuji Matsumoto
- Department of Thoracic OncologyNational Cancer Center HospitalTokyoJapan
| | - Yusuke Okuma
- Department of Thoracic OncologyNational Cancer Center HospitalTokyoJapan
| | - Yasushi Goto
- Department of Thoracic OncologyNational Cancer Center HospitalTokyoJapan
| | | | - Noboru Yamamoto
- Department of Thoracic OncologyNational Cancer Center HospitalTokyoJapan
- Department of Experimental TherapeuticsNational Cancer Center HospitalTokyoJapan
| | | | - Tomoaki Hoshino
- Division of Respirology, Neurology, and Rheumatology, Department of MedicineKurume University School of MedicineFukuokaJapan
| | - Yasushi Yatabe
- Department of Diagnostic PathologyNational Cancer Center HospitalTokyoJapan
| | - Yuichiro Ohe
- Department of Thoracic OncologyNational Cancer Center HospitalTokyoJapan
| |
Collapse
|
|
5
|
Mirgayazova R, Khadiullina R, Gilyazova E, Davletshin D, Ganeeva I, Zmievskaya E, Chasov V, Valiullina A, Bulatov E. The importance of TP53 status in cancer therapy: The example of chronic lymphocytic leukemia. MOLECULAR BIOLOGY RESEARCH COMMUNICATIONS 2025; 14:179-198. [PMID: 40321704 PMCID: PMC12046366 DOI: 10.22099/mbrc.2025.51477.2054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
The TP53 gene encodes the tumor suppressor protein p53, which plays a critical role in genomic stability and cell cycle regulation. TP53 mutations are prevalent in approximately half of all human malignancies and are associated with poor clinical outcomes, including increased genomic instability, chemoresistance, and reduced survival rates. However, the prognostic and predictive value of TP53 status remains inconsistent across cancer types. Chronic lymphocytic leukemia (CLL) stands out as a disease where TP53 alterations have a well-established clinical significance, influencing treatment decisions and patient prognosis. In CLL, TP53 mutations and 17p deletions are strongly correlated with advanced disease stages, resistance to chemo-immunotherapy, and poor overall survival. The European Research Initiative for CLL (ERIC) has recognized TP53 status as a crucial prognostic biomarker, advocating for its routine assessment in clinical practice. Given the limitations of traditional therapies in TP53-mutated CLL, novel targeted therapies, including BCL2 and BTK inhibitors, as well as CAR-T cell therapy, are being explored to improve patient outcomes. This review provides an in-depth analysis of the evolving role of TP53 status in CLL, with a particular focus on emerging therapeutic strategies, including CAR-T cell therapy, and their potential to overcome TP53-driven treatment resistance.
Collapse
Affiliation(s)
- Regina Mirgayazova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Raniya Khadiullina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Elvina Gilyazova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Damir Davletshin
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Irina Ganeeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Ekaterina Zmievskaya
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Vitaly Chasov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Aygul Valiullina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Emil Bulatov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
| |
Collapse
|
|
6
|
Miglietta G, Russo M, Capranico G, Marinello J. Stimulation of cGAS-STING pathway as a challenge in the treatment of small cell lung cancer: a feasible strategy? Br J Cancer 2024; 131:1567-1575. [PMID: 39215193 PMCID: PMC11555062 DOI: 10.1038/s41416-024-02821-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 08/03/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024] Open
Abstract
Lung cancer has a significant incidence among the population and, unfortunately, has an unfavourable prognosis in most cases. The World Health Organization (WHO) classifies lung tumours into two subtypes based on their phenotype: the Non-Small Cell Lung Cancer (NSCLC) and the Small Cell Lung Cancer (SCLC). SCLC treatment, despite advances in chemotherapy and radiotherapy, is often unsuccessful for cancer recurrence highlighting the need to develop novel therapeutic strategies. In this review, we describe the genetic landscape and tumour microenvironment that characterize the pathological processes of SCLC and how they are responsible for tumour immune evasion. The immunosuppressive mechanisms engaged in SCLC are critical factors to understand the failure of immunotherapy in SCLC and, conversely, suggest that new signalling pathways, such as cGAS/STING, should be investigated as possible targets to stimulate an innate immune response in this subtype of lung cancer. The full comprehension of the innate immunity of cancer cells is thus crucial to open new challenges for successful immunotherapy in treating SCLC and improving patient outcomes.
Collapse
Affiliation(s)
- Giulia Miglietta
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Marco Russo
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Giovanni Capranico
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
| | - Jessica Marinello
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
| |
Collapse
|
|
7
|
Finkelstein SR, Patel R, Deland K, Mercer J, Starr B, Zhu D, Min H, Reinsvold M, Campos LDS, Williams NT, Luo L, Ma Y, Neff J, Hoenerhoff MJ, Moding EJ, Kirsch DG. 56Fe-ion Exposure Increases the Incidence of Lung and Brain Tumors at a Similar Rate in Male and Female Mice. Radiat Res 2024; 202:734-744. [PMID: 39307527 DOI: 10.1667/rade-24-00004.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 08/23/2024] [Indexed: 09/25/2024]
Abstract
The main deterrent to long-term space travel is the risk of Radiation Exposure Induced Death (REID). The National Aeronautics and Space Administration (NASA) has adopted Permissible Exposure Levels (PELs) to limit the probability of REID to 3% for the risk of death due to radiation-induced carcinogenesis. The most significant contributor to current REID estimates for astronauts is the risk of lung cancer. Recently updated lung cancer estimates from Japan's atomic bomb survivors showed that the excess relative risk of lung cancer by age 70 is roughly fourfold higher in females compared to males. However, whether sex differences may impact the risk of lung cancer due to exposure to high charge and energy (HZE) radiation is not well studied. Thus, to evaluate the impact of sex differences on the risk of solid cancer development after HZE radiation exposure, we irradiated Rbfl/fl, Trp53fl/+ male and female mice infected with Adeno-Cre with various doses of 320 kVp X rays or 600 MeV/n 56Fe ions and monitored them for any radiation-induced malignancies. We conducted complete necropsy and histopathology of major organs on 183 male and 157 female mice after following them for 350 days postirradiation. We observed that lung adenomas/carcinomas and esthesioneuroblastomas (ENBs) were the most common primary malignancies in mice exposed to X rays and 56Fe ions, respectively. In addition, 1 Gy 56Fe-ion exposure compared to X-ray exposure led to a significantly increased incidence of lung adenomas/carcinomas (P = 0.02) and ENBs (P < 0.0001) in mice. However, we did not find a significantly higher incidence of any solid malignancies in female mice as compared to male mice, regardless of radiation quality. Furthermore, gene expression analysis of ENBs suggested a distinct gene expression pattern with similar hallmark pathways altered, such as MYC targets and MTORC1 signaling, in ENBs induced by X rays and 56Fe ions. Thus, our data revealed that 56Fe-ion exposure significantly accelerated the development of lung adenomas/carcinomas and ENBs compared to X rays, but the rate of solid malignancies was similar between male and female mice, regardless of radiation quality.
Collapse
Affiliation(s)
- Sophie R Finkelstein
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Rutulkumar Patel
- Department of Radiation Oncology, Baylor College of Medicine, Houston, Texas
| | - Katherine Deland
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Joshua Mercer
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Bryce Starr
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Daniel Zhu
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Hooney Min
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Michael Reinsvold
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | | | - Nerissa T Williams
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Lixia Luo
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Yan Ma
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Jadee Neff
- Department of Pathology, Duke University, Durham, North Carolina
| | - Mark J Hoenerhoff
- Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Everett J Moding
- Department of Radiation Oncology, Stanford University, Stanford, California
| | - David G Kirsch
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
- Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, North Carolina
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario
- Department of Radiation Oncology and Department of Medical Biophysics, University of Toronto, Toronto, Ontario
| |
Collapse
|
|
8
|
Tyagi A, Karapurkar JK, Colaco JC, Sarodaya N, Antao AM, Kaushal K, Haq S, Chandrasekaran AP, Das S, Singh V, Hong SH, Suresh B, Kim KS, Ramakrishna S. USP19 Negatively Regulates p53 and Promotes Cervical Cancer Progression. Mol Biotechnol 2024; 66:2032-2045. [PMID: 37572221 DOI: 10.1007/s12033-023-00814-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 06/29/2023] [Indexed: 08/14/2023]
Abstract
p53 is a tumor suppressor gene activated in response to cellular stressors that inhibits cell cycle progression and induces pro-apoptotic signaling. The protein level of p53 is well balanced by the action of several E3 ligases and deubiquitinating enzymes (DUBs). Several DUBs have been reported to negatively regulate and promote p53 degradation in tumors. In this study, we identified USP19 as a negative regulator of p53 protein level. We demonstrate a direct interaction between USP19 and p53 by pull down assay. The overexpression of USP19 promoted ubiquitination of p53 and reduced its protein half-life. We also demonstrate that CRISPR/Cas9-mediated knockout of USP19 in cervical cancer cells elevates p53 protein levels, resulting in reduced colony formation, cell migration, and cell invasion. Overall, our results indicate that USP19 negatively regulates p53 protein levels in cervical cancer progression.
Collapse
Affiliation(s)
- Apoorvi Tyagi
- Graduate School of Biomedical Science and Engineering, Hanyang University, 04763, Seoul, South Korea
| | | | - Jencia Carminha Colaco
- Graduate School of Biomedical Science and Engineering, Hanyang University, 04763, Seoul, South Korea
| | - Neha Sarodaya
- Graduate School of Biomedical Science and Engineering, Hanyang University, 04763, Seoul, South Korea
| | - Ainsley Mike Antao
- Graduate School of Biomedical Science and Engineering, Hanyang University, 04763, Seoul, South Korea
| | - Kamini Kaushal
- Graduate School of Biomedical Science and Engineering, Hanyang University, 04763, Seoul, South Korea
| | - Saba Haq
- Department of Life Science, College of Natural Sciences, Hanyang University, 04763, Seoul, South Korea
| | | | - Soumyadip Das
- Graduate School of Biomedical Science and Engineering, Hanyang University, 04763, Seoul, South Korea
| | - Vijai Singh
- Department of Biosciences, School of Science, Rajpur, Indrashil University, 382715, Mehsana, Gujarat, India
| | - Seok-Ho Hong
- Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, South Korea
| | - Bharathi Suresh
- Graduate School of Biomedical Science and Engineering, Hanyang University, 04763, Seoul, South Korea.
| | - Kye-Seong Kim
- Graduate School of Biomedical Science and Engineering, Hanyang University, 04763, Seoul, South Korea.
- College of Medicine, Hanyang University, 04763, Seoul, South Korea.
| | - Suresh Ramakrishna
- Graduate School of Biomedical Science and Engineering, Hanyang University, 04763, Seoul, South Korea
- College of Medicine, Hanyang University, 04763, Seoul, South Korea
| |
Collapse
|
|
9
|
Liu Y, Su Z, Tavana O, Gu W. Understanding the complexity of p53 in a new era of tumor suppression. Cancer Cell 2024; 42:946-967. [PMID: 38729160 PMCID: PMC11190820 DOI: 10.1016/j.ccell.2024.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/15/2024] [Accepted: 04/16/2024] [Indexed: 05/12/2024]
Abstract
p53 was discovered 45 years ago as an SV40 large T antigen binding protein, coded by the most frequently mutated TP53 gene in human cancers. As a transcription factor, p53 is tightly regulated by a rich network of post-translational modifications to execute its diverse functions in tumor suppression. Although early studies established p53-mediated cell-cycle arrest, apoptosis, and senescence as the classic barriers in cancer development, a growing number of new functions of p53 have been discovered and the scope of p53-mediated anti-tumor activity is largely expanded. Here, we review the complexity of different layers of p53 regulation, and the recent advance of the p53 pathway in metabolism, ferroptosis, immunity, and others that contribute to tumor suppression. We also discuss the challenge regarding how to activate p53 function specifically effective in inhibiting tumor growth without harming normal homeostasis for cancer therapy.
Collapse
Affiliation(s)
- Yanqing Liu
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Zhenyi Su
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Omid Tavana
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Wei Gu
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
| |
Collapse
|
|
10
|
Lee S, Bondaruk J, Wang Y, Chen H, Lee JG, Majewski T, Mullen RD, Cogdell D, Chen J, Wang Z, Yao H, Kus P, Jeong J, Lee I, Choi W, Navai N, Guo C, Dinney C, Baggerly K, Mendelsohn C, McConkey D, Behringer RR, Kimmel M, Wei P, Czerniak B. Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis. Cell Rep 2024; 43:114146. [PMID: 38676926 PMCID: PMC11265536 DOI: 10.1016/j.celrep.2024.114146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 02/19/2024] [Accepted: 04/09/2024] [Indexed: 04/29/2024] Open
Abstract
We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term "forerunner" genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two of these genes, LPAR6 and CAB39L, are preferentially downregulated in the luminal and basal subtypes of bladder cancer, respectively. Their loss of function dysregulates urothelial differentiation, sensitizing the urothelium to N-butyl-N-(4-hydroxybutyl)nitrosamine-induced cancers, which recapitulate the luminal and basal subtypes of human bladder cancer.
