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1
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Casacuberta-Serra S, González-Larreategui Í, Capitán-Leo D, Soucek L. MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer. Signal Transduct Target Ther 2024; 9:205. [PMID: 39164274 PMCID: PMC11336233 DOI: 10.1038/s41392-024-01907-z] [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: 01/12/2024] [Revised: 06/05/2024] [Accepted: 06/24/2024] [Indexed: 08/22/2024] Open
Abstract
RAS and MYC rank amongst the most commonly altered oncogenes in cancer, with RAS being the most frequently mutated and MYC the most amplified. The cooperative interplay between RAS and MYC constitutes a complex and multifaceted phenomenon, profoundly influencing tumor development. Together and individually, these two oncogenes regulate most, if not all, hallmarks of cancer, including cell death escape, replicative immortality, tumor-associated angiogenesis, cell invasion and metastasis, metabolic adaptation, and immune evasion. Due to their frequent alteration and role in tumorigenesis, MYC and RAS emerge as highly appealing targets in cancer therapy. However, due to their complex nature, both oncogenes have been long considered "undruggable" and, until recently, no drugs directly targeting them had reached the clinic. This review aims to shed light on their complex partnership, with special attention to their active collaboration in fostering an immunosuppressive milieu and driving immunotherapeutic resistance in cancer. Within this review, we also present an update on the different inhibitors targeting RAS and MYC currently undergoing clinical trials, along with their clinical outcomes and the different combination strategies being explored to overcome drug resistance. This recent clinical development suggests a paradigm shift in the long-standing belief of RAS and MYC "undruggability", hinting at a new era in their therapeutic targeting.
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Affiliation(s)
| | - Íñigo González-Larreategui
- Models of cancer therapies Laboratory, Vall d'Hebron Institute of Oncology, Cellex Centre, Hospital University Vall d'Hebron Campus, Barcelona, Spain
| | - Daniel Capitán-Leo
- Models of cancer therapies Laboratory, Vall d'Hebron Institute of Oncology, Cellex Centre, Hospital University Vall d'Hebron Campus, Barcelona, Spain
| | - Laura Soucek
- Peptomyc S.L., Barcelona, Spain.
- Models of cancer therapies Laboratory, Vall d'Hebron Institute of Oncology, Cellex Centre, Hospital University Vall d'Hebron Campus, Barcelona, Spain.
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
- Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Bellaterra, Spain.
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2
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Zhang R, Li S, Schippers K, Eimers B, Niu J, Hornung BVH, van den Hout MCGN, van Ijcken WFJ, Peppelenbosch MP, Smits R. Unraveling the impact of AXIN1 mutations on HCC development: Insights from CRISPR/Cas9 repaired AXIN1-mutant liver cancer cell lines. PLoS One 2024; 19:e0304607. [PMID: 38848383 PMCID: PMC11161089 DOI: 10.1371/journal.pone.0304607] [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: 09/27/2023] [Accepted: 05/14/2024] [Indexed: 06/09/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a highly aggressive liver cancer with significant morbidity and mortality rates. AXIN1 is one of the top-mutated genes in HCC, but the mechanism by which AXIN1 mutations contribute to HCC development remains unclear. METHODS In this study, we utilized CRISPR/Cas9 genome editing to repair AXIN1-truncated mutations in five HCC cell lines. RESULTS For each cell line we successfully obtained 2-4 correctly repaired clones, which all show reduced β-catenin signaling accompanied with reduced cell viability and colony formation. Although exposure of repaired clones to Wnt3A-conditioned medium restored β-catenin signaling, it did not or only partially recover their growth characteristics, indicating the involvement of additional mechanisms. Through RNA-sequencing analysis, we explored the gene expression patterns associated with repaired AXIN1 clones. Except for some highly-responsive β-catenin target genes, no consistent alteration in gene/pathway expression was observed. This observation also applies to the Notch and YAP/TAZ-Hippo signaling pathways, which have been associated with AXIN1-mutant HCCs previously. The AXIN1-repaired clones also cannot confirm a recent observation that AXIN1 is directly linked to YAP/TAZ protein stability and signaling. CONCLUSIONS Our study provides insights into the effects of repairing AXIN1 mutations on β-catenin signaling, cell viability, and colony formation in HCC cell lines. However, further investigations are necessary to understand the complex mechanisms underlying HCC development associated with AXIN1 mutations.
