|
1
|
Tang J, Li X, Tang N, Lin X, Du Y, Zhang S, Li Q, Zhang Y, Zhang Y, Hang H, Qiu T, Qiu Y, Cheng H, Dai Z, Hong H, Wei W, He J, Yan C. CD44 identified as a diagnostic biomarker for highly malignant CA19-9 negative pancreatic cancer. Cancer Lett 2025; 622:217713. [PMID: 40216152 DOI: 10.1016/j.canlet.2025.217713] [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: 02/26/2025] [Revised: 03/25/2025] [Accepted: 04/08/2025] [Indexed: 04/16/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited diagnostic biomarkers. Carbohydrate antigen 19-9 (CA19-9) is a widely used clinical biomarker and is generally considered to correlate with PDAC malignancy. However, the relationship between CA19-9 expression levels and tumor aggressiveness remains underexplored. In this study, we report a biphasic relationship between CA19-9 expression levels and PDAC malignancy, where both negative (<5 U/mL) and high (>37 U/mL) CA19-9 levels are associated with increased tumor aggressiveness. We defined CA19-9 negative PDAC as tumors that lack CA19-9 expression intracellulary, on the cell membrane, and in secreted form. In PDAC cell lines and patient-derived organoids, CA19-9 negativity, confirmed by immunofluorescence, flow cytometry and ELISA, correlated with more aggressive behaviors. In PDAC patients, tumors from those with serum CA19-9 levels below 5 U/mL exhibited stronger metabolically activity, more immunosuppressive tumor microenvironment, and worse survival than CA19-9 positive tumors, with over 90 % showing absent CA19-9 expression by immunohistochemistry (IHC). Glycoproteomics profiling identified CD44 as a highly expressed biomarker in CA19-9 negative PDAC. Elevated CD44 expression effectively distinguished CA19-9 negative PDAC from both CA19-9 positive PDAC and CA19-9 negative benign pancreatic diseases, suggesting its potential as a diagnostic tool. Furthermore, we developed a radionuclide-labeled CD44 antibody 89Zr-1M2E3, which specifically recognized CA19-9 negative PDAC tumors in preclinical models using PET-CT imaging. These findings highlight CD44 as a promising biomarker and therapeutic target for diagnosing and treating CA19-9 negative PDAC.
Collapse
Affiliation(s)
- Jiatong Tang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu Province, China; Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing, Jiangsu Province, China; State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing, Jiangsu Province, China
| | - Xiaoyang Li
- Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing, Jiangsu Province, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Neng Tang
- Department of Pancreatic and Metabolic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Xiawen Lin
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Yixiang Du
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu Province, China
| | - Shuo Zhang
- Department of Pancreatic and Metabolic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Qi Li
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Yifan Zhang
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Yixuan Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu Province, China; Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing, Jiangsu Province, China; State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing, Jiangsu Province, China
| | - Hexing Hang
- Department of Pancreatic and Metabolic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Tongtong Qiu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu Province, China; Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing, Jiangsu Province, China; State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing, Jiangsu Province, China
| | - Yudong Qiu
- Department of Pancreatic and Metabolic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Institute of Pancreatology, Nanjing University, Nanjing, Jiangsu Province, China
| | - Hao Cheng
- Department of Pancreatic and Metabolic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Zhan Dai
- Nanjing Okay Biotechnology Co., Ltd, Nanjing, Jiangsu Provinve, China
| | - Hao Hong
- Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing, Jiangsu Province, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Wei Wei
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu Province, China; Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing, Jiangsu Province, China; State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing, Jiangsu Province, China.
| | - Jian He
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Institute of Pancreatology, Nanjing University, Nanjing, Jiangsu Province, China.
| | - Chao Yan
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu Province, China; Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing, Jiangsu Province, China; Department of Pancreatic and Metabolic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Institute of Pancreatology, Nanjing University, Nanjing, Jiangsu Province, China.