Collapse
Affiliation(s)
- Sangkyou Lee
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jolanta Bondaruk
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yishan Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Huiqin Chen
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - June Goo Lee
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Tadeusz Majewski
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rachel D Mullen
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - David Cogdell
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jiansong Chen
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ziqiao Wang
- Department of Biostatistics, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Hui Yao
- Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Pawel Kus
- Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland
| | - Joon Jeong
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ilkyun Lee
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Woonyoung Choi
- Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Neema Navai
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Charles Guo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Colin Dinney
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Keith Baggerly
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Cathy Mendelsohn
- Department of Urology, Genetics & Development and Pathology, Columbia University, New York, NY 10032, USA
| | - David McConkey
- Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Richard R Behringer
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Marek Kimmel
- Department of Statistics, Rice University, Houston, TX 77005, USA
| | - Peng Wei
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bogdan Czerniak
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| |
Collapse
|
|
11
|
Gu Y, Benavente CA. Landscape and Treatment Options of Shapeshifting Small Cell Lung Cancer. J Clin Med 2024; 13:3120. [PMID: 38892831 PMCID: PMC11173155 DOI: 10.3390/jcm13113120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/20/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
Small cell lung cancer (SCLC) is a deadly neuroendocrine malignancy, notorious for its rapid tumor growth, early metastasis, and relatively "cold" immune environment. Only standard chemotherapies and a few immune checkpoint inhibitors have been approved for SCLC treatment, revealing an urgent need for novel therapeutic approaches. Moreover, SCLC has been recently recognized as a malignancy with high intratumoral and intertumoral heterogeneity, which explains the modest response rate in some patients and the early relapse. Molecular subtypes defined by the expression of lineage-specific transcription factors (ASCL1, NEUROD1, POU2F3, and, in some studies, YAP1) or immune-related genes display different degrees of neuroendocrine differentiation, immune cell infiltration, and response to treatment. Despite the complexity of this malignancy, a few biomarkers and targets have been identified and many promising drugs are currently undergoing clinical trials. In this review, we integrate the current progress on the genomic landscape of this shapeshifting malignancy, the characteristics and treatment vulnerabilities of each subtype, and promising drugs in clinical phases.
Collapse
Affiliation(s)
- Yijun Gu
- Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA;
| | - Claudia A. Benavente
- Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA;
- Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA
- Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA
| |
Collapse
|
|
12
|
Pal Choudhuri S, Girard L, Lim JYS, Wise JF, Freitas B, Yang D, Wong E, Hamilton S, Chien VD, Kim YJ, Gilbreath C, Zhong J, Phat S, Myers DT, Christensen CL, Mazloom-Farsibaf H, Stanzione M, Wong KK, Hung YP, Farago AF, Meador CB, Dyson NJ, Lawrence MS, Wu S, Drapkin BJ. Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs. Cancer Discov 2024; 14:804-827. [PMID: 38386926 PMCID: PMC11061613 DOI: 10.1158/2159-8290.cd-23-0656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 12/15/2023] [Accepted: 02/20/2024] [Indexed: 02/24/2024]
Abstract
Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a preclinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC. SIGNIFICANCE SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC. This article is featured in Selected Articles from This Issue, p. 695.
Collapse
Affiliation(s)
- Shreoshi Pal Choudhuri
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Luc Girard
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jun Yi Stanley Lim
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jillian F. Wise
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Braeden Freitas
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Di Yang
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Edmond Wong
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Seth Hamilton
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Victor D. Chien
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Yoon Jung Kim
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Collin Gilbreath
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jun Zhong
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Sarah Phat
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - David T. Myers
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | | | - Hanieh Mazloom-Farsibaf
- Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Marcello Stanzione
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Kwok-Kin Wong
- Perlmutter Cancer Center, NYU Langone Health, New York, New York
| | - Yin P. Hung
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Anna F. Farago
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Catherine B. Meador
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Nicholas J. Dyson
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Michael S. Lawrence
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Sihan Wu
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Benjamin J. Drapkin
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| |
Collapse
|
|
13
|
Khan R, Pari B, Puszynski K. Comprehensive Bioinformatic Investigation of TP53 Dysregulation in Diverse Cancer Landscapes. Genes (Basel) 2024; 15:577. [PMID: 38790205 PMCID: PMC11121236 DOI: 10.3390/genes15050577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/23/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024] Open
Abstract
P53 overexpression plays a critical role in cancer pathogenesis by disrupting the intricate regulation of cellular proliferation. Despite its firmly established function as a tumor suppressor, elevated p53 levels can paradoxically contribute to tumorigenesis, influenced by factors such as exposure to carcinogens, genetic mutations, and viral infections. This phenomenon is observed across a spectrum of cancer types, including bladder (BLCA), ovarian (OV), cervical (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), diffuse large B-cell lymphoma (DLBC), esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and uterine corpus endometrial carcinoma (UCEC). This broad spectrum of cancers is often associated with increased aggressiveness and recurrence risk. Effective therapeutic strategies targeting tumors with p53 overexpression require a comprehensive approach, integrating targeted interventions aimed at the p53 gene with conventional modalities such as chemotherapy, radiation therapy, and targeted drugs. In this extensive study, we present a detailed analysis shedding light on the multifaceted role of TP53 across various cancers, with a specific emphasis on its impact on disease-free survival (DFS). Leveraging data from the TCGA database and the GTEx dataset, along with GEPIA, UALCAN, and STRING, we identify TP53 overexpression as a significant prognostic indicator, notably pronounced in prostate adenocarcinoma (PRAD). Supported by compelling statistical significance (p < 0.05), our analysis reveals the distinct influence of TP53 overexpression on DFS outcomes in PRAD. Additionally, graphical representations of overall survival (OS) underscore the notable disparity in OS duration between tumors exhibiting elevated TP53 expression (depicted by the red line) and those with lower TP53 levels (indicated by the blue line). The hazard ratio (HR) further emphasizes the profound impact of TP53 on overall survival. Moreover, our investigation delves into the intricate TP53 protein network, unveiling genes exhibiting robust positive correlations with TP53 expression across 13 out of 27 cancers. Remarkably, negative correlations emerge with pivotal tumor suppressor genes. This network analysis elucidates critical proteins, including SIRT1, CBP, p300, ATM, DAXX, HSP 90-alpha, Mdm2, RPA70, 14-3-3 protein sigma, p53, and ASPP2, pivotal in regulating cell cycle dynamics, DNA damage response, and transcriptional regulation. Our study underscores the paramount importance of deciphering TP53 dynamics in cancer, providing invaluable insights into tumor behavior, disease-free survival, and potential therapeutic avenues.
Collapse
Affiliation(s)
- Ruby Khan
- Department of Systems Biology and Engineering, Silesian University of Technology, 44-100 Gliwice, Poland;
| | - Bakht Pari
- Principal, Nursing School, Lady Reading Hospital Peshawar, Peshawar 25000, Pakistan;
| | - Krzysztof Puszynski
- Department of Systems Biology and Engineering, Silesian University of Technology, 44-100 Gliwice, Poland;
| |
Collapse
|
|
14
|
Fűr GM, Nemes K, Magó É, Benő AÁ, Topolcsányi P, Moldvay J, Pongor LS. Applied models and molecular characteristics of small cell lung cancer. Pathol Oncol Res 2024; 30:1611743. [PMID: 38711976 PMCID: PMC11070512 DOI: 10.3389/pore.2024.1611743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 04/03/2024] [Indexed: 05/08/2024]
Abstract
Small cell lung cancer (SCLC) is a highly aggressive type of cancer frequently diagnosed with metastatic spread, rendering it surgically unresectable for the majority of patients. Although initial responses to platinum-based therapies are often observed, SCLC invariably relapses within months, frequently developing drug-resistance ultimately contributing to short overall survival rates. Recently, SCLC research aimed to elucidate the dynamic changes in the genetic and epigenetic landscape. These have revealed distinct subtypes of SCLC, each characterized by unique molecular signatures. The recent understanding of the molecular heterogeneity of SCLC has opened up potential avenues for precision medicine, enabling the development of targeted therapeutic strategies. In this review, we delve into the applied models and computational approaches that have been instrumental in the identification of promising drug candidates. We also explore the emerging molecular diagnostic tools that hold the potential to transform clinical practice and patient care.
Collapse
Affiliation(s)
- Gabriella Mihalekné Fűr
- Cancer Genomics and Epigenetics Core Group, Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Szeged, Hungary
| | - Kolos Nemes
- Cancer Genomics and Epigenetics Core Group, Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Szeged, Hungary
| | - Éva Magó
- Cancer Genomics and Epigenetics Core Group, Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Szeged, Hungary
- Genome Integrity and DNA Repair Core Group, Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Szeged, Hungary
| | - Alexandra Á. Benő
- Cancer Genomics and Epigenetics Core Group, Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Szeged, Hungary
| | - Petronella Topolcsányi
- Cancer Genomics and Epigenetics Core Group, Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Szeged, Hungary
| | - Judit Moldvay
- Department of Pulmonology, Szeged University Szent-Gyorgyi Albert Medical School, Szeged, Hungary
- 1st Department of Pulmonology, National Koranyi Institute of Pulmonology, Budapest, Hungary
| | - Lőrinc S. Pongor
- Cancer Genomics and Epigenetics Core Group, Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Szeged, Hungary
| |
Collapse
|
|
15
|
Jin B, Wang M, Sun Y, Lee PAH, Zhang X, Lu Y, Zhao B. CHIP suppresses the proliferation and migration of A549 cells by mediating the ubiquitination of eIF2α and upregulation of tumor suppressor RBM5. J Biol Chem 2024; 300:105673. [PMID: 38272235 PMCID: PMC10877634 DOI: 10.1016/j.jbc.2024.105673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 01/05/2024] [Indexed: 01/27/2024] Open
Abstract
The protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor 2 subunit α (eIF2α) pathway plays an essential role in endoplasmic reticulum (ER) stress. When the PERK-eIF2α pathway is activated, PERK phosphorylates eIF2α (p-eIF2α) at Ser51 and quenches global protein synthesis. In this study, we verified eIF2α as a bona fide substrate of the E3 ubiquitin ligase carboxyl terminus of the HSC70-interaction protein (CHIP) both in vitro and in cells. CHIP mediated the ubiquitination and degradation of nonphosphorylated eIF2α in a chaperone-independent manner and promoted the upregulation of the cyclic AMP-dependent transcription factor under endoplasmic reticulum stress conditions. Cyclic AMP-dependent transcription factor induced the transcriptional enhancement of the tumor suppressor genes PTEN and RBM5. Although transcription was enhanced, the PTEN protein was subsequently degraded by CHIP, but the expression of the RBM5 protein was upregulated, thereby suppressing the proliferation and migration of A549 cells. Overall, our study established a new mechanism that deepened the understanding of the PERK-eIF2α pathway through the ubiquitination and degradation of eIF2α. The crosstalk between the phosphorylation and ubiquitination of eIF2α shed light on a new perspective for tumor progression.
Collapse
Affiliation(s)
- Bo Jin
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China
| | - Mengran Wang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China
| | - Yiheng Sun
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China
| | - Priscilla Ann Hweek Lee
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China
| | - Xiangqi Zhang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China
| | - Yao Lu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China
| | - Bo Zhao
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China.
| |
Collapse
|
|
16
|
Scheicher NV, Berchtold S, Beil J, Smirnow I, Schenk A, Lauer UM. In Vitro Sensitivity of Neuroendocrine Neoplasms to an Armed Oncolytic Measles Vaccine Virus. Cancers (Basel) 2024; 16:488. [PMID: 38339240 PMCID: PMC10854751 DOI: 10.3390/cancers16030488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/10/2024] [Accepted: 01/17/2024] [Indexed: 02/12/2024] Open
Abstract
Neuroendocrine neoplasms represent a heterogenous group of rare tumors whose current therapeutic options show only limited efficacy. Oncolytic viruses exert their mode of action through (onco-)lysis of infected tumor cells and the induction of a systemic antitumoral immune response in a virus-induced inflammatory micromilieu. Here, we investigated the potential of our well-established second-generation suicide-gene armed oncolytic measles vaccine virus (MeV-SCD) in five human NEN cell lines. First, (i) expression of the MeV receptor CD46 and (ii) its correlation with primary infection rates were analyzed. Next, (iii) promising combination partners for MeV-SCD were tested by employing either the prodrug 5-fluorocytosine, which is converted into the chemotherapeutic compound 5-fluorouracil, or the mTOR-inhibitor everolimus. As a result, MeV-SCD was found to kill all NEN tumor cell lines efficiently in a dose-dependent manner. This oncolytic effect was further enhanced by exploiting the prodrug-converting system, which was found to be highly instrumental in overcoming the partial resistance found in a single NEN cell line. Furthermore, viral replication was unaffected by everolimus, which is a basic requirement for combined use in NEN patients. These data suggest that MeV-SCD has profound potential for patients with NEN, thus paving the way for early clinical trials.