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Affiliation(s)
- Ruyi Zhang
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center, Rotterdam, The Netherlands
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, School of Chemistry & Environment, Yunnan Minzu University, Kunming, China
| | - Shanshan Li
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Kelly Schippers
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Boaz Eimers
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Jiahui Niu
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Bastian V. H. Hornung
- Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | | | - Maikel P. Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Ron Smits
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center, Rotterdam, The Netherlands
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3
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Chen S, Zhou B, Huang W, Li Q, Yu Y, Kuang X, Huang H, Wang W, Xie P. The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression. Cell Death Dis 2023; 14:830. [PMID: 38097536 PMCID: PMC10721641 DOI: 10.1038/s41419-023-06358-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: 07/27/2023] [Revised: 11/22/2023] [Accepted: 11/30/2023] [Indexed: 12/17/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest malignancies in the world. Research into the key genes that maintain the malignant behavior of cancer cells is crucial for the treatment of HCC. Here, we identified ubiquitin-specific peptidase 44 (USP44), a member of the deubiquitinase family, as a novel regulator of HCC progression. The tumor suppressive function of USP44 was evaluated in a series of in vitro and in vivo experiments. Through quantitative proteomics examination, we demonstrated that USP44 inhibits HCC PDL1 expression by downregulating the Hedgehog (Hh) signaling pathway. Mechanistically, we found that USP44 directly interacts with Itch, an E3 ligase involved in Hh signaling, and promotes the deubiquitination and stabilization of Itch. These events result in the proteasomal degradation of Gli1 and subsequent inactivation of Hh signaling, which ultimately suppresses PDL1 expression and the progression of HCC. Furthermore, the HCC tissue microarray was analyzed by immunohistochemistry to evaluate the pathological relevance of the USP44/Itch/Gli1/PDL1 axis. Finally, the Gli1 inhibitor GANT61 was found to act in synergy with anti-PDL1 therapy. Overall, USP44 can act as a suppressive gene in HCC by modulating Hh signaling, and co-inhibition of Gli1 and PDL1 might be an effective novel combination strategy for treating HCC patients.
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Affiliation(s)
- Sisi Chen
- Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Binghai Zhou
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Wei Huang
- Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Qing Li
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Ye Yu
- Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Xiuqing Kuang
- Department of Physical Examination, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Huabin Huang
- Department of Medical Imaging, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Wei Wang
- Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China.
| | - Peiyi Xie
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
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4
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Lee E, Cheung J, Bialkowska AB. Krüppel-like Factors 4 and 5 in Colorectal Tumorigenesis. Cancers (Basel) 2023; 15:cancers15092430. [PMID: 37173904 PMCID: PMC10177156 DOI: 10.3390/cancers15092430] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 05/15/2023] Open
Abstract
Krüppel-like factors (KLFs) are transcription factors regulating various biological processes such as proliferation, differentiation, migration, invasion, and homeostasis. Importantly, they participate in disease development and progression. KLFs are expressed in multiple tissues, and their role is tissue- and context-dependent. KLF4 and KLF5 are two fascinating members of this family that regulate crucial stages of cellular identity from embryogenesis through differentiation and, finally, during tumorigenesis. They maintain homeostasis of various tissues and regulate inflammation, response to injury, regeneration, and development and progression of multiple cancers such as colorectal, breast, ovarian, pancreatic, lung, and prostate, to name a few. Recent studies broaden our understanding of their function and demonstrate their opposing roles in regulating gene expression, cellular function, and tumorigenesis. This review will focus on the roles KLF4 and KLF5 play in colorectal cancer. Understanding the context-dependent functions of KLF4 and KLF5 and the mechanisms through which they exert their effects will be extremely helpful in developing targeted cancer therapy.