| |
Collapse
|
|
2
|
Shang T, Jia Z, Li J, Cao H, Xu H, Cong L, Ma D, Wang X, Liu J. Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance. J Hematol Oncol 2025; 18:32. [PMID: 40102937 PMCID: PMC11921735 DOI: 10.1186/s13045-025-01684-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 03/05/2025] [Indexed: 03/20/2025] Open
Abstract
In the domain of addressing cancer resistance, challenges such as limited effectiveness and treatment resistance remain persistent. Hypoxia is a key feature of solid tumors and is strongly associated with poor prognosis in cancer patients. Another significant portion of the development of acquired drug resistance is attributed to tumor stemness. Cancer stem cells (CSCs), a small tumor cell subset with self-renewal and proliferative abilities, are crucial for tumor initiation, metastasis, and intra-tumoral heterogeneity. Studies have shown a significant association between hypoxia and CSCs in the context of tumor resistance. Recent studies reveal a strong link between hypoxia and tumor stemness, which together promote tumor survival and progression during treatment. This review elucidates the interplay between hypoxia and CSCs, as well as their correlation with resistance to therapeutic drugs. Targeting pivotal genes associated with hypoxia and stemness holds promise for the development of novel therapeutics to combat tumor resistance.
Collapse
Affiliation(s)
- Tongxuan Shang
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Ziqi Jia
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiayi Li
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China
| | - Heng Cao
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hengyi Xu
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lin Cong
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Dongxu Ma
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiang Wang
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jiaqi Liu
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| |
Collapse
|
|
3
|
Morin C, Paraqindes H, Van Long FN, Isaac C, Thomas E, Pedri D, Pulido-Vicuna CA, Morel AP, Marchand V, Motorin Y, Carrere M, Auclair J, Attignon V, Pommier RM, Ruiz E, Bourdelais F, Catez F, Durand S, Ferrari A, Viari A, Marine JC, Puisieux A, Diaz JJ, Moyret-Lalle C, Marcel V. Specific modulation of 28S_Um2402 rRNA 2'- O-ribose methylation as a novel epitranscriptomic marker of ZEB1-induced epithelial-mesenchymal transition in different mammary cell contexts. NAR Cancer 2025; 7:zcaf001. [PMID: 39877292 PMCID: PMC11773364 DOI: 10.1093/narcan/zcaf001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 01/27/2025] [Indexed: 01/31/2025] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a dynamic transdifferentiation of epithelial cells into mesenchymal cells. EMT programs exhibit great diversity, based primarily on the distinct impact of molecular activities of the EMT transcription factors. Using a panel of cancer cell lines and a series of 71 triple-negative primary breast tumors, we report that the EMT transcription factor ZEB1 modulates site-specific chemical modifications of ribosomal RNA (rRNA). Overexpression of ZEB1 and ZEB2, but not TWIST1, decreased the level of 2'-O-ribose methylation (2'Ome) of 28S rRNA at position Um2402. ZEB1 overexpression specifically reduced the expression of the corresponding C/D box small nucleolar RNAs (snoRNAs) SNORD143/144, which guide the rRNA 2'Ome complex at the 28S_Um2402 site. During ZEB1-induced EMT induction/reversion, the levels of both 2'Ome at 28S_Um2402 and SNORD143/144 were dynamically comodulated. Taken together, these data demonstrate that 2'Ome rRNA epitranscriptomics is a novel marker of ZEB1-induced EMT.