Collapse
Affiliation(s)
- Nikolai V. Scheicher
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (N.V.S.)
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Susanne Berchtold
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (N.V.S.)
| | - Julia Beil
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (N.V.S.)
- German Cancer Consortium (DKTK), Partner Site Tübingen, a Partnership between DKFZ and University Hospital Tübingen, 72076 Tübingen, Germany
| | - Irina Smirnow
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (N.V.S.)
| | - Andrea Schenk
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (N.V.S.)
| | - Ulrich M. Lauer
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (N.V.S.)
- German Cancer Consortium (DKTK), Partner Site Tübingen, a Partnership between DKFZ and University Hospital Tübingen, 72076 Tübingen, Germany
| |
Collapse
|
|
17
|
Duabil AJN, Cooper CR, Aldujaily E, Halford SER, Hirschberg S, Katugampola SD, Jones GDD. Investigations of the novel checkpoint kinase 1 inhibitor SRA737 in non-small cell lung cancer and colorectal cancer cells of differing tumour protein 53 gene status. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:1210-1226. [PMID: 38214010 PMCID: PMC10776598 DOI: 10.37349/etat.2023.00193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 10/16/2023] [Indexed: 01/13/2024] Open
Abstract
Aim In response to DNA damage the serine/threonine-specific protein kinase checkpoint kinase 1 (CHK1) is activated allowing cells to enter S phase (S) and G2 phase (G2) cell-cycle arrest. CHK1 inhibitors are expected to prevent cells from entering such arrest, thereby enhancing DNA damage-induced cytotoxicity. In contrast, normal cells with intact ataxia-telangiectasia mutated (ATM), CHK2 and tumour suppressor protein 53 (P53) signalling are still able to enter cell-cycle arrest using the functioning G1/S checkpoint, thereby being rescued from enhanced cytotoxicity. The main objective of this work is to investigate the in vitro effects of the novel CHK1 inhibitor SRA737 on pairs of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) cell lines, all with genetic aberrations rendering them susceptible to replication stress but of differing tumour protein 53 (TP53) gene status, focusing on DNA damage induction and the subsequent effects on cell proliferation and viability. Methods NSCLC cell lines H23 [TP53 mutant (MUT)] and A549 [TP53 wild-type (WT)] and CRC cell lines HT29 (TP53 MUT) and HCT116 (TP53 WT) were incubated with differing micromolar concentrations of SRA737 for 24 h and then analysed using alkaline comet and phosphorylated H2A.X variant histone (γH2AX)-foci assays to assess mostly DNA single strand break and double strand break damage, respectively. Cell-counting/trypan blue staining was also performed to assess cell proliferation/viability. Results Clear concentration-dependent increases in comet formation and γH2AX-foci/cell were noted for the TP53 MUT cells with no or lower increases being noted in the corresponding TP53 WT cells. Also, greater anti-proliferative and cell killing effects were noted in the TP53 MUT cells than in the TP53 WT cells. Conclusions This study's data suggests that P53 status/functioning is a key factor in determining the sensitivity of NSCLC and CRC cancer cells towards CHK1 inhibition, even in circumstances conducive to high replicative stress.
Collapse
Affiliation(s)
- Ali JN Duabil
- Leicester Cancer Research Centre, Department of Genetics & Genome Biology, University of Leicester, LE1 7RH Leics, UK
- Department of Surgery, Faculty of Medicine, University of Kufa, Najaf, Iraq
| | - Christian R Cooper
- Leicester Cancer Research Centre, Department of Genetics & Genome Biology, University of Leicester, LE1 7RH Leics, UK
- MRC Oxford Institute for Radiation Oncology, University of Oxford, OX3 7DQ Oxon, UK
| | - Esraa Aldujaily
- Leicester Cancer Research Centre, Department of Genetics & Genome Biology, University of Leicester, LE1 7RH Leics, UK
- Department of Pathology & Forensic Medicine, Faculty of Medicine, University of Kufa, Najaf, Iraq
| | - Sarah ER Halford
- Cancer Research UK Centre for Drug Development, London E20 1JQ, UK
| | | | | | - George DD Jones
- Leicester Cancer Research Centre, Department of Genetics & Genome Biology, University of Leicester, LE1 7RH Leics, UK
| |
Collapse
|
|
18
|
Zhou F. Prognostic value of CASC15 and LINC01600 as competitive endogenous RNAs in lung adenocarcinoma: An observational study. Medicine (Baltimore) 2023; 102:e36026. [PMID: 37960753 PMCID: PMC10637420 DOI: 10.1097/md.0000000000036026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 10/18/2023] [Indexed: 11/15/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) can directly or indirectly regulate gene expression through interacting with microRNAs (miRNAs). Competitive endogenous RNAs render the roles of lncRNAs more complicated in the process of tumor occurrence and progression. However, the prognostic value of lncRNAs as potential biomarkers and their functional roles as competitive endogenous RNAs have not been clearly described for lung adenocarcinoma (LUAD). In the present study, the aberrant expression profiles of lncRNAs and miRNAs were analyzed at cBioPortal by interrogating LUAD dataset from The Cancer Genome Atlas (TCGA) database with 517 tissue samples. A total of 92 lncRNAs and 125 miRNAs with highly genetic alterations were identified. Further bioinformatics analysis was performed to construct a LUAD-related lncRNA-miRNA-mRNA ceRNA network, which included 24 highly altered lncRNAs, 21 miRNAs and 142 mRNAs. Some key lncRNAs in this network were subsequently identified as LUAD prognosis-related, and of those, CASC15 and LINC01600 both performed the potential prognostic characteristics with LUAD regarding OS and recurrence. Comprehensive analysis indicated that the expression of LINC01600 was significantly associated with KRAS mutation and lymph node metastasis, and CASC15 and LINC01600 were significantly tended towards co-occurrence, which may be due to the similarity of genes co-expressed by these 2 lncRNAs. Our findings provided novel insight into better understanding of ceRNA regulatory mechanisms in the pathogenesis of LUAD and facilitated the identification of potential biomarkers for prognosis.
Collapse
Affiliation(s)
- Fangbin Zhou
- Department of Tropical Diseases, Naval Medical University, Shanghai, China
| |
Collapse
|
|
19
|
Megyesfalvi Z, Gay CM, Popper H, Pirker R, Ostoros G, Heeke S, Lang C, Hoetzenecker K, Schwendenwein A, Boettiger K, Bunn PA, Renyi-Vamos F, Schelch K, Prosch H, Byers LA, Hirsch FR, Dome B. Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions. CA Cancer J Clin 2023; 73:620-652. [PMID: 37329269 DOI: 10.3322/caac.21785] [Citation(s) in RCA: 143] [Impact Index Per Article: 71.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/30/2023] [Accepted: 04/04/2023] [Indexed: 06/19/2023] Open
Abstract
Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.
Collapse
Affiliation(s)
- Zsolt Megyesfalvi
- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary
- National Koranyi Institute of Pulmonology, Budapest, Hungary
| | - Carl M Gay
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Helmut Popper
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Robert Pirker
- Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Gyula Ostoros
- National Koranyi Institute of Pulmonology, Budapest, Hungary
| | - Simon Heeke
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christian Lang
- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Division of Pulmonology, Department of Medicine II, Medical University of Vienna, Vienna, Austria
| | - Konrad Hoetzenecker
- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Anna Schwendenwein
- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Kristiina Boettiger
- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Paul A Bunn
- University of Colorado School of Medicine, Aurora, CO, USA
| | - Ferenc Renyi-Vamos
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary
- National Koranyi Institute of Pulmonology, Budapest, Hungary
| | - Karin Schelch
- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Helmut Prosch
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Lauren A Byers
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fred R Hirsch
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Tisch Cancer Institute, Center for Thoracic Oncology, Mount Sinai Health System, New York, NY, USA
| | - Balazs Dome
- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary
- National Koranyi Institute of Pulmonology, Budapest, Hungary
- Department of Translational Medicine, Lund University, Lund, Sweden
| |
Collapse
|
|
20
|
Peng M, Hu Q, Wu Z, Wang B, Wang C, Yu F. Mutation of TP53 Confers Ferroptosis Resistance in Lung Cancer Through the FOXM1/MEF2C Axis. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1587-1602. [PMID: 37236507 DOI: 10.1016/j.ajpath.2023.05.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/17/2023] [Accepted: 05/02/2023] [Indexed: 05/28/2023]
Abstract
Ferroptosis is a highly regulated tumor suppressor process. Loss or mutation of TP53 can cause changes in sensitivity to ferroptosis. Mutations in TP53 may be associated with the malignant or indolent progression of ground glass nodules in early lung cancer, but whether ferroptosis may also be involved in determining this biological process has not yet been determined. Using in vivo and in vitro gain- and loss-of-function approaches, this study used clinical tissue for mutation analysis and pathological research to show that wild-type TP53 inhibited the expression of forkhead box M1 (FOXM1) by binding to peroxisome proliferator-activated receptor-γ coactivator 1α, maintaining the mitochondrial function and thus affecting the sensitivity to ferroptosis. This function was absent in mutant cells, resulting in overexpression of FOXM1 and ferroptosis resistance. Mechanistically, FOXM1 activated the transcription level of myocyte-specific enhancer factor 2C in the mitogen-activated protein kinase signaling pathway, leading to stress protection when exposed to ferroptosis inducers. This study provides new insights into the mechanism of association between TP53 mutation and ferroptosis tolerance, which can aid a deeper understanding of the role of TP53 in the malignant progression of lung cancer.
Collapse
Affiliation(s)
- Muyun Peng
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Qikang Hu
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Zeyu Wu
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Bin Wang
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Cheng Wang
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Fenglei Yu
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.
| |
Collapse
|
|
21
|
Song Z, Zhang J, Sun Y, Jiang Z, Liu X. Establishment and validation of an immune infiltration predictive model for ovarian cancer. BMC Med Genomics 2023; 16:227. [PMID: 37759229 PMCID: PMC10538244 DOI: 10.1186/s12920-023-01657-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND The most prevalent mutation in ovarian cancer is the TP53 mutation, which impacts the development and prognosis of the disease. We looked at how the TP53 mutation associates the immunophenotype of ovarian cancer and the prognosis of the disease. METHODS We investigated the state of TP53 mutations and expression profiles in culturally diverse groups and datasets and developed an immune infiltration predictive model relying on immune-associated genes differently expressed between TP53 WT and TP53 MUT ovarian cancer cases. We aimed to construct an immune infiltration predictive model (IPM) to enhance the prognosis of ovarian cancer and investigate the impact of the IPM on the immunological microenvironment. RESULTS TP53 mutagenesis affected the expression of seventy-seven immune response-associated genes. An IPM was implemented and evaluated on ovarian cancer patients to distinguish individuals with low- and high-IPM subgroups of poor survival. For diagnostic and therapeutic use, a nomogram is thus created. According to pathway enrichment analysis, the pathways of the human immune response and immune function abnormalities were the most associated functions and pathways with the IPM genes. Furthermore, patients in the high-risk group showed low proportions of macrophages M1, activated NK cells, CD8+ T cells, and higher CTLA-4, PD-1, PD-L1, and TIM-3 than patients in the low-risk group. CONCLUSIONS The IPM model may identify high-risk patients and integrate other clinical parameters to predict their overall survival, suggesting it is a potential methodology for optimizing ovarian cancer prognosis.