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Affiliation(s)
- Esther Lee
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Jacky Cheung
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Agnieszka B Bialkowska
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
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5
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Hedgehog-GLI and Notch Pathways Sustain Chemoresistance and Invasiveness in Colorectal Cancer and Their Inhibition Restores Chemotherapy Efficacy. Cancers (Basel) 2023; 15:cancers15051471. [PMID: 36900263 PMCID: PMC10000782 DOI: 10.3390/cancers15051471] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 02/16/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related mortality and chemoresistance is a major medical issue. The epithelial-to-mesenchymal transition (EMT) is the primary step in the emergence of the invasive phenotype and the Hedgehog-GLI (HH-GLI) and NOTCH signaling pathways are associated with poor prognosis and EMT in CRC. CRC cell lines harboring KRAS or BRAF mutations, grown as monolayers and organoids, were treated with the chemotherapeutic agent 5-Fluorouracil (5-FU) alone or combined with HH-GLI and NOTCH pathway inhibitors GANT61 and DAPT, or arsenic trioxide (ATO) to inhibit both pathways. Treatment with 5-FU led to the activation of HH-GLI and NOTCH pathways in both models. In KRAS mutant CRC, HH-GLI and NOTCH signaling activation co-operate to enhance chemoresistance and cell motility, while in BRAF mutant CRC, the HH-GLI pathway drives the chemoresistant and motile phenotype. We then showed that 5-FU promotes the mesenchymal and thus invasive phenotype in KRAS and BRAF mutant organoids and that chemosensitivity could be restored by targeting the HH-GLI pathway in BRAF mutant CRC or both HH-GLI and NOTCH pathways in KRAS mutant CRC. We suggest that in KRAS-driven CRC, the FDA-approved ATO acts as a chemotherapeutic sensitizer, whereas GANT61 is a promising chemotherapeutic sensitizer in BRAF-driven CRC.
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6
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Stoletov K, Sanchez S, Gorroño I, Rabano M, Vivanco MDM, Kypta R, Lewis JD. Intravital imaging of Wnt/β-catenin and ATF2-dependent signalling pathways during tumour cell invasion and metastasis. J Cell Sci 2023; 136:286293. [PMID: 36621522 PMCID: PMC10022745 DOI: 10.1242/jcs.260285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 12/13/2022] [Indexed: 01/10/2023] Open
Abstract
Wnt signalling has been implicated as a driver of tumour cell metastasis, but less is known about which branches of Wnt signalling are involved and when they act in the metastatic cascade. Here, using a unique intravital imaging platform and fluorescent reporters, we visualised β-catenin/TCF-dependent and ATF2-dependent signalling activities during human cancer cell invasion, intravasation and metastatic lesion formation in the chick embryo host. We found that cancer cells readily shifted between states of low and high canonical Wnt activity. Cancer cells that displayed low Wnt canonical activity showed higher invasion and intravasation potential in primary tumours and in metastatic lesions. In contrast, cancer cells showing low ATF2-dependent activity were significantly less invasive both at the front of primary tumours and in metastatic lesions. Simultaneous visualisation of both these reporters using a double-reporter cell line confirmed their complementary activities in primary tumours and metastatic lesions. These findings might inform the development of therapies that target different branches of Wnt signalling at specific stages of metastasis.
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Affiliation(s)
- Konstantin Stoletov
- Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | - Saray Sanchez
- Centre for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
| | - Irantzu Gorroño
- Centre for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
| | - Miriam Rabano
- Centre for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
| | - Maria D M Vivanco
- Centre for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
| | - Robert Kypta
- Centre for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain.,Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK
| | - John D Lewis
- Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
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7
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Fetisov TI, Borunova AA, Antipova AS, Antoshina EE, Trukhanova LS, Gorkova TG, Zuevskaya SN, Maslov A, Gurova K, Gudkov A, Lesovaya EA, Belitsky GA, Yakubovskaya MG, Kirsanov KI. Targeting Features of Curaxin CBL0137 on Hematological Malignancies In Vitro and In Vivo. Biomedicines 2023; 11:biomedicines11010230. [PMID: 36672738 PMCID: PMC9856019 DOI: 10.3390/biomedicines11010230] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/31/2022] [Accepted: 01/12/2023] [Indexed: 01/19/2023] Open
Abstract
The anticancer activity of Curaxin CBL0137, a DNA-binding small molecule with chromatin remodulating effect, has been demonstrated in different cancers. Herein, a comparative evaluation of CBL0137 activity was performed in respect to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia and multiple myeloma (MM) cultured in vitro. MTT assay showed AML and MM higher sensitivity to CBL0137's cytostatic effect comparatively to other hematological malignancy cells. Flow cytometry cell cycle analysis revealed an increase in subG1 and G2/M populations after CBL0137 cell treatment, but the prevalent type of arrest varied. Apoptosis activation by CBL0137 measured by Annexin-V/PI dual staining was more active in AML and MM cells. RT2 PCR array showed that changes caused by CBL0137 in signaling pathways involved in cancer pathogenesis were more intensive in AML and MM cells. On the murine model of AML WEHI-3, CBL0137 showed significant anticancer effects in vivo, which were evaluated by corresponding changes in spleen and liver. Thus, more pronounced anticancer effects of CBL0137 in vitro were observed in respect to AML and MM. Experiments in vivo also indicated the perspective of CBL0137 use for AML treatment. This in accordance with the frontline treatment approach in AML using epigenetic drugs.