Collapse
Affiliation(s)
- Chloé Morin
- Ribosome, Translation and Cancer Team, LaEx DEVweCAN, Institut Convergence Plascan, LYriCAN+, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Hermes Paraqindes
- Ribosome, Translation and Cancer Team, LaEx DEVweCAN, Institut Convergence Plascan, LYriCAN+, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
- Bioinformatics Platform Gilles Thomas, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, Synergie Lyon Cancer Fondation, 69008 Lyon, France
| | - Flora Nguyen Van Long
- Ribosome, Translation and Cancer Team, LaEx DEVweCAN, Institut Convergence Plascan, LYriCAN+, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Caroline Isaac
- Ribosome, Translation and Cancer Team, LaEx DEVweCAN, Institut Convergence Plascan, LYriCAN+, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Emilie Thomas
- Bioinformatics Platform Gilles Thomas, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, Synergie Lyon Cancer Fondation, 69008 Lyon, France
| | - Dennis Pedri
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, 3001 Leuven, Belgium
- Laboratory for Molecular Cancer Biology, Department of Oncology, KU 3000 Leuven, Belgium
| | - Carlos Ariel Pulido-Vicuna
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, 3001 Leuven, Belgium
- Laboratory for Molecular Cancer Biology, Department of Oncology, KU 3000 Leuven, Belgium
| | - Anne-Pierre Morel
- EMT and Cancer Cell Plasticity Team, Centre Léon Bérard, 69008 Lyon, France
| | - Virginie Marchand
- UMS2008 IBSLor CNRS-INSERM-Lorraine University, Biopôle, 9 avenue de la forêt de haye, 54505 Vandoeuvre-les-Nancy, France
| | - Yuri Motorin
- UMS2008 IBSLor CNRS-INSERM-Lorraine University, Biopôle, 9 avenue de la forêt de haye, 54505 Vandoeuvre-les-Nancy, France
- IMoPA, UMR 7365 CNRS-UL, Biopole UL, 54500 Vandoeuvre-les-Nancy, France
| | - Marjorie Carrere
- Cancer Genomic Platform, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Jessie Auclair
- Cancer Genomic Platform, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Valéry Attignon
- Cancer Genomic Platform, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Roxane M Pommier
- Bioinformatics Platform Gilles Thomas, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, Synergie Lyon Cancer Fondation, 69008 Lyon, France
| | - Emmanuelle Ruiz
- Department of Pathobiological Sciences, School of Veterinary and Medicine, Louisiana State University, 70802 Baton Rouge, LA, United States
| | - Fleur Bourdelais
- RibosOMICS Platform, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Frédéric Catez
- Ribosome, Translation and Cancer Team, LaEx DEVweCAN, Institut Convergence Plascan, LYriCAN+, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Sébastien Durand
- Ribosome, Translation and Cancer Team, LaEx DEVweCAN, Institut Convergence Plascan, LYriCAN+, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
- RibosOMICS Platform, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Anthony Ferrari
- Bioinformatics Platform Gilles Thomas, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, Synergie Lyon Cancer Fondation, 69008 Lyon, France
| | - Alain Viari
- Bioinformatics Platform Gilles Thomas, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, Synergie Lyon Cancer Fondation, 69008 Lyon, France
- INRIA Grenoble Rhône-Alpes, Montbonnot-Saint-Martin 38334, France
| | - Jean-Christophe Marine
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, 3001 Leuven, Belgium
- Laboratory for Molecular Cancer Biology, Department of Oncology, KU 3000 Leuven, Belgium
| | - Alain Puisieux
- Institut Curie, PSL Research University, 75005 Paris, France
- Chemical Biology of Cancer Laboratory, CNRS UMR3666, INSERM U1143, Paris, France
| | - Jean-Jacques Diaz
- Ribosome, Translation and Cancer Team, LaEx DEVweCAN, Institut Convergence Plascan, LYriCAN+, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Caroline Moyret-Lalle
- Ribosome, Translation and Cancer Team, LaEx DEVweCAN, Institut Convergence Plascan, LYriCAN+, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Virginie Marcel
- Ribosome, Translation and Cancer Team, LaEx DEVweCAN, Institut Convergence Plascan, LYriCAN+, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
- RibosOMICS Platform, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| |
Collapse
|
|
4
|
Bajdak-Rusinek K, Diak N, Gutmajster E, Fus-Kujawa A, Stępień KL, Wójtowicz W, Kalina M, Mandera M. The EMT status in the primary tumor of adamantinomatous craniopharyngioma predict postoperative recurrence in children. Childs Nerv Syst 2024; 41:68. [PMID: 39715857 DOI: 10.1007/s00381-024-06731-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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 12/19/2024] [Indexed: 12/25/2024]
Abstract
INTRODUCTION Adamantinomatous craniopharyngiomas (ACP) are rare epithelial tumors, which by the WHO are classified as non-malignant tumors. Despite radical tumor regression, almost 57% of patients develop a craniopharyngioma recurrence. The pathogenesis of epithelial cancers involves a process called epithelial-mesenchymal transition (EMT), which is involved in tumor progression and its invasion, and the loss of E-cadherin is crucial for this process. Undoubtedly, EMT also plays a role in the progression of ACP, but there are no studies that would examine its role in predicting postoperative tumor recurrence. Therefore, in our study, we aimed to compare the expression of EMT inducers and their markers, namely E-cadherin and vimentin, in material from two groups of pediatric patients, first with postoperative ACP relapse and second without relapse. METHODS A total of 35 formalin-fixed, paraffin-embedded tissue blocks of pediatric patients (19 girls and 16 boys, from 2 to 17 years old) were included. The material was collected during craniopharyngioma resection in the years 2000-2019 and after then examined by the Department of Pathomorphology. Gene expression analysis was done using qRT-PCR. RESULTS In the studied group of 35 patients, high levels of E-cad and low levels of vimentin expression were found in patients who did not experience relapse (n = 25, p < 0.0001). The opposite was observed in patients who experienced a recurrence (n = 10, p < 0.0001). In contrast, analysis of the recurrent tissue itself showed low levels of vimentin and re-expression of E-cadherin (n = 10, p < 0.0001). Furthermore, our study shows that Snail is a key inducer of EMT in ACP. CONCLUSION We believe that the evaluation of the EMT profile in ACP could be a prognostic marker for predicting tumor recurrence in children, which would certainly contribute to a better prognosis for these patients.