Collapse
Affiliation(s)
- Zhenxia Song
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Jingwen Zhang
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Yue Sun
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Zhongmin Jiang
- Department of Pathology, Tian Jin Fifth's Central Hospital, #41 Zhejiang Road, Binhai District, Tianjin, 300450, P. R. China
| | - Xiaoning Liu
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China.
| |
Collapse
|
|
22
|
Choudhuri SP, Girard L, Lim JYS, Wise JF, Freitas B, Yang D, Wong E, Hamilton S, Chien VD, Gilbreath C, Zhong J, Phat S, Myers DT, Christensen CL, Stanzione M, Wong KK, Farago AF, Meador CB, Dyson NJ, Lawrence MS, Wu S, Drapkin BJ. Acquired Cross-resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC paralogs. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.23.546278. [PMID: 37425738 PMCID: PMC10327110 DOI: 10.1101/2023.06.23.546278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here we present a pre-clinical system that recapitulates acquired cross-resistance in SCLC, developed from 51 patient-derived xenografts (PDXs). Each model was tested for in vivo sensitivity to three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These functional profiles captured hallmark clinical features, such as the emergence of treatment-refractory disease after early relapse. Serially derived PDX models from the same patient revealed that cross-resistance was acquired through a MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that this was not unique to one patient, as MYC paralog amplifications on ecDNAs were recurrent among cross-resistant models derived from patients after relapse. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC. SIGNIFICANCE SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC.
Collapse
|
|
23
|
Finkelstein SR, Patel R, Deland K, Mercer J, Starr B, Zhu D, Min H, Reinsvold M, Campos LDS, Williams N, Luo L, Ma Y, Neff J, Hoenerhoff M, Moding EJ, Kirsch DG. 56 Fe ion exposure increases the incidence of lung and brain tumors at a similar rate in male and female mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.06.543754. [PMID: 37333373 PMCID: PMC10274718 DOI: 10.1101/2023.06.06.543754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
The main deterrent to long-term space travel is the risk of Radiation Exposure Induced Death (REID). The National Aeronautics and Space Administration (NASA) has adopted Permissible Exposure Levels (PELs) to limit the probability of REID to 3% for the risk of death due to radiation-induced carcinogenesis. The most significant contributor to current REID estimates for astronauts is the risk of lung cancer. Recently updated lung cancer estimates from Japan's atomic bomb survivors showed that the excess relative risk of lung cancer by age 70 is roughly four-fold higher in females compared to males. However, whether sex differences may impact the risk of lung cancer due to exposure to high charge and energy (HZE) radiation is not well studied. Thus, to evaluate the impact of sex differences on the risk of solid cancer development post-HZE radiation exposure, we irradiated Rb fl/fl ; Trp53 fl/+ male and female mice infected with Adeno-Cre with various doses of 320 kVp X-rays or 600 MeV/n 56 Fe ions and monitored them for any radiation-induced malignancies. We observed that lung adenomas/carcinomas and esthesioneuroblastomas (ENBs) were the most common primary malignancies in X-ray and 56 Fe ion-exposed mice, respectively. In addition, 1 Gy 56 Fe ion exposure compared to X-rays led to a significantly higher incidence of lung adenomas/carcinomas (p=0.02) and ENBs (p<0.0001). However, we did not find a significantly higher incidence of any solid malignancies in female mice as compared to male mice, regardless of radiation quality. Furthermore, gene expression analysis of ENBs suggested a distinct gene expression pattern with similar hallmark pathways altered, such as MYC targets and MTORC1 signaling, in X-ray and 56 Fe ion-induced ENBs. Thus, our data revealed that 56 Fe ion exposure significantly accelerated the development of lung adenomas/carcinomas and ENBs compared to X-rays, but the rate of solid malignancies was similar between male and female mice, regardless of radiation quality.
Collapse
|
|
24
|
Dervovic D, Malik AA, Chen ELY, Narimatsu M, Adler N, Afiuni-Zadeh S, Krenbek D, Martinez S, Tsai R, Boucher J, Berman JM, Teng K, Ayyaz A, Lü Y, Mbamalu G, Loganathan SK, Lee J, Zhang L, Guidos C, Wrana J, Valipour A, Roux PP, Reimand J, Jackson HW, Schramek D. In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer. Nat Commun 2023; 14:3150. [PMID: 37258521 PMCID: PMC10232477 DOI: 10.1038/s41467-023-38841-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 05/18/2023] [Indexed: 06/02/2023] Open
Abstract
How the genetic landscape governs a tumor's response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by KrasG12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies.
Collapse
Affiliation(s)
- Dzana Dervovic
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Ahmad A Malik
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Edward L Y Chen
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Masahiro Narimatsu
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Nina Adler
- Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Somaieh Afiuni-Zadeh
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Dagmar Krenbek
- Department of Pathology and Bacteriology, Klinik Floridsdorf, Vienna, Austria
| | - Sebastien Martinez
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Ricky Tsai
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Jonathan Boucher
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada
| | - Jacob M Berman
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Katie Teng
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Arshad Ayyaz
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - YiQing Lü
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Geraldine Mbamalu
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Sampath K Loganathan
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Otolaryngology, Head and Neck Surgery, McGill University, Montreal, QC, Canada
| | - Jongbok Lee
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Li Zhang
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Departments of Laboratory Medicine and Pathobiology, Immunology, University of Toronto, Toronto, ON, Canada
| | - Cynthia Guidos
- SickKids Research Institute, University Health Network, Toronto, ON, Canada
| | - Jeffrey Wrana
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Arschang Valipour
- Karl-Landsteiner-Institute for Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria
| | - Philippe P Roux
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada
- Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
| | - Jüri Reimand
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Hartland W Jackson
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Daniel Schramek
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
| |
Collapse
|
|
25
|
Wei SJ, Yang IH, Mohiuddin IS, Kshirsagar GJ, Nguyen TH, Trasti S, Maurer BJ, Kang MH. DNA-PKcs as an upstream mediator of OCT4-induced MYC activation in small cell lung cancer. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194939. [PMID: 37116859 DOI: 10.1016/j.bbagrm.2023.194939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 04/30/2023]
Abstract
Small cell lung cancer (SCLC) is a neuroendocrine tumor noted for the rapid development of both metastases and resistance to chemotherapy. High mutation burden, ubiquitous loss of TP53 and RB1, and a mutually exclusive amplification of MYC gene family members contribute to genomic instability and make the development of new targeted agents a challenge. Previously, we reported a novel OCT4-induced MYC transcriptional activation pathway involving c-MYC, pOCT4S111, and MAPKAPK2 in progressive neuroblastoma, also a neuroendocrine tumor. Using tumor microarray analysis of clinical samples and preclinical models, we now report a correlation in expression between these proteins in SCLC. In correlating c-MYC protein expression with genomic amplification, we determined that some SCLC cell lines exhibited high c-MYC without genomic amplification, implying amplification-independent MYC activation. We then confirmed direct interaction between OCT4 and DNA-PKcs and identified specific OCT4 and DNA-PKcs binding sites. Knock-down of both POU5F1 (encoding OCT4) and PRKDC (encoding DNA-PKcs) resulted in decreased c-MYC expression. Further, we confirmed binding of OCT4 to the promoter/enhancer region of MYC. Together, these data establish the presence of a DNA-PKcs/OCT4/c-MYC pathway in SCLCs. We then disruptively targeted this pathway and demonstrated anticancer activity in SCLC cell lines and xenografts using both DNA-PKcs inhibitors and a protein-protein interaction inhibitor of DNA-PKcs and OCT4. In conclusion, we demonstrate here that DNA-PKcs can mediate high c-MYC expression in SCLCs, and that this pathway may represent a new therapeutic target for SCLCs with high c-MYC expression.
Collapse
Affiliation(s)
- Sung-Jen Wei
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - In-Hyoung Yang
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Ismail S Mohiuddin
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Ganesh J Kshirsagar
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Thinh H Nguyen
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Scott Trasti
- Laboratory Animal Resources Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Barry J Maurer
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Min H Kang
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| |
Collapse
|
|
26
|
Yang J, Hou C, Wang H, Perez EA, Do-Umehara HC, Dong H, Arunagiri V, Tong F, Van Scoyk M, Cho M, Liu X, Ge X, Winn RA, Ridge KM, Wang X, Chandel NS, Liu J. Miz1 promotes KRAS-driven lung tumorigenesis by repressing the protocadherin Pcdh10. Cancer Lett 2023; 555:216025. [PMID: 36538983 PMCID: PMC9870713 DOI: 10.1016/j.canlet.2022.216025] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 11/03/2022] [Accepted: 11/22/2022] [Indexed: 12/23/2022]
Abstract
Targeting KRAS-mutated non-small-cell lung cancer (NSCLC) remains clinically challenging. Here we show that loss of function of Miz1 inhibits lung tumorigenesis in a mouse model of oncogenic KRAS-driven lung cancer. In vitro, knockout or silencing of Miz1 decreases cell proliferation, clonogenicity, migration, invasion, or anchorage-independent growth in mutant (MT) KRAS murine or human NSCLC cells but has unremarkable impact on non-tumorigenic cells or wild-type (WT) KRAS human NSCLC cells. RNA-sequencing reveals Protocadherin-10 (Pcdh10) as the top upregulated gene by Miz1 knockout in MT KRAS murine lung tumor cells. Chromatin immunoprecipitation shows Miz1 binding on the Pcdh10 promoter in MT KRAS lung tumor cells but not non-tumorigenic cells. Importantly, silencing of Pcdh10 rescues cell proliferation and clonogenicity in Miz1 knockout/knockdown MT KRAS murine or human tumor cells, and rescues allograft tumor growth of Miz1 knockout tumor cells in vivo. Miz1 is upregulated in MT KRAS lung tumor tissues compared with adjacent non-involved tissues in mice. Consistent with this, Miz1 is upregulated while Pcdh10 is downregulated in human lung adenocarcinomas (LUAD) compared with normal tissues, and high Miz1 levels or low Pcdh10 levels are associated with poor survival in lung cancer patients. Furthermore, the Miz1 signature is associated with worse survival in MT but not WT KRAS LUAD, and Pcdh10 is downregulated in MT compared to WT KRAS LUAD. Taken together, our studies implicate the Miz1/Pcdh10 axis in oncogenic KRAS-driven lung tumorigenesis.
Collapse
Affiliation(s)
- Jing Yang
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Changchun Hou
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Huashan Wang
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Edith A Perez
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Hanh Chi Do-Umehara
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Huali Dong
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Vinothini Arunagiri
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Fangjia Tong
- Department of Pharmacology and Regenerative Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Michelle Van Scoyk
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Minsu Cho
- Department of Pharmacology and Regenerative Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Xinyi Liu
- Department of Pharmacology and Regenerative Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL, 60612, USA
| | - Robert A Winn
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Karen M Ridge
- Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Xiaowei Wang
- Department of Pharmacology and Regenerative Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Navdeep S Chandel
- Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Jing Liu
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA.
| |
Collapse
|
|
27
|
Weeraddana P, Dmitriev M, Thomas T, Gao W, Weerasooriya N, Sandeep F. Case Report of Painless Obstructive Jaundice: A Rare First Presentation of Small-Cell Lung Cancer. Cureus 2023; 15:e35561. [PMID: 37007420 PMCID: PMC10060124 DOI: 10.7759/cureus.35561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2023] [Indexed: 03/02/2023] Open
Abstract
Small-cell lung cancer (SCLC) is a very aggressive type of lung cancer that is of neuroendocrine origin. Because of the high levels of circulating tumor cells, it has a very high rate of metastasis. Obstructive jaundice as the initial manifestation of small cell lung carcinoma is rare. Most of the cases are due to extrahepatic cholestasis by biliary duct obstruction. The biliary duct obstruction may be secondary to metastasis to lymph nodes or pancreatic head metastasis. Obstructive jaundice secondary to intrahepatic cholestasis is even rarer. A 75-year-old male presented to the emergency department (ED) with a complaint of new-onset painless jaundice that his dentist incidentally detected. Examination revealed a mass in the right upper quadrant (RUQ) of the abdomen. Computed tomography (CT) angiography of the abdomen, pancreas, and pelvis shows innumerable hepatic hypodensities highly suspicious for metastatic disease. However, there was no extrahepatic dilatation or pancreatic mass. He was diagnosed with diffuse metastasis of small cell lung carcinoma (SCLC) by needle biopsy of the liver. He developed acute kidney injury and liver damage and thus compromised chemotherapy for SCLC. Later, the patient chose comfort care and passed away the next day. To our knowledge, this is the second reported case of SCLC initially presenting as obstructive jaundice secondary intrahepatic cholestasis by diffuse liver metastases.