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Affiliation(s)
- Timur I. Fetisov
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Anna A. Borunova
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Alina S. Antipova
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Elena E. Antoshina
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Lubov S. Trukhanova
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Tatyana G. Gorkova
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | | | - Alexei Maslov
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Katerina Gurova
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Andrei Gudkov
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Ekaterina A. Lesovaya
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
- Department of Oncology, I.P. Pavlov Ryazan State Medical University, 390026 Ryazan, Russia
| | - Gennady A. Belitsky
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | | | - Kirill I. Kirsanov
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
- Correspondence:
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8
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Fröhlich J, Rose K, Hecht A. Transcriptional activity mediated by β-CATENIN and TCF/LEF family members is completely dispensable for survival and propagation of multiple human colorectal cancer cell lines. Sci Rep 2023; 13:287. [PMID: 36609428 PMCID: PMC9822887 DOI: 10.1038/s41598-022-27261-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 12/29/2022] [Indexed: 01/08/2023] Open
Abstract
Unrestrained transcriptional activity of β-CATENIN and its binding partner TCF7L2 frequently underlies colorectal tumor initiation and is considered an obligatory oncogenic driver throughout intestinal carcinogenesis. Yet, the TCF7L2 gene carries inactivating mutations in about 10% of colorectal tumors and is non-essential in colorectal cancer (CRC) cell lines. To determine whether CRC cells acquire TCF7L2-independence through cancer-specific compensation by other T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) family members, or rather lose addiction to β-CATENIN/TCF7L2-driven gene expression altogether, we generated multiple CRC cell lines entirely negative for TCF/LEF or β-CATENIN expression. Survival of these cells and the ability to propagate them demonstrate their complete β-CATENIN- and TCF/LEF-independence. Nonetheless, one β-CATENIN-deficient cell line eventually became senescent, and absence of TCF/LEF proteins and β-CATENIN consistently impaired CRC cell proliferation, reminiscent of mitogenic effects of WNT/β-CATENIN signaling in the healthy intestine. Despite this common phenotype, β-CATENIN-deficient cells exhibited highly cell-line-specific gene expression changes with little overlap between β-CATENIN- and TCF7L2-dependent transcriptomes. Apparently, β-CATENIN and TCF7L2 independently control sizeable fractions of their target genes. The observed divergence of β-CATENIN and TCF7L2 transcriptional programs, and the finding that neither β-CATENIN nor TCF/LEF activity is strictly required for CRC cell survival has important implications when evaluating these factors as potential drug targets.
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Affiliation(s)
- Janna Fröhlich
- grid.5963.9Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Stefan-Meier-Str. 17, 79104 Freiburg, Germany ,grid.5963.9Faculty of Biology, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany
| | - Katja Rose
- grid.5963.9Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Stefan-Meier-Str. 17, 79104 Freiburg, Germany
| | - Andreas Hecht
- Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Stefan-Meier-Str. 17, 79104, Freiburg, Germany. .,Faculty of Biology, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany. .,BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany.
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9
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Swiderska-Syn M, Mir-Pedrol J, Oles A, Schleuger O, Salvador AD, Greiner SM, Seward C, Yang F, Babcock BR, Shen C, Wynn DT, Sanchez-Mejias A, Gershon TR, Martin V, McCrea HJ, Lindsey KG, Krieg C, Rodriguez-Blanco J. Noncanonical activation of GLI signaling in SOX2 + cells drives medulloblastoma relapse. SCIENCE ADVANCES 2022; 8:eabj9138. [PMID: 35857834 PMCID: PMC9299538 DOI: 10.1126/sciadv.abj9138] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 06/03/2022] [Indexed: 05/04/2023]
Abstract
SRY (sex determining region Y)-box 2 (SOX2)-labeled cells play key roles in chemoresistance and tumor relapse; thus, it is critical to elucidate the mechanisms propagating them. Single-cell transcriptomic analyses of the most common malignant pediatric brain tumor, medulloblastoma (MB), revealed the existence of astrocytic Sox2+ cells expressing sonic hedgehog (SHH) signaling biomarkers. Treatment with vismodegib, an SHH inhibitor that acts on Smoothened (Smo), led to increases in astrocyte-like Sox2+ cells. Using SOX2-enriched MB cultures, we observed that SOX2+ cells required SHH signaling to propagate, and unlike in the proliferative tumor bulk, the SHH pathway was activated in these cells downstream of Smo in an MYC-dependent manner. Functionally different GLI inhibitors depleted vismodegib-resistant SOX2+ cells from MB tissues, reduced their ability to further engraft in vivo, and increased symptom-free survival. Our results emphasize the promise of therapies targeting GLI to deplete SOX2+ cells and provide stable tumor remission.