Collapse
Affiliation(s)
- K Bajdak-Rusinek
- Department of Medical Genetics, Medical University of Silesia, Katowice, Poland.
| | - N Diak
- Department of Medical Genetics, Medical University of Silesia, Katowice, Poland
| | - E Gutmajster
- Biotechnology Centre, Silesian University of Technology, Gliwice, Poland
| | - A Fus-Kujawa
- Department of Medical Genetics, Medical University of Silesia, Katowice, Poland
| | - K L Stępień
- Department of Molecular Biology, Medical University of Silesia, Katowice, Poland
| | - W Wójtowicz
- Department of Medical Genetics, Medical University of Silesia, Katowice, Poland
- Students Scientific Society, Medical University of Silesia, Katowice, Poland
| | - M Kalina
- Department of Medical Genetics, Medical University of Silesia, Katowice, Poland
| | - M Mandera
- Department of Pediatric Neurosurgery, Medical University of Silesia, Katowice, Poland
| |
Collapse
|
|
5
|
Naro C, Ruta V, Sette C. Splicing dysregulation: hallmark and therapeutic opportunity in pancreatic cancer. Trends Mol Med 2024:S1471-4914(24)00308-3. [PMID: 39648052 DOI: 10.1016/j.molmed.2024.11.007] [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: 09/16/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 12/10/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by dismal prognosis. Late diagnosis, resistance to chemotherapy, and lack of efficacious targeted therapies render PDAC almost untreatable. Dysregulation of splicing, the process that excises the introns from nascent transcripts, is emerging as a hallmark of PDAC and a possible vulnerability of this devastating cancer. Splicing factors are deregulated in PDAC and contribute to all steps of tumorigenesis, from inflammation-related early events to metastasis and acquisition of chemoresistance. At the same time, splicing dysregulation offers a therapeutic opportunity to target cancer-specific vulnerabilities. We discuss mounting evidence that splicing plays a key role in PDAC and the opportunities that this essential process offers for developing new targeted therapies.
Collapse
Affiliation(s)
- Chiara Naro
- Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168 Rome, Italy; Gemelli Science and Technology Park (GSTeP) Organoids Research Core Facility, Fondazione Policlinico A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168 Rome, Italy
| | - Veronica Ruta
- Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Claudio Sette
- Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168 Rome, Italy; Gemelli Science and Technology Park (GSTeP) Organoids Research Core Facility, Fondazione Policlinico A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168 Rome, Italy.