Collapse
|
|
28
|
Wang Y, Qi J, Ai D. DPADM: a novel algorithm for detecting drug-pathway associations based on high-throughput transcriptional response to compounds. Brief Bioinform 2023; 24:6889446. [PMID: 36511223 DOI: 10.1093/bib/bbac517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 10/23/2022] [Accepted: 10/31/2022] [Indexed: 12/14/2022] Open
Abstract
Pathway genes functionally participate in the same biological process. They typically act cooperatively, and none is considered dispensable. The dominant paradigm in drug discovery is the one-to-one strategy, which aims to find the most sensitive drug to act on an individual target. However, many complex diseases, such as cancer, are caused by dysfunction among multiple-gene pathways, not just one. Therefore, identifying pathway genes that are responsive to synthetic compounds in a global physiological environment may be more effective in drug discovery. The high redundancy of crosstalk between biological pathways, though, hints that the covariance matrix, which only connects genes with strong marginal correlations, may miss higher-level interactions, such as group interactions. We herein report the development of DPADM-a Drug-Pathway association Detection Model that infers pathways responsive to specific drugs. This model elucidates higher-level gene-gene interactions by evaluating the conditional dependencies between genes under different drug treatments. The advantage of the proposed method is demonstrated using simulation studies by comparing with another two methods. We applied this model to the Connectivity Map data set (CMap), and demonstrated that DPADM is able to identify many drug-pathway associations, such as mitoxantrone (MTX)- PI3K/AKT association, which targets the topological conditions of DNA transcription. Surprisingly, apart from identifying pathways corresponding to specific drugs, our methodology also revealed new drug-related pathways with functions similarly to those of seed genes.
Collapse
Affiliation(s)
- Yishu Wang
- School of Mathematics and Physics at University of Science and Technology Beijing
| | - Juan Qi
- School of Mathematics and Physics at University of Science and Technology Beijing
| | - Dongmei Ai
- School of Mathematics and Physics at University of Science and Technology Beijing
| |
Collapse
|
|
29
|
Wang Q, Gümüş ZH, Colarossi C, Memeo L, Wang X, Kong CY, Boffetta P. SCLC: Epidemiology, Risk Factors, Genetic Susceptibility, Molecular Pathology, Screening, and Early Detection. J Thorac Oncol 2023; 18:31-46. [PMID: 36243387 PMCID: PMC10797993 DOI: 10.1016/j.jtho.2022.10.002] [Citation(s) in RCA: 100] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/13/2022]
Abstract
We review research regarding the epidemiology, risk factors, genetic susceptibility, molecular pathology, and early detection of SCLC, a deadly tumor that accounts for 14% of lung cancers. We first summarize the changing incidences of SCLC globally and in the United States among males and females. We then review the established risk factor (i.e., tobacco smoking) and suspected nonsmoking-related risk factors for SCLC, and emphasize the importance of continued effort in tobacco control worldwide. Review of genetic susceptibility and molecular pathology suggests different molecular pathways in SCLC development compared with other types of lung cancer. Last, we comment on the limited utility of low-dose computed tomography screening in SCLC and on several promising blood-based molecular biomarkers as potential tools in SCLC early detection.
Collapse
Affiliation(s)
- Qian Wang
- University Hospitals Seidman Cancer Center, Cleveland, Ohio.
| | - Zeynep H Gümüş
- Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York; Center for Thoracic Oncology, Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Cristina Colarossi
- Pathology Unit, Department of Experimental Oncology, Mediterranean Institute of Oncology, Catania, Italy
| | - Lorenzo Memeo
- Pathology Unit, Department of Experimental Oncology, Mediterranean Institute of Oncology, Catania, Italy
| | - Xintong Wang
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Chung Yin Kong
- Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Paolo Boffetta
- Department of Family, Population & Preventive Medicine, Stony Brook University, Stony Brook, New York; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| |
Collapse
|
|
30
|
Iwai M, Kajino T, Nakatochi M, Yanagisawa K, Hosono Y, Isomura H, Shimada Y, Suzuki M, Taguchi A, Takahashi T. Long non-coding RNA TILR constitutively represses TP53 and apoptosis in lung cancer. Oncogene 2023; 42:364-373. [PMID: 36522487 DOI: 10.1038/s41388-022-02546-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 11/04/2022] [Accepted: 11/10/2022] [Indexed: 12/16/2022]
Abstract
Non-coding RNAs have an integral regulatory role in numerous functions related to lung cancer development. Here, we report identification of a novel lncRNA, termed TP53-inhibiting lncRNA (TILR), which was found to function as a constitutive negative regulator of p53 expression, including activation of downstream genes such as p21 and MDM2, and induction of apoptosis. A proteomic search for TILR-associated proteins revealed an association with PCBP2, while the mid-portion of TILR was found to be required for both PCBP2 and p53 mRNA binding. In addition, depletion of PCBP2 resulted in phenocopied effects of TILR silencing. TILR was also shown to suppress p53 expression in a post-transcriptional manner, as well as via a positive feedback loop involving p53 and Fanconi anemia pathway genes. Taken together, the present findings clearly demonstrate that TILR constitutively inhibits p53 expression in cooperation with PCBP2, thus maintaining p53 transcriptional activity at a level sufficiently low for avoidance of spurious apoptosis induction.
Collapse
Affiliation(s)
- Mika Iwai
- Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Taisuke Kajino
- Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.,Division of Molecular Diagnostics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
| | - Masahiro Nakatochi
- Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, 461-8673, Japan
| | - Kiyoshi Yanagisawa
- Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.,Department of Molecular and Cancer Medicine, Faculty of Pharmacy, Meijo University, Nagoya, 468-8502, Japan
| | - Yasuyuki Hosono
- Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan.,Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Hisanori Isomura
- Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.,Division of Molecular Diagnostics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
| | - Yukako Shimada
- Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.,Division of Molecular Diagnostics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
| | - Motoshi Suzuki
- Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.,Department of Molecular Oncology, School of Medicine, Fujita Health University, Toyoake, 470-1192, Japan
| | - Ayumu Taguchi
- Division of Molecular Diagnostics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan.,Division of Advanced Cancer Diagnostics, Department of Cancer Diagnostics and Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, 464-8681, Japan
| | - Takashi Takahashi
- Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. .,Aichi Cancer Center, Nagoya, 464-8681, Japan.
| |
Collapse
|
|
31
|
Chen X, Liu T, Wu J, Zhu C, Guan G, Zou C, Guo Q, Ren X, Li C, Cheng P, Cheng W, Wu A. Molecular profiling identifies distinct subtypes across TP53 mutant tumors. JCI Insight 2022; 7:156485. [PMID: 36256461 PMCID: PMC9746906 DOI: 10.1172/jci.insight.156485] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 10/14/2022] [Indexed: 01/12/2023] Open
Abstract
Tumor protein 53 mutation (TP53mut) is one of the most important driver events facilitating tumorigenesis, which could induce a series of chain reactions to promote tumor malignant transformation. However, the malignancy progression patterns under TP53 mutation remain less known. Clarifying the molecular landscapes of TP53mut tumors will help us understand the process of tumor development and aid precise treatment. Here, we distilled genetic and epigenetic features altered in TP53mut cancers for cluster-of-clusters analysis. Using integrated classification, we derived 5 different subtypes of TP53mut patients. These subtypes have distinct features in genomic alteration, clinical relevance, microenvironment dysregulation, and potential therapeutics. Among the 5 subtypes, COCA3 was identified as the subtype with worst prognosis, causing an immunosuppressive microenvironment and immunotherapeutic resistance. Further drug efficacy research highlighted olaparib as the most promising therapeutic agents for COCA3 tumors. Importantly, the therapeutic efficacy of olaparib in COCA3 and immunotherapy in non-COCA3 tumors was validated via in vivo experimentation. Our study explored the important molecular events and developed a subtype classification system with distinct targeted therapy strategies for different subtypes of TP53mut tumors. These multiomics classification systems provide a valuable resource that significantly expands the knowledge of TP53mut tumors and may eventually benefit in clinical practice.
Collapse
Affiliation(s)
- Xin Chen
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Tianqi Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jianqi Wu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chen Zhu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Gefei Guan
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Cunyi Zou
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qing Guo
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaolin Ren
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China.,Department of Neurosurgery, Shenyang Red Cross Hospital, Shenyang, Liaoning, China
| | - Chen Li
- Department of Orthodontics, Stomatological Hospital of China Medical University, Shenyang, Liaoning, China
| | - Peng Cheng
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wen Cheng
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.,Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Anhua Wu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.,Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| |
Collapse
|
|
32
|
McCorkell G, Nakayama M, Feltis B, Piva T, Geso M. Ultrasound-Stimulated Microbubbles Enhance Radiation-Induced Cell Killing. ULTRASOUND IN MEDICINE & BIOLOGY 2022; 48:2449-2460. [PMID: 36100510 DOI: 10.1016/j.ultrasmedbio.2022.07.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 03/29/2022] [Accepted: 07/01/2022] [Indexed: 06/15/2023]
Abstract
Recent in vivo studies using ultrasound-stimulated microbubbles as a localized radiosensitizer have had impressive results. While in vitro studies have also obtained similar results using human umbilical vein endothelial cells (HUVEC), studies using other cell lines have had varying results. This study was aimed at investigating any increases in radiation-induced cell killing in vitro using two carcinoma lines not previously investigated before (metastatic follicular thyroid carcinoma cells [FTC-238] and non-small cell lung carcinoma cells [NCI-H727]), in addition to HUVEC. Cells were treated using a combination of 1.6% (v/v) microbubbles, ∼90 s of 2-MHz ultrasound (mechanical index = 0.8) and 0-6 Gy of kilovolt or MV X-rays. Cell viability assays obtained 72 h post-treatment were normalized to untreated controls, and analysis of variance was used to determine statistical significance. All cells treated with combined ultrasound-stimulated microbubbles and radiation exhibited decreased normalized survival, with statistically significant effects observed for the NCI-H727 cells. No statistically significant differences in effects were observed using kV compared with MV radiation. Further studies using increased microbubble concentrations may be required to achieve statistically significant results for the FTC-238 and HUVEC lines.
Collapse
Affiliation(s)
- Giulia McCorkell
- Department of Medical Radiations, School of Health and Biomedical Sciences, RMIT University, Victoria, Australia
| | - Masao Nakayama
- Division of Radiation Oncology, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Bryce Feltis
- Department of Human Bioscience, School of Health and Biomedical Sciences, RMIT University, Victoria, Australia
| | - Terrence Piva
- Department of Human Bioscience, School of Health and Biomedical Sciences, RMIT University, Victoria, Australia
| | - Moshi Geso
- Department of Medical Radiations, School of Health and Biomedical Sciences, RMIT University, Victoria, Australia.
| |
Collapse
|
|
33
|
Patil MR, Bihari A. A comprehensive study of p53 protein. J Cell Biochem 2022; 123:1891-1937. [PMID: 36183376 DOI: 10.1002/jcb.30331] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/02/2022] [Accepted: 09/13/2022] [Indexed: 01/10/2023]
Abstract
The protein p53 has been extensively investigated since it was found 43 years ago and has become a "guardian of the genome" that regulates the division of cells by preventing the growth of cells and dividing them, that is, inhibits the development of tumors. Initial proof of protein existence by researchers in the mid-1970s was found by altering and regulating the SV40 big T antigen termed the A protein. Researchers demonstrated how viruses play a role in cancer by employing viruses' ability to create T-antigens complex with viral tumors, which was discovered in 1979 following a viral analysis and cancer analog research. Researchers later in the year 1989 explained that in Murine Friend, a virus-caused erythroleukemia, commonly found that p53 was inactivated to suggest that p53 could be a "tumor suppressor gene." The TP53 gene, encoding p53, is one of human cancer's most frequently altered genes. The protein-regulated biological functions of all p53s include cell cycles, apoptosis, senescence, metabolism of the DNA, angiogenesis, cell differentiation, and immunological response. We tried to unfold the history of the p53 protein, which was discovered long back in 1979, that is, 43 years of research on p53, and how p53's function has been developed through time in this article.
Collapse
Affiliation(s)
- Manisha R Patil
- Department of Computer-Applications, School of Information Technology and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Anand Bihari
- Department of Computational Intelligence, School of Computer Science and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| |
Collapse
|
|
34
|
Capuozzo M, Santorsola M, Bocchetti M, Perri F, Cascella M, Granata V, Celotto V, Gualillo O, Cossu AM, Nasti G, Caraglia M, Ottaiano A. p53: From Fundamental Biology to Clinical Applications in Cancer. BIOLOGY 2022; 11:1325. [PMID: 36138802 PMCID: PMC9495382 DOI: 10.3390/biology11091325] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/04/2022] [Accepted: 09/06/2022] [Indexed: 11/18/2022]
Abstract
p53 tumour suppressor gene is our major barrier against neoplastic transformation. It is involved in many cellular functions, including cell cycle arrest, senescence, DNA repair, apoptosis, autophagy, cell metabolism, ferroptosis, immune system regulation, generation of reactive oxygen species, mitochondrial function, global regulation of gene expression, miRNAs, etc. Its crucial importance is denounced by the high percentage of amino acid sequence identity between very different species (Homo sapiens, Drosophila melanogaster, Rattus norvegicus, Danio rerio, Canis lupus familiaris, Gekko japonicus). Many of its activities allowed life on Earth (e.g., repair from radiation-induced DNA damage) and directly contribute to its tumour suppressor function. In this review, we provide paramount information on p53, from its discovery, which is an interesting paradigm of science evolution, to potential clinical applications in anti-cancer treatment. The description of the fundamental biology of p53 is enriched by specific information on the structure and function of the protein as well by tumour/host evolutionistic perspectives of its role.