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Affiliation(s)
- Marzena Swiderska-Syn
- Darby Children’s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Júlia Mir-Pedrol
- Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona 08002, Spain
| | - Alexander Oles
- Darby Children’s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Olga Schleuger
- Darby Children’s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
| | - April D. Salvador
- Darby Children’s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Sean M. Greiner
- Darby Children’s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Cara Seward
- Darby Children’s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Fan Yang
- Molecular Oncology Program, The Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL 33136, USA
| | - Benjamin R. Babcock
- Lowance Center for Human Immunology, Department of Medicine, Emory University, Atlanta, GA 30322, USA
- Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
| | - Chen Shen
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Daniel T. Wynn
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Avencia Sanchez-Mejias
- Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona 08002, Spain
| | - Timothy R. Gershon
- Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
| | - Vanesa Martin
- Department of Anatomy and Cell Biology, University of Oviedo, Oviedo, Asturias 33006, Spain
| | - Heather J. McCrea
- Department of Clinical Neurological Surgery, University of Miami, Miami, FL 33136, USA
| | - Kathryn G. Lindsey
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Carsten Krieg
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Jezabel Rodriguez-Blanco
- Darby Children’s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
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10
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Spano D, Colanzi A. Golgi Complex: A Signaling Hub in Cancer. Cells 2022; 11:1990. [PMID: 35805075 PMCID: PMC9265605 DOI: 10.3390/cells11131990] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/17/2022] [Accepted: 06/19/2022] [Indexed: 02/01/2023] Open
Abstract
The Golgi Complex is the central hub in the endomembrane system and serves not only as a biosynthetic and processing center but also as a trafficking and sorting station for glycoproteins and lipids. In addition, it is an active signaling hub involved in the regulation of multiple cellular processes, including cell polarity, motility, growth, autophagy, apoptosis, inflammation, DNA repair and stress responses. As such, the dysregulation of the Golgi Complex-centered signaling cascades contributes to the onset of several pathological conditions, including cancer. This review summarizes the current knowledge on the signaling pathways regulated by the Golgi Complex and implicated in promoting cancer hallmarks and tumor progression.
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Affiliation(s)
- Daniela Spano
- Institute of Biochemistry and Cell Biology, National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy
| | - Antonino Colanzi
- Institute for Endocrinology and Experimental Oncology “G. Salvatore”, National Research Council, 80131 Naples, Italy;
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11
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Conod A, Silvano M, Ruiz i Altaba A. On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm. Cell Rep 2022; 38:110490. [PMID: 35263600 DOI: 10.1016/j.celrep.2022.110490] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 12/07/2021] [Accepted: 02/14/2022] [Indexed: 12/12/2022] Open
Abstract
How metastatic cells arise is unclear. Here, we search for the induction of recently characterized pro-metastatic states as a surrogate for the origin of metastasis. Since cell-death-inducing therapies can paradoxically promote metastasis, we ask if such treatments induce pro-metastatic states in human colon cancer cells. We find that post-near-death cells acquire pro-metastatic states (PAMEs) and form distant metastases in vivo. These PAME ("let's go" in Greek) cells exhibit a multifactorial cytokine storm as well as signs of enhanced endoplasmic reticulum (ER) stress and nuclear reprogramming, requiring CXCL8, INSL4, IL32, PERK-CHOP, and NANOG. PAMEs induce neighboring tumor cells to become PAME-induced migratory cells (PIMs): highly migratory cells that re-enact the storm and enhance PAME migration. Metastases are thus proposed to originate from the induction of pro-metastatic states through intrinsic and extrinsic cues in a pro-metastatic tumoral ecosystem, driven by an impending cell-death experience involving ER stress modulation, metastatic reprogramming, and paracrine recruitment via a cytokine storm.