| |
Collapse
|
|
6
|
Kinoshita S, Terai T, Nagai M, Nakamura K, Kohara Y, Yasuda S, Matsuo Y, Doi S, Sakata T, Migita K, Ouji-Sageshima N, Ito T, Sho M. Clinical significance and therapeutic implication of CD200 in pancreatic cancer. Pancreatology 2024; 24:1280-1287. [PMID: 39419752 DOI: 10.1016/j.pan.2024.10.007] [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: 03/16/2024] [Revised: 09/29/2024] [Accepted: 10/12/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND CD200, a negative regulator of T cells as well as a marker for cancer stem cells, represents a significant prognostic factor and potential therapeutic target in certain cancers. However, its clinical significance remains unknown in pancreatic ductal adenocarcinoma (PDAC). METHODS CD200 was assessed in 220 resected PDAC patients who underwent surgery with or without neoadjuvant chemoradiotherapy (NACRT). We examined the clinicopathological outcomes associated with CD200 and further assessed its clinical implications regarding immunological and cancer stem cell properties. RESULTS NACRT was associated with higher CD200 expression (66.4 % vs. 32.2 %, P < 0.001) compared to upfront surgery. CD200 was identified as an independent poor prognostic factor in NACRT (hazard ratio 1.90, 95 % confidence interval 1.12-3.23, P = 0.016), but not in upfront surgery patients. Post-recurrence survival was significantly worse in CD200+ patients compared to CD200- patients in the NACRT group, but there was no significant difference observed in the upfront surgery group. CD200 expression was correlated with significantly lower levels of CD4+, CD8+, and CD45RO+ tumor-infiltrating lymphocytes. Furthermore, the correlation of CD200 with pancreatic cancer stem cell markers CD44/CD24/ESA was stronger in irradiated human pancreatic cancer cells. CONCLUSIONS Our data underscore novel roles for CD200 in immune evasion as well as therapy resistance in pancreatic cancer. CD200 may represent a novel poor prognostic predictive factor and potential therapeutic target for PDAC with NACRT.
Collapse
Affiliation(s)
- Shoichi Kinoshita
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Taichi Terai
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Minako Nagai
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Kota Nakamura
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Yuichiro Kohara
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Satoshi Yasuda
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Yasuko Matsuo
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Shunsuke Doi
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Takeshi Sakata
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Kazuhiro Migita
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Noriko Ouji-Sageshima
- Department of Immunology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Toshihiro Ito
- Department of Immunology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Masayuki Sho
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.
| |
Collapse
|
|
7
|
Menche C, Schuhwerk H, Armstark I, Gupta P, Fuchs K, van Roey R, Mosa MH, Hartebrodt A, Hajjaj Y, Clavel Ezquerra A, Selvaraju MK, Geppert CI, Bärthel S, Saur D, Greten FR, Brabletz S, Blumenthal DB, Weigert A, Brabletz T, Farin HF, Stemmler MP. ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer. EMBO Rep 2024; 25:3406-3431. [PMID: 38937629 PMCID: PMC11315988 DOI: 10.1038/s44319-024-00186-7] [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: 04/16/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/29/2024] Open
Abstract
The EMT-transcription factor ZEB1 is heterogeneously expressed in tumor cells and in cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). While ZEB1 in tumor cells regulates metastasis and therapy resistance, its role in CAFs is largely unknown. Combining fibroblast-specific Zeb1 deletion with immunocompetent mouse models of CRC, we observe that inflammation-driven tumorigenesis is accelerated, whereas invasion and metastasis in sporadic cancers are reduced. Single-cell transcriptomics, histological characterization, and in vitro modeling reveal a crucial role of ZEB1 in CAF polarization, promoting myofibroblastic features by restricting inflammatory activation. Zeb1 deficiency impairs collagen deposition and CAF barrier function but increases NFκB-mediated cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, the Zeb1-deficient CAF repertoire sensitizes to immune checkpoint inhibition, offering a therapeutic opportunity of targeting ZEB1 in CAFs and its usage as a prognostic biomarker. Collectively, we demonstrate that ZEB1-dependent plasticity of CAFs suppresses anti-tumor immunity and promotes metastasis.
Collapse
Affiliation(s)
- Constantin Menche
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
- Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, Germany
| | - Harald Schuhwerk
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Isabell Armstark
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Pooja Gupta
- Core Unit for Bioinformatics, Data Integration and Analysis, Center for Medical Information and Communication Technology, University Hospital Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Kathrin Fuchs
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Ruthger van Roey
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Mohammed H Mosa
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
- Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, Germany
| | - Anne Hartebrodt
- Biomedical Network Science Lab, Department Artificial Intelligence in Biomedical Engineering (AIBE), FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Yussuf Hajjaj
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Ana Clavel Ezquerra
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Manoj K Selvaraju
- Core Unit for Bioinformatics, Data Integration and Analysis, Center for Medical Information and Communication Technology, University Hospital Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Carol I Geppert
- Institute of Pathology, University Hospital Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Stefanie Bärthel
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Dieter Saur
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Florian R Greten
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
- Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, Germany
- German Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany
| | - Simone Brabletz
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - David B Blumenthal
- Biomedical Network Science Lab, Department Artificial Intelligence in Biomedical Engineering (AIBE), FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Andreas Weigert
- Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany
- Institute of Biochemistry I, Goethe University, Frankfurt am Main, Germany
| | - Thomas Brabletz
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, FAU Erlangen-Nürnberg, Erlangen, Germany.
| | - Henner F Farin
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
- Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, Germany.