Collapse
Affiliation(s)
| | - Mariachiara Santorsola
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
| | - Marco Bocchetti
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy
- Laboratory of Molecular and Precision Oncology, Biogem Scarl, Institute of Genetic Research, 83031 Ariano Irpino, Italy
| | - Francesco Perri
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
| | - Marco Cascella
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
| | - Vincenza Granata
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
| | - Venere Celotto
- Coordinamento Farmaceutico, ASL-Naples-3, 80056 Ercolano, Italy
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Alessia Maria Cossu
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy
- Laboratory of Molecular and Precision Oncology, Biogem Scarl, Institute of Genetic Research, 83031 Ariano Irpino, Italy
| | - Guglielmo Nasti
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy
| | - Alessandro Ottaiano
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
| |
Collapse
|
|
35
|
Xiong J, Barayan R, Louie AV, Lok BH. Novel therapeutic combinations with PARP inhibitors for small cell lung cancer: A bench-to-bedside review. Semin Cancer Biol 2022; 86:521-542. [PMID: 35917883 DOI: 10.1016/j.semcancer.2022.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/02/2022] [Accepted: 07/29/2022] [Indexed: 10/31/2022]
Abstract
Small cell lung cancer (SCLC) is treated as a monolithic disease despite the evident intra- and intertumoral heterogeneity. Non-specific DNA-damaging agents have remained the first-line treatment for decades. Recently, emerging transcriptomic and genomic profiling of SCLC tumors identified distinct SCLC subtypes and vulnerabilities towards targeted therapeutics, including inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARPi). SCLC cell lines and tumors exhibited an elevated level of PARP1 protein and mRNA compared to healthy lung tissues and other subtypes of lung tumors. Notable responses to PARPi were also observed in preclinical SCLC models. Clinically, PARPi monotherapy exerted variable benefits for SCLC patients. To date, research is being vigorously conducted to examine predictive biomarkers of PARPi response and various PARPi combination strategies to maximize the clinical utility of PARPi. This narrative review summarizes existing preclinical evidence supporting PARPi monotherapy, combination therapy, and respective translation to the clinic. Specifically, we covered the combination of PARPi with DNA-damaging chemotherapy (cisplatin, etoposide, temozolomide), thoracic radiotherapy, immunotherapy (immune checkpoint inhibitors), and many other novel therapeutic agents that target DNA damage response, tumor microenvironment, epigenetic modulation, angiogenesis, the ubiquitin-proteasome system, or autophagy. Putative biomarkers, such as SLFN11 expression, MGMT methylation, E2F1 expression, and platinum sensitivity, which may be predictive of response to distinct therapeutic combinations, were also discussed. The future of SCLC treatment is undergoing rapid change with a focus on tailored and personalized treatment strategies. Further development of cancer therapy with PARPi will immensely benefit at least a subset of biomarker-defined SCLC patients.
Collapse
Affiliation(s)
- Jiaqi Xiong
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Ranya Barayan
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Alexander V Louie
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Odette Cancer Centre - Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
| | - Benjamin H Lok
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
36
|
Interdiction in the Early Folding of the p53 DNA-Binding Domain Leads to Its Amyloid-Like Misfolding. Molecules 2022; 27:molecules27154810. [PMID: 35956758 PMCID: PMC9370011 DOI: 10.3390/molecules27154810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/18/2022] [Accepted: 07/23/2022] [Indexed: 11/17/2022] Open
Abstract
In this article, we investigate two issues: (a) the initial contact formation events along the folding pathway of the DNA-binding domain of the tumor suppressor protein p53 (core p53); and (b) the intermolecular events leading to its conversion into a prion-like form upon incubation with peptide P8(250-257). In the case of (a), the calculations employ the sequential collapse model (SCM) to identify the segments involved in the initial contact formation events that nucleate the folding pathway. The model predicts that there are several possible initial non-local contacts of comparative stability. The most stable of these possible initial contacts involve the protein segments 159AMAIY163 and 251ILTII255, and it is the only native-like contact. Thus, it is predicted to constitute “Nature’s shortcut” to the native structure of the core domain of p53. In the case of issue (b), these findings are then combined with experimental evidence showing that the incubation of the core domain of p53 with peptide P8(250-257), which is equivalent to the native protein segment 250PILTIITL257, leads to an amyloid conformational transition. It is explained how the SCM predicts that P8(250-257) effectively interdicts in the formation of the most stable possible initial contact and, thereby, disrupts the subsequent normal folding. Interdiction by polymeric P8(250-257) seeds is also studied. It is then hypothesized that enhanced folding through one or several of the less stable contacts could play a role in P8(250-257)-promoted core p53 amyloid misfolding. These findings are compared to previous results obtained for the prion protein. Experiments are proposed to test the hypothesis presented regarding core p53 amyloid misfolding.
Collapse
|
|
37
|
Bosáková V, De Zuani M, Sládková L, Garlíková Z, Jose SS, Zelante T, Hortová Kohoutková M, Frič J. Lung Organoids—The Ultimate Tool to Dissect Pulmonary Diseases? Front Cell Dev Biol 2022; 10:899368. [PMID: 35912110 PMCID: PMC9326165 DOI: 10.3389/fcell.2022.899368] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 06/24/2022] [Indexed: 11/15/2022] Open
Abstract
Organoids are complex multicellular three-dimensional (3D) in vitro models that are designed to allow accurate studies of the molecular processes and pathologies of human organs. Organoids can be derived from a variety of cell types, such as human primary progenitor cells, pluripotent stem cells, or tumor-derived cells and can be co-cultured with immune or microbial cells to further mimic the tissue niche. Here, we focus on the development of 3D lung organoids and their use as disease models and drug screening tools. We introduce the various experimental approaches used to model complex human diseases and analyze their advantages and disadvantages. We also discuss validation of the organoids and their physiological relevance to the study of lung diseases. Furthermore, we summarize the current use of lung organoids as models of host-pathogen interactions and human lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, or SARS-CoV-2 infection. Moreover, we discuss the use of lung organoids derived from tumor cells as lung cancer models and their application in personalized cancer medicine research. Finally, we outline the future of research in the field of human induced pluripotent stem cell-derived organoids.
Collapse
Affiliation(s)
- Veronika Bosáková
- International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czechia
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Marco De Zuani
- International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czechia
| | - Lucie Sládková
- Institute of Hematology and Blood Transfusion, Prague, Czechia
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czechia
| | - Zuzana Garlíková
- International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czechia
| | - Shyam Sushama Jose
- International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czechia
| | - Teresa Zelante
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Jan Frič
- International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czechia
- Institute of Hematology and Blood Transfusion, Prague, Czechia
- *Correspondence: Jan Frič,
| |
Collapse
|
|
38
|
Yang Y, Qu Y, Li Z, Tan Z, Lei Y, Bai S. Identification of Novel Characteristics in TP53-Mutant Hepatocellular Carcinoma Using Bioinformatics. Front Genet 2022; 13:874805. [PMID: 35651938 PMCID: PMC9149291 DOI: 10.3389/fgene.2022.874805] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/20/2022] [Indexed: 11/29/2022] Open
Abstract
Background: TP53 mutations are the most frequent mutations in hepatocellular carcinoma (HCC) and affect the occurrence and development of this cancer type. Therefore, it is essential to clarify the function and mechanism of TP53 mutations in HCC. Methods: We performed a sequence of bioinformatic analyses to elucidate the characteristics of TP53 mutations in HCC. We downloaded the data of hepatocellular carcinoma from The Cancer Genome Atlas database and used different R packages for serial analyses, including gene mutation analysis, copy number variation analysis, analysis of the tumor mutational burden and microsatellite instability, differential gene expression analysis, and functional enrichment analysis of TP53 mutations, and performed gene set enrichment analysis. We established a protein-protein interaction network using the STRING online database and used the Cytoscape software for network visualization, and hub gene screening. In addition, we performed anticancer drug sensitivity analysis using data from the Genomics of Drug Sensitivity in Cancer. Immune infiltration and prognosis analyses were also performed. Results: Missense mutations accounted for a great proportion of HCC mutations, the frequency of single nucleotide polymorphisms was high, and C > T was the most common form of single nucleotide variations. TP53 had a mutation rate of 30% and was the most commonly mutated gene in HCC. In the TP53 mutant group, the tumor mutational burden (p < 0.001), drug sensitivity (p < 0.05), ESTIMATE score (p = 0.038), and stromal score (p < 0.001) dramatically decreased. The Cytoscape software screened ten hub genes, including CT45A1, XAGE1B, CT55, GAGE2A, PASD1, MAGEA4, CTAG2, MAGEA10, MAGEC1, and SAGE1. The prognostic model showed a poor prognosis in the TP53 mutation group compared with that in the wild-type group (overall survival, p = 0.023). Univariate and multivariate cox regression analyses revealed that TP53 mutation was an independent risk factor for the prognosis of HCC patients (p <0.05). The constructed prognostic model had a favorable forecast value for the prognosis of HCC patients at 1 and 3 years (1-year AUC = 0.752, 3-years AUC = 0.702). Conclusion: This study further deepened our understanding of TP53-mutated HCC, provided new insights into a precise individualized therapy for HCC, and has particular significance for prognosis prediction.
Collapse
Affiliation(s)
- Yang Yang
- The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yajuan Qu
- Department of Rehabilitation Medicine, Qujing Second People's Hospital, Qujing, China
| | - Zhaopeng Li
- The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhiyong Tan
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Youming Lei
- The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Song Bai
- The First Affiliated Hospital of Kunming Medical University, Kunming, China
| |
Collapse
|
|
39
|
Tikhomirova M, Topchu I, Mazitova A, Barmin V, Ratner E, Sabirov A, Abramova Z, Deneka AY. NEDD9 Restrains dsDNA Damage Response during Non-Small Cell Lung Cancer (NSCLC) Progression. Cancers (Basel) 2022; 14:2517. [PMID: 35626121 PMCID: PMC9139181 DOI: 10.3390/cancers14102517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/05/2022] [Accepted: 05/18/2022] [Indexed: 12/10/2022] Open
Abstract
DNA damaging modalities are the backbone of treatments for non-small cell lung cancer (NSCLC). Alterations in DNA damage response (DDR) in tumor cells commonly contribute to emerging resistance to platinating agents, other targeted therapies, and radiation. The goal of this study is to identify the previously unreported role of NEDD9 scaffolding protein in controlling DDR processes and sensitivity to DNA damaging therapies. Using a siRNA-mediated approach to deplete NEDD9 in a group of human and murine KRAS/TP53-mutant NSCLC cell lines, coupled with a set of cell viability and clonogenic assays, flow cytometry analysis, and Western blotting, we evaluated the effects of NEDD9 silencing on cellular proliferation, DDR and epithelial-to-mesenchymal transition (EMT) signaling, cell cycle, and sensitivity to cisplatin and UV irradiation. Using publicly available NSCLC datasets (TCGA) and an independent cohort of primary NSCLC tumors, subsequent in silico and immunohistochemical (IHC) analyses were performed to assess relevant changes in NEDD9 RNA and protein expression across different stages of NSCLC. The results of our study demonstrate that NEDD9 depletion is associated with the increased tumorigenic capacity of NSCLC cells. These phenotypes were accompanied by significantly upregulated ATM-CHK2 signaling, shifting towards a more mesenchymal phenotype in NEDD9 depleted cells and elevated sensitivity to UV-irradiation. IHC analyses revealed an association between reduced NEDD9 protein expression and a decrease in overall (OS) and progression-free survival (PFS) of the NSCLC patients. These data, for the first time, identified NEDD9 as a negative regulator of ATM kinase activity and related DDR signaling in numerous KRAS/TP53 mutated NSCLC, with its effects on the regulation of DDR-dependent EMT signaling, sensitivity to DNA damaging modalities in tumor cells, and the survival of the patients.
Collapse
Affiliation(s)
- Mariya Tikhomirova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420000 Kazan, Russia; (M.T.); (I.T.); (A.M.); (Z.A.)
| | - Iuliia Topchu
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420000 Kazan, Russia; (M.T.); (I.T.); (A.M.); (Z.A.)
- Feinberg School of Medicine, Northwestern University, Chicago, IL 60610, USA
| | - Aleksandra Mazitova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420000 Kazan, Russia; (M.T.); (I.T.); (A.M.); (Z.A.)