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Affiliation(s)
- Arwen Conod
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Marianna Silvano
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Ariel Ruiz i Altaba
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
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12
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Massó-Vallés D, Beaulieu ME, Jauset T, Giuntini F, Zacarías-Fluck MF, Foradada L, Martínez-Martín S, Serrano E, Martín-Fernández G, Casacuberta-Serra S, Castillo Cano V, Kaur J, López-Estévez S, Morcillo MÁ, Alzrigat M, Mahmoud L, Luque-García A, Escorihuela M, Guzman M, Arribas J, Serra V, Larsson LG, Whitfield JR, Soucek L. MYC Inhibition Halts Metastatic Breast Cancer Progression by Blocking Growth, Invasion, and Seeding. CANCER RESEARCH COMMUNICATIONS 2022; 2:110-130. [PMID: 36860495 PMCID: PMC9973395 DOI: 10.1158/2767-9764.crc-21-0103] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/31/2021] [Accepted: 02/01/2022] [Indexed: 11/16/2022]
Abstract
MYC's role in promoting tumorigenesis is beyond doubt, but its function in the metastatic process is still controversial. Omomyc is a MYC dominant negative that has shown potent antitumor activity in multiple cancer cell lines and mouse models, regardless of their tissue of origin or driver mutations, by impacting on several of the hallmarks of cancer. However, its therapeutic efficacy against metastasis has not been elucidated yet. Here we demonstrate for the first time that MYC inhibition by transgenic Omomyc is efficacious against all breast cancer molecular subtypes, including triple-negative breast cancer, where it displays potent antimetastatic properties both in vitro and in vivo. Importantly, pharmacologic treatment with the recombinantly produced Omomyc miniprotein, recently entering a clinical trial in solid tumors, recapitulates several key features of expression of the Omomyc transgene, confirming its clinical applicability to metastatic breast cancer, including advanced triple-negative breast cancer, a disease in urgent need of better therapeutic options. Significance While MYC role in metastasis has been long controversial, this manuscript demonstrates that MYC inhibition by either transgenic expression or pharmacologic use of the recombinantly produced Omomyc miniprotein exerts antitumor and antimetastatic activity in breast cancer models in vitro and in vivo, suggesting its clinical applicability.
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Affiliation(s)
- Daniel Massó-Vallés
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain.,Peptomyc S.L., Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Marie-Eve Beaulieu
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain.,Peptomyc S.L., Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Toni Jauset
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain.,Peptomyc S.L., Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Fabio Giuntini
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain
| | - Mariano F. Zacarías-Fluck
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain
| | - Laia Foradada
- Peptomyc S.L., Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Sandra Martínez-Martín
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Erika Serrano
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain
| | - Génesis Martín-Fernández
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain
| | | | | | - Jastrinjan Kaur
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain
| | | | - Miguel Ángel Morcillo
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain
| | - Mohammad Alzrigat
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Loay Mahmoud
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Antonio Luque-García
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain
| | - Marta Escorihuela
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain
| | - Marta Guzman
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain
| | - Joaquín Arribas
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Violeta Serra
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain
| | - Lars-Gunnar Larsson
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Jonathan R. Whitfield
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain
| | - Laura Soucek
- Preclinical & Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret, Barcelona, Spain.,Peptomyc S.L., Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.,Corresponding Author: Laura Soucek, Vall d'Hebron Institute of Oncology (VHIO), C/ Natzaret, 115-117, CELLEX Centre, Barcelona 08035, Spain. Phone: 349-3254-3450; E-mail:
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13
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Chen GT, Tifrea DF, Murad R, Habowski AN, Lyou Y, Duong MR, Hosohama L, Mortazavi A, Edwards RA, Waterman ML. Disruption of beta-catenin dependent Wnt signaling in colon cancer cells remodels the microenvironment to promote tumor invasion. Mol Cancer Res 2021; 20:468-484. [PMID: 34799404 DOI: 10.1158/1541-7786.mcr-21-0349] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 09/29/2021] [Accepted: 11/12/2021] [Indexed: 11/16/2022]
Abstract
The recent classification of colon cancer into molecular subtypes revealed that patients with the poorest prognosis harbor tumors with the lowest levels of Wnt signaling. This is contrary to the general understanding that overactive Wnt signaling promotes tumor progression from early initiation stages through to the later stages including invasion and metastasis. Here, we directly test this assumption by reducing the activity of ß-catenin-dependent Wnt signaling in colon cancer cell lines at either an upstream or downstream step in the pathway. We determine that Wnt-reduced cancer cells exhibit a more aggressive disease phenotype, including increased mobility in vitro and disruptive invasion into mucosa and smooth muscle in an orthotopic mouse model. RNA sequencing reveals that interference with Wnt signaling leads to an upregulation of gene programs that favor cell migration and invasion and a downregulation of inflammation signatures in the tumor microenvironment. We identify a set of upregulated genes common among the Wnt perturbations that are predictive of poor patient outcomes in early-invasive colon cancer. Our findings suggest that while targeting Wnt signaling may reduce tumor burden, an inadvertent side effect is the emergence of invasive cancer. Implications: Decreased Wnt signaling in colon tumors leads to a more aggressive disease phenotype due to an upregulation of gene programs favoring cell migration in the tumor and downregulation of inflammation programs in the tumor microenvironment; these impacts must be carefully considered in developing Wnt-targeting therapies.