- German Research Center (DKFZ), Heidelberg, Germany.
- German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany.
| | - Marc P Stemmler
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, FAU Erlangen-Nürnberg, Erlangen, Germany.
| |
Collapse
|
|
8
|
Haruna T, Kudo M, Ishino K, Ueda J, Shintani-Domoto Y, Yoshimori D, Fuji T, Kawamoto Y, Teduka K, Kitamura T, Yoshida H, Ohashi R. Molecular biological role of epithelial splicing regulatory protein 1 in intrahepatic cholangiocarcinoma. Hepatol Res 2024. [PMID: 39037743 DOI: 10.1111/hepr.14096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/03/2024] [Accepted: 07/05/2024] [Indexed: 07/23/2024]
Abstract
AIM Epithelial splicing regulatory protein 1 (ESRP1) regulates tumor progression and metastasis through the epithelial‒mesenchymal transition by interacting with zinc finger E-box binding 1 (ZEB1) and CD44 in cancers. However, the role of ESRP1 in intrahepatic cholangiocarcinoma (iCCA) remains unclear. METHODS Three iCCA cell lines (HuCCT-1, SSP-25, and KKU-100) were analyzed using small interfering RNA to investigate the molecular biological functions of ESRP1 and ZEB1. The association between clinicopathological features and the expression of ESRP1 and ZEB1 in iCCA tissues was analyzed immunohistochemically. Proteomic analysis was performed to identify molecules related to ESRP1 expression. RESULTS ESRP1 expression was upregulated in HuCCT-1 and SSP-25 cells. Cell migration and invasion were enhanced, and the expression of ZEB1 and CD44s (CD44 standard) isoforms were upregulated in the ESRP1 silencing cells. Moreover, ESRP1 silencing increased the expression of N-cadherin and vimentin, indicating the presence of mesenchymal properties. Conversely, ZEB1 silencing increased the expression of ESRP1 and CD44v (CD44 variant) isoforms. Immunohistochemical analysis revealed that a lower ESRP1-to-ZEB1 expression ratio was associated with poor recurrence-free survival in patients with iCCA. Flotillin 2, a lipid raft marker related to epithelial‒mesenchymal transition, was identified as a protein related to the interactive feedback loop in proteomic analysis. CONCLUSIONS ESRP1 suppresses tumor progression in iCCA by interacting with ZEB1 and CD44 to regulate epithelial‒mesenchymal transition.
Collapse
Affiliation(s)
- Takahiro Haruna
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School Hospital, Tokyo, Japan
| | - Mitsuhiro Kudo
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
| | - Kousuke Ishino
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
| | - Junji Ueda
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School Hospital, Tokyo, Japan
| | | | - Daigo Yoshimori
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School Hospital, Tokyo, Japan
| | - Takenori Fuji
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
| | - Yoko Kawamoto
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
| | - Kiyoshi Teduka
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
| | - Taeko Kitamura
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
| | - Hiroshi Yoshida
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School Hospital, Tokyo, Japan
| | - Ryuji Ohashi
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
| |
Collapse
|
|
9
|
Bracken CP, Goodall GJ, Gregory PA. RNA regulatory mechanisms controlling TGF-β signaling and EMT in cancer. Semin Cancer Biol 2024; 102-103:4-16. [PMID: 38917876 DOI: 10.1016/j.semcancer.2024.06.001] [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: 12/15/2023] [Revised: 06/05/2024] [Accepted: 06/13/2024] [Indexed: 06/27/2024]
Abstract
Epithelial-mesenchymal transition (EMT) is a major contributor to metastatic progression and is prominently regulated by TGF-β signalling. Both EMT and TGF-β pathway components are tightly controlled by non-coding RNAs - including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) - that collectively have major impacts on gene expression and resulting cellular states. While miRNAs are the best characterised regulators of EMT and