- Department of Medicine and Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Vitaly Barmin
- Moscow P.A. Gertsen Oncological Research Institute, 125284 Moscow, Russia;
| | - Ekaterina Ratner
- Republican M.Z.Sigal Clinical Oncology Hospital, 420029 Kazan, Russia; (E.R.); (A.S.)
| | - Alexey Sabirov
- Republican M.Z.Sigal Clinical Oncology Hospital, 420029 Kazan, Russia; (E.R.); (A.S.)
| | - Zinaida Abramova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420000 Kazan, Russia; (M.T.); (I.T.); (A.M.); (Z.A.)
| | - Alexander Y. Deneka
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420000 Kazan, Russia; (M.T.); (I.T.); (A.M.); (Z.A.)
- Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| |
Collapse
|
|
40
|
Marzio A, Kurz E, Sahni JM, Di Feo G, Puccini J, Jiang S, Hirsch CA, Arbini AA, Wu WL, Pass HI, Bar-Sagi D, Papagiannakopoulos T, Pagano M. EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion. Cell 2022; 185:169-183.e19. [PMID: 34963055 PMCID: PMC8751279 DOI: 10.1016/j.cell.2021.12.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 09/01/2021] [Accepted: 12/04/2021] [Indexed: 01/01/2023]
Abstract
Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.
Collapse
Affiliation(s)
- Antonio Marzio
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA.
| | - Emma Kurz
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Jennifer M Sahni
- Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Giuseppe Di Feo
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Joseph Puccini
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Shaowen Jiang
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Carolina Alcantara Hirsch
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Arnaldo A Arbini
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Warren L Wu
- Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Harvey I Pass
- Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA; Department of Cardiothoracic Surgery, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Dafna Bar-Sagi
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Thales Papagiannakopoulos
- Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.
| | - Michele Pagano
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, NY 10016, USA.
| |
Collapse
|
|
41
|
Chauhan S, Sen S, Chauhan SS, Pushker N, Tandon R, Kashyap S, Vanathi M, Bajaj MS. Stratifin in ocular surface squamous neoplasia and its association with p53. Acta Ophthalmol 2021; 99:e1483-e1491. [PMID: 33769712 DOI: 10.1111/aos.14844] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 02/23/2021] [Indexed: 11/28/2022]
Abstract
PURPOSE Sunlight-induced p53 mutations are known to contribute towards increased risk of ocular surface squamous neoplasia (OSSN). Stratifin (14-3-3σ)/HEM (human epithelial marker) is a p53-mediated inhibitor of cell cycle progression and has been shown to be a target of epigenetic deregulation in various carcinomas. In the present study, Stratifin expression, its promoter methylation status as well as expression of mutant p53 in early and advanced AJCC stages (8th edition) of OSSN, was evaluated. METHODS Sixty-four OSSN [20 conjunctival intraepithelial neoplasia (CIN) and 44 squamous cell carcinoma (SCC)] patients were registered for this study, and they were followed up for 36-58 months (mean 48 ± 3.6). Immunoexpression of Stratifin and mutant p53 protein, mRNA expression of Stratifin by reverse transcription polymerase chain reaction (PCR) and methylation status of Stratifin by methylation-specific PCR, was undertaken. RESULTS Hypermethylation of Stratifin promoter in 63% (40/64), loss of Stratifin expression in 75% (48/64) and downregulation of Stratifin mRNA in 61% (39/64) were observed. Stratifin hypermethylation was significantly associated with reduced disease-free survival in both early and advanced T stage SCC cases. Expression of mutant p53 expression was seen in 48% (31/64) OSSN cases. Of the 31 patients with mutant p53 expression, 87% (27/31) also demonstrated loss of Stratifin immunoexpression. A significant association was seen between mutant p53 expression and Stratifin loss (p = 0.01) in advanced T stage SCC cases. CONCLUSIONS Hypermethylation of Stratifin gene and its reduced mRNA expression both are potential biomarkers for identifying high-risk OSSN patients. Aberrant methylation of Stratifin and simultaneous mutant p53 expression implicates involvement of p53-Stratifin mediated signalling pathway in the pathogenesis of OSSN.
Collapse
Affiliation(s)
- Sheetal Chauhan
- Department of Ocular Pathology Dr. Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi India
| | - Seema Sen
- Department of Ocular Pathology Dr. Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi India
| | - Shyam S. Chauhan
- Department of Biochemistry All India Institute of Medical Sciences New Delhi India
| | - Neelam Pushker
- Ophthalmoplasty Service Dr. Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi India
| | - Radhika Tandon
- Cornea and External Disease, Cataract and Refractive Ocular Oncology and Low Vision Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi India
| | - Seema Kashyap
- Department of Ocular Pathology Dr. Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi India
| | - Murugesan Vanathi
- Cornea & Ocular Surface Cataract & Refractive Services Dr. Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi India
| | - Mandeep S. Bajaj
- Ophthalmoplasty Service Dr. Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi India
| |
Collapse
|
|
42
|
Chang JM, Wu JY, Chen SH, Chao WY, Chuang HH, Kam KH, Zhao PW, Li YZ, Yen YP, Lee YR. 9-O-Terpenyl-Substituted Berberrubine Derivatives Suppress Tumor Migration and Increase Anti-Human Non-Small-Cell Lung Cancer Activity. Int J Mol Sci 2021; 22:ijms22189864. [PMID: 34576028 PMCID: PMC8469690 DOI: 10.3390/ijms22189864] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/06/2021] [Accepted: 09/10/2021] [Indexed: 01/06/2023] Open
Abstract
Lung cancer is one of the most common cancers and the leading cause of death in humans worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and is often diagnosed at a late stage. Among patients with NSCLC, 50% die within 1 year after diagnosis. Even with clinical intervention, the 5-year survival rate is only approximately 20%. Therefore, the development of an advanced therapeutic strategy or novel agent is urgently required for treating NSCLC. Berberine exerts therapeutic activity toward NSCLC; therefore, its activity as an antitumor agent needs to be explored further. In this study, three terpenylated-bromide derivatives of berberrubine were synthesized and their anti-NSCLC activities were evaluated. Each derivative had higher anti-NSCLCs activity than berberrubine and berberine. Among them, 9-O-gernylberberrubine bromide (B4) and 9-O-farnesylberberrubine bromide (B5) showed greater growth inhibition, cell-cycle regulation, in vitro tumorigenesis suppression, and tumor migration reduction. In addition, some degree of apoptosis and autophagic flux blocking was noted in the cells under B4 and B5 treatments. Our study demonstrates that the berberrubine derivatives, B4 and B5, exhibit impressive anti-NSCLC activities and have potential for use as chemotherapeutic agents against NSCLC.
Collapse
Affiliation(s)
- Jia-Ming Chang
- Department of Surgery, Division of Thoracic Surgery, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City 60002, Taiwan; (J.-M.C.); (K.-H.K.)
- Department of Physical Therapy, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan
- Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City 60002, Taiwan; (S.-H.C.); (P.-W.Z.); (Y.-Z.L.); (Y.-P.Y.)
| | - Jin-Yi Wu
- Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi 60004, Taiwan;
| | - Shu-Hsin Chen
- Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City 60002, Taiwan; (S.-H.C.); (P.-W.Z.); (Y.-Z.L.); (Y.-P.Y.)
| | - Wen-Ying Chao
- Department of Nursing, Min-Hwei College of Health Care Management, Tainan 73658, Taiwan;
| | - Hsiang-Hao Chuang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Kam-Hong Kam
- Department of Surgery, Division of Thoracic Surgery, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City 60002, Taiwan; (J.-M.C.); (K.-H.K.)
| | - Pei-Wen Zhao
- Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City 60002, Taiwan; (S.-H.C.); (P.-W.Z.); (Y.-Z.L.); (Y.-P.Y.)
| | - Yi-Zhen Li
- Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City 60002, Taiwan; (S.-H.C.); (P.-W.Z.); (Y.-Z.L.); (Y.-P.Y.)
| | - Yu-Pei Yen
- Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City 60002, Taiwan; (S.-H.C.); (P.-W.Z.); (Y.-Z.L.); (Y.-P.Y.)
| | - Ying-Ray Lee
- Department of Microbiology and Immunology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: ; Tel.: +886-7-3121101
| |
Collapse
|
|
43
|
Wang Q, Gu J, Wang L, Chang DW, Ye Y, Huang M, Roth JA, Wu X. Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancer. J Immunother Cancer 2021; 8:jitc-2019-000336. [PMID: 32764075 PMCID: PMC7412613 DOI: 10.1136/jitc-2019-000336] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/27/2020] [Indexed: 12/14/2022] Open
Abstract
Background Recent advances in T cell-related immunotherapy have brought remarkable progress in the treatment of non-small cell lung cancer (NSCLC). However, whether and how genetic variations of T cell cancer immune response genes can influence clinical outcomes of NSCLC patients remain obscure. Methods In this multiphase study, we assessed 2450 single-nucleotide polymorphisms (SNPs) from 280 T cell cancer immune response-related genes in 941 early-stage NSCLC patients (discovery n=536; validation n=405) to analyze the variants’ associations with outcomes and to observe the effects on T cell phenotypes. Results We found 14 SNPs in 10 genes were associated with NSCLC outcomes (p<0.05) in both phases. Among them, TRB:rs1964986 was the most significant variant associated with recurrence risk after meta-analysis (HR 1.84, 95% CI 1.35 to 2.52, p=1.15E-04), while IDO1:rs10108662 was the most significant SNP associated with death risk (HR 1.87, 95% CI 1.40 to 2.51, p=2.17E-05). Analysis of unfavorable genotypes indicated cumulative effects on death and recurrence risks. Seven treatment-specific variants were found to predict opposite outcomes in surgery-only and surgery-plus-chemotherapy subgroups. Expression quantitative trait loci analysis indicated that six SNPs significantly correlated with their corresponding gene expression. T cells from high-risk subjects displayed reduced degranulation (p=0.02) and decreased cytotoxicity against cancer cells (p<0.01). Gene expression profile indicated increased IDO1 expression and decreased IL2, PRF and GZMB expression in high-risk subjects. Conclusions Genetic variations in T cell cancer immune response pathways can impact outcomes and may be served as predictors for treatment efficacy in early-stage NSCLC patients. The correlation between immune genotypes and T cell antitumor immunity suggests a biological link between host immune genetics and NSCLC prognosis.
Collapse
Affiliation(s)
- Qinchuan Wang
- Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.,Department of Epidemiology, Center for Biostatistics, Bioinformatics, and Big Data, Second Affiliated Hospital and Department of Big Data in Health Science, School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jianchun Gu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.,Department of Epidemiology, Medical Oncology, Shanghai Jiaotong University School of Medicine Xinhua Hospital, Shanghai, China
| | - Linbo Wang
- Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - David W Chang
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Yuanqing Ye
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States .,Department of Epidemiology, Center for Biostatistics, Bioinformatics, and Big Data, Second Affiliated Hospital and Department of Big Data in Health Science, School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Maosheng Huang
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Jack A Roth
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Xifeng Wu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States .,Department of Epidemiology, Center for Biostatistics, Bioinformatics, and Big Data, Second Affiliated Hospital and Department of Big Data in Health Science, School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,National Institute for Data Science in Health and Medicine, Hangzhou, Zhejiang, China
| |
Collapse
|
|
44
|
Aldakheel FM, Abuderman AA, Alali BH, Mateen A, Alduraywish SA, jamil K, Alqahtani MS, Syed R. Smoking and P53 polymorphism association with chromosomal aberration in lung cancer. JOURNAL OF KING SAUD UNIVERSITY - SCIENCE 2021; 33:101533. [DOI: 10.1016/j.jksus.2021.101533] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
45
|
Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation. Nat Commun 2021; 12:4853. [PMID: 34381046 PMCID: PMC8357888 DOI: 10.1038/s41467-021-24898-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 07/14/2021] [Indexed: 12/22/2022] Open
Abstract
SMAD4 is mutated in human lung cancer, but the underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis is yet to be elucidated. Here, we generate a highly aggressive lung cancer mouse model bearing conditional KrasG12D, p53fl/fl LOF and Smad4fl/fl LOF mutations (SPK), showing a much higher incidence of tumor metastases than the KrasG12D, p53fl/fl (PK) mice. Molecularly, PAK3 is identified as a downstream effector of Smad4, mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3 by Smad4 LOF in SPK mice is achieved by attenuating Smad4-dependent transcription of miR-495 and miR-543. These microRNAs (miRNAs) directly bind to the PAK3 3'UTR for blockade of PAK3 production, ultimately regulating lung cancer metastasis. An inverse correlation between Smad4 and PAK3 pathway components is observed in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.