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Affiliation(s)
- George T Chen
- Microbiology & Molecular Genetics, University of California, Irvine
| | | | - Rabi Murad
- Developmental and Cell Biology, University of California, Irvine
| | - Amber N Habowski
- Microbiology & Molecular Genetics, University of California, Irvine
| | - Yung Lyou
- Microbiology and Molecular Genetics, University of California, Irvine
| | | | - Linzi Hosohama
- Microbiology & Molecular Genetics, University of California, Irvine
| | - Ali Mortazavi
- Department of Developmental & Cell Biology, University of California, Irvine
| | | | - Marian L Waterman
- Microbiology and Molecular Genetics, University of California, Irvine
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14
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Duarte D, Vale N. Combining repurposed drugs to treat colorectal cancer. Drug Discov Today 2021; 27:165-184. [PMID: 34592446 DOI: 10.1016/j.drudis.2021.09.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 07/19/2021] [Accepted: 09/22/2021] [Indexed: 02/08/2023]
Abstract
The drug development process, especially of antineoplastic agents, has become increasingly costly and ineffective. Drug repurposing and drug combination are alternatives to de novo drug development, being low cost, rapid, and easy to apply. These strategies allow higher efficacy, decreased toxicity, and overcoming of drug resistance. The combination of antineoplastic agents is already being applied in cancer therapy, but the combination of repurposed drugs is still under-explored in pre- and clinical development. In this review, we provide a set of pharmacological concepts focusing on drug repurposing for treating colorectal cancer (CRC) and that are relevant for the application of new drug combinations against this disease.
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Affiliation(s)
- Diana Duarte
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal; Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal; Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
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15
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Chai JY, Sugumar V, Alshanon AF, Wong WF, Fung SY, Looi CY. Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches. Cancers (Basel) 2021; 13:4746. [PMID: 34638233 PMCID: PMC8507559 DOI: 10.3390/cancers13194746] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 12/15/2022] Open
Abstract
Insight into cancer signaling pathways is vital in the development of new cancer treatments to improve treatment efficacy. A relatively new but essential developmental signaling pathway, namely Hedgehog (Hh), has recently emerged as a major mediator of cancer progression and chemoresistance. The evolutionary conserved Hh signaling pathway requires an in-depth understanding of the paradigm of Hh signaling transduction, which is fundamental to provide the necessary means for the design of novel tools for treating cancer related to aberrant Hh signaling. This review will focus substantially on the canonical Hh signaling and the treatment strategies employed in different studies, with special emphasis on the molecular mechanisms and combination treatment in regard to Hh inhibitors and chemotherapeutics. We discuss our views based on Hh signaling's role in regulating DNA repair machinery, autophagy, tumor microenvironment, drug inactivation, transporters, epithelial-to-mesenchymal transition, and cancer stem cells to promote chemoresistance. The understanding of this Achilles' Heel in cancer may improve the therapeutic outcome for cancer therapy.
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Affiliation(s)
- Jian Yi Chai
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, Subang Jaya 47500, Malaysia;
| | - Vaisnevee Sugumar
- School of Medicine, Faculty of Health & Medical Sciences, Taylor’s University, Subang Jaya 47500, Malaysia;
| | - Ahmed F. Alshanon
- Center of Biotechnology Researches, University of Al-Nahrain, Baghdad 10072, Iraq;
| | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;
| | - Shin Yee Fung
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Chung Yeng Looi
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, Subang Jaya 47500, Malaysia;
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16
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Chai JY, Sugumar V, Alshawsh MA, Wong WF, Arya A, Chong PP, Looi CY. The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis. Biomedicines 2021; 9:1188. [PMID: 34572373 PMCID: PMC8466551 DOI: 10.3390/biomedicines9091188] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/29/2021] [Accepted: 09/01/2021] [Indexed: 12/22/2022] Open
Abstract
The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.