Collapse
|
|
46
|
Sharma B, Angurana S, Bhat A, Verma S, Bakshi D, Bhat GR, Jamwal RS, Amin A, Qadri RA, Shah R, Kumar R. Genetic analysis of colorectal carcinoma using high throughput single nucleotide polymorphism genotyping technique within the population of Jammu and Kashmir. Mol Biol Rep 2021; 48:5889-5895. [PMID: 34319543 DOI: 10.1007/s11033-021-06583-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 07/20/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND SNP genotyping has become increasingly more common place to understand the genetic basis of complex diseases like cancer. SNP-genotyping through MassARRAY™ is a cost-effective method to quantitatively analyse the variation of gene expression in multiple samples, making it a potential tool to identify the underlying causes of colorectal carcinogenesis. METHODS In the present study, SNP genotyping was carried out using Agena MassARRAY™, which is a cost-effective, robust, and sensitive method to analyse multiple SNPs simultaneously. We analysed 7 genes in 492 samples (100 cases and 392 controls) associated with CRC within the population of Jammu and Kashmir. These SNPs were selected based on their association with multiple cancers in literature. RESULTS This is the first study to explore these SNPs with colorectal cancer within the J&K population.7 SNPs with a call rate of 90% were selected for the study. Out of these, five SNPs rs2234593, rs1799966, rs2229080, rs8034191, rs1042522 were found to be significantly associated with the current study under the allelic model with an Odds Ratio OR = 2.981(1.731-5.136 at 95% CI); p value = 4.81E-05 for rs2234593,OR = 1.685(1.073-2.647 at 95% CI);; p value = 0.02292 for rs1799966, OR = 1.5 (1.1-2.3 at 95% CI), p value = 0.02 for rs2229080, OR = 1.699(1.035-2.791 at 95% CI); p value = 0.03521 for rs8034191, OR = 20.07 (11.26-35.75); p value = 1.84E-34 for rs1042522 respectively. CONCLUSION This is the first study to find the relation of Genetic variants with the colorectal cancer within the studied population using high throughput MassARRAY™ technology. It is further anticipated that the variants should be evaluated in other population groups that may aid in understanding the genetic complexity and bridge the missing heritability.
Collapse
Affiliation(s)
- Bhanu Sharma
- School of Biotechnology, Shri Mata Vaishno Devi University, Jammu and Kashmir 182320, Katra, India
| | | | - Amrita Bhat
- School of Biotechnology, Shri Mata Vaishno Devi University, Jammu and Kashmir 182320, Katra, India
| | - Sonali Verma
- School of Biotechnology, Shri Mata Vaishno Devi University, Jammu and Kashmir 182320, Katra, India
| | - Divya Bakshi
- School of Biotechnology, Shri Mata Vaishno Devi University, Jammu and Kashmir 182320, Katra, India
| | - Ghulam Rasool Bhat
- School of Biotechnology, Shri Mata Vaishno Devi University, Jammu and Kashmir 182320, Katra, India
| | - Rajeshwer Singh Jamwal
- School of Biotechnology, Shri Mata Vaishno Devi University, Jammu and Kashmir 182320, Katra, India
| | - Asif Amin
- Department of Biotechnology, University of Kashmir, Srinagar, 190006, India
| | - Raies Ahmed Qadri
- Department of Biotechnology, University of Kashmir, Srinagar, 190006, India
| | - Ruchi Shah
- Department of Biotechnology, University of Kashmir, Srinagar, 190006, India.
| | - Rakesh Kumar
- School of Biotechnology, Shri Mata Vaishno Devi University, Jammu and Kashmir 182320, Katra, India.
| |
Collapse
|
|
47
|
TP53 mutations in circulating tumor DNA in advanced epidermal growth factor receptor-mutant lung adenocarcinoma patients treated with gefitinib. Transl Oncol 2021; 14:101163. [PMID: 34192651 PMCID: PMC8254117 DOI: 10.1016/j.tranon.2021.101163] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 12/25/2022] Open
Abstract
We evaluated 180 patients' EGFR and TP53 co-mutation types, who received gefitinib targeted therapy, through sequencing their ctDNA in plasma. Patients with TP53 mutation is predictive of poor survival. Patients with EGFR exon 19 and TP53 co-mutations had better prognosis value than those with EGFR L585R and TP53 co-mutations. 4.Patients with TP53 mutations, especially in exons 6 and 7, had a lower response rate and shorter PFS and OS when treated with gefitinib. TP53 exon 5 mutation divided TP53 mutations in disruptive and non-disruptive types. Tumor protein p53 (TP53) is a tumor suppressor gene and TP53 mutations are associated with poor prognosis in non-small cell lung cancer. However, the in-depth classification of TP53 and its relationship with treatment response and prognosis in epidermal growth factor receptor (EGFR)-mutant tumors treated with EGFR tyrosine kinase inhibitors are unclear. Circulating tumor DNA was prospectively collected at baseline in advanced treatment-naïve EGFR-mutant lung adenocarcinoma patients treated with gefitinib in an open-label, single-arm, prospective, multicenter, phase 2 clinical trial (BENEFIT trial) and analyzed using next-generation sequencing. Survival was estimated using the Kaplan–Meier method. Of the 180 enrolled patients, 115 (63.9%) harbored TP53 mutations. The median progression-free survival (PFS) and overall survival (OS) of patients with TP53-wild type tumors were significantly longer than those of patients with TP53-mutant tumors. Mutations in exons 5–8 accounted for 80.9% of TP53 mutations. Mutations in TP53 exons 6 and 7 were significantly associated with inferior PFS and OS compared to wild-type TP53. TP53 mutation also influenced the prognosis of patients with different EGFR mutations. Patients with TP53 and EGFR exon 19 mutations had significantly longer PFS and OS than patients with TP53 and EGFR L858R mutations, and both groups had worse survival than patients with only EGFR mutations. Patients with TP53 mutations, especially in exons 6 and 7, had a lower response rate and shorter PFS and OS when treated with gefitinib. Moreover, TP53 exon 5 mutation divided TP53 mutations in disruptive and non-disruptive types.
Collapse
|
|
48
|
Patel S, Petty WJ, Sands JM. An overview of lurbinectedin as a new second-line treatment option for small cell lung cancer. Ther Adv Med Oncol 2021; 13:17588359211020529. [PMID: 34104228 PMCID: PMC8165873 DOI: 10.1177/17588359211020529] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 05/05/2021] [Indexed: 12/16/2022] Open
Abstract
Small cell lung cancer (SCLC) is a highly proliferative, aggressive form of lung cancer that carries a poor prognosis. Recent approvals with new therapeutic options represent the first in more than a decade for SCLC. Lurbinectedin, a newly approved second-line option, is a synthetic alkaloid that covalently binds DNA, generating double-strand breaks, and disrupts DNA-protein interactions and RNA transcription. Lurbinectedin may also modulate the tumor microenvironment by inducing apoptosis of peripheral blood monocytes and tumor associated macrophages, decreasing expression of the inflammatory chemokine (C-C motif) ligand 2 (CCL2) and reducing tumor angiogenesis. A single-arm, open-label, basket trial included 105 patients with SCLC that had received one prior line of therapy. Patients received lurbinectedin 3.2 mg/m2 as an intravenous infusion every 3 weeks, resulting in a response rate of 35.2% and a disease control rate of 68.6%. The response rate was 45% among those with >90 days chemotherapy free interval (CTFI) and 22% in the resistant group (CTFI < 90 days). The median overall survival was 9.3 months. Myelosuppression is the most frequent clinically significant adverse event, particularly neutropenia; however, neutropenic fever occurred in only 5% of those in the SCLC cohort of the basket trial. Nausea and fatigue were also noted. The side effect profile compares favorably to topotecan, while a direct comparison of tolerability can be made between lurbinectedin versus topotecan or pegylated-liposomal doxorubicin from CORAIL, a randomized study for platinum-resistant/refractory ovarian cancer. A press release has reported the ongoing clinical trial for SCLC including combination lurbinectedin and doxorubicin versus topotecan or cyclophosphamide, doxorubicin, and vinblastine to be negative. The details may provide more insight at publication, and future trials will be important to further define the clinical utility of lurbinectedin. Lurbinectedin represents a new option in second-line SCLC.
Collapse
Affiliation(s)
- Shetal Patel
- Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - William Jeffrey Petty
- Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Jacob M Sands
- Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA Department of Medicine, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
49
|
Deneka AY, Kopp MC, Nikonova AS, Gaponova AV, Kiseleva AA, Hensley HH, Flieder DB, Serebriiskii IG, Golemis EA. Nedd9 Restrains Autophagy to Limit Growth of Early Stage Non-Small Cell Lung Cancer. Cancer Res 2021; 81:3717-3726. [PMID: 34006524 DOI: 10.1158/0008-5472.can-20-3626] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 03/16/2021] [Accepted: 04/26/2021] [Indexed: 01/22/2023]
Abstract
Non-small cell lung cancer (NSCLC) is the most common cancer worldwide. With overall 5-year survival estimated at <17%, it is critical to identify factors that regulate NSCLC disease prognosis. NSCLC is commonly driven by mutations in KRAS and TP53, with activation of additional kinases such as SRC promoting tumor invasion. In this study, we investigated the role of NEDD9, a SRC activator and scaffolding protein, in NSCLC tumorigenesis. In an inducible model of NSCLC dependent on Kras mutation and Trp53 loss (KP mice), deletion of Nedd9 (KPN mice) led to the emergence of larger tumors characterized by accelerated rates of tumor growth and elevated proliferation. Orthotopic injection of KP and KPN tumors into the lungs of Nedd9-wild-type and -null mice indicated the effect of Nedd9 loss was cell-autonomous. Tumors in KPN mice displayed reduced activation of SRC and AKT, indicating that activation of these pathways did not mediate enhanced growth of KPN tumors. NSCLC tumor growth has been shown to require active autophagy, a process dependent on activation of the kinases LKB1 and AMPK. KPN tumors contained high levels of active LKB1 and AMPK and increased autophagy compared with KP tumors. Treatment with the autophagy inhibitor chloroquine completely eliminated the growth advantage of KPN tumors. These data for the first time identify NEDD9 as a negative regulator of LKB1/AMPK-dependent autophagy during early NSCLC tumor growth. SIGNIFICANCE: This study demonstrates a novel role for the scaffolding protein NEDD9 in regulating LKB1-AMPK signaling in early stage non-small cell lung cancer, suppressing autophagy and tumor growth.
Collapse
Affiliation(s)
- Alexander Y Deneka
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA.,Kazan Federal University, Kazan, Russian Federation, Kazan, Tatarstan, Russia
| | - Meghan C Kopp
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA.,Cancer Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Anna S Nikonova
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA
| | - Anna V Gaponova
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA
| | - Anna A Kiseleva
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA
| | - Harvey H Hensley
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA
| | - Douglas B Flieder
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA.,Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | | | - Erica A Golemis
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA.
| |
Collapse
|
|
50
|
Goliwas KF, Ashraf HM, Wood AM, Wang Y, Hough KP, Bodduluri S, Athar M, Berry JL, Ponnazhagan S, Thannickal VJ, Deshane JS. Extracellular Vesicle Mediated Tumor-Stromal Crosstalk Within an Engineered Lung Cancer Model. Front Oncol 2021; 11:654922. [PMID: 33968758 PMCID: PMC8103208 DOI: 10.3389/fonc.2021.654922] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 04/06/2021] [Indexed: 12/14/2022] Open
Abstract
Tumor-stromal interactions within the tumor microenvironment (TME) influence lung cancer progression and response to therapeutic interventions, yet traditional in vitro studies fail to replicate the complexity of these interactions. Herein, we developed three-dimensional (3D) lung tumor models that mimic the human TME and demonstrate tumor-stromal crosstalk mediated by extracellular vesicles (EVs). EVs released by tumor cells, independent of p53 status, and fibroblasts within the TME mediate immunomodulatory effects; specifically, monocyte/macrophage polarization to a tumor-promoting M2 phenotype within this 3D-TME. Additionally, immune checkpoint inhibition in a 3D model that included T cells showed an inhibition of tumor growth and reduced hypoxia within the TME. Thus, perfused 3D tumor models incorporating diverse cell types provide novel insights into EV-mediated tumor-immune interactions and immune-modulation for existing and emerging cancer therapies.
Collapse
Affiliation(s)
- Kayla F Goliwas
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Hannah M Ashraf
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Anthony M Wood
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Yong Wang
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Kenneth P Hough
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Sandeep Bodduluri
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Mohammad Athar
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Joel L Berry
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Selvarangan Ponnazhagan
- Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Victor J Thannickal
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jessy S Deshane
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| |
Collapse
|