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Affiliation(s)
- Jian Yi Chai
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
| | - Vaisnevee Sugumar
- School of Medicine, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia;
| | | | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;
| | - Aditya Arya
- School of Biosciences, Faculty of Science, Building 184, The University of Melbourne, Melbourne, VIC 3010, Australia;
| | - Pei Pei Chong
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia
| | - Chung Yeng Looi
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia
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17
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Zárate AM, Espinosa-Bustos C, Guerrero S, Fierro A, Oyarzún-Ampuero F, Quest AFG, Di Marcotullio L, Loricchio E, Caimano M, Calcaterra A, González-Quiroz M, Aguirre A, Meléndez J, Salas CO. A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo. Int J Mol Sci 2021; 22:8372. [PMID: 34445078 PMCID: PMC8395040 DOI: 10.3390/ijms22168372] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 12/14/2022] Open
Abstract
The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.
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Affiliation(s)
- Ana María Zárate
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago 702843, Chile; (A.M.Z.); (A.F.)
| | - Christian Espinosa-Bustos
- Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago 702843, Chile;
| | - Simón Guerrero
- Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Sergio Livingstone 1007, Independencia, Santiago 8380492, Chile; (S.G.); (F.O.-A.); (A.F.G.Q.)
- Instituto de Investigación Interdisciplinar en Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad SEK (I3CBSEK), Fernando Manterola 0789, Providencia, Santiago 7520317, Chile
| | - Angélica Fierro
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago 702843, Chile; (A.M.Z.); (A.F.)
| | - Felipe Oyarzún-Ampuero
- Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Sergio Livingstone 1007, Independencia, Santiago 8380492, Chile; (S.G.); (F.O.-A.); (A.F.G.Q.)
- Departamento de Ciencias y Tecnología Farmacéuticas, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago 8380494, Chile
| | - Andrew F. G. Quest
- Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Sergio Livingstone 1007, Independencia, Santiago 8380492, Chile; (S.G.); (F.O.-A.); (A.F.G.Q.)
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Program of Cellular and Molecular Biology, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago 8380453, Chile
| | - Lucia Di Marcotullio
- Laboratory Affiliated to Insituto Pasteur Italia, Fondazione Cenci Bognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy;
| | - Elena Loricchio
- Center For Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy;
| | - Miriam Caimano
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy;
| | - Andrea Calcaterra
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy;
| | - Matías González-Quiroz
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Universidad de Chile, Independencia 1027, Santiago 8380453, Chile;
| | - Adam Aguirre
- Laboratorio de Medicina Traslacional, Fundación Arturo López Pérez, Rancagua 878, Lower Fifth Floor, Providencia, Santiago 8320000, Chile;
| | - Jaime Meléndez
- Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago 702843, Chile;
| | - Cristian O. Salas
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago 702843, Chile; (A.M.Z.); (A.F.)
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18
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Ternet C, Kiel C. Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage. Cell Commun Signal 2021; 19:31. [PMID: 33691728 PMCID: PMC7945333 DOI: 10.1186/s12964-021-00712-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/25/2021] [Indexed: 02/06/2023] Open
Abstract
The intestinal epithelium acts as a physical barrier that separates the intestinal microbiota from the host and is critical for preserving intestinal homeostasis. The barrier is formed by tightly linked intestinal epithelial cells (IECs) (i.e. enterocytes, goblet cells, neuroendocrine cells, tuft cells, Paneth cells, and M cells), which constantly self-renew and shed. IECs also communicate with microbiota, coordinate innate and adaptive effector cell functions. In this review, we summarize the signaling pathways contributing to intestinal cell fates and homeostasis functions. We focus especially on intestinal stem cell proliferation, cell junction formation, remodelling, hypoxia, the impact of intestinal microbiota, the immune system, inflammation, and metabolism. Recognizing the critical role of KRAS mutants in colorectal cancer, we highlight the connections of KRAS signaling pathways in coordinating these functions. Furthermore, we review the impact of KRAS colorectal cancer mutants on pathway rewiring associated with disruption and dysfunction of the normal intestinal homeostasis. Given that KRAS is still considered undruggable and the development of treatments that directly target KRAS are unlikely, we discuss the suitability of targeting pathways downstream of KRAS as well as alterations of cell extrinsic/microenvironmental factors as possible targets for modulating signaling pathways in colorectal cancer.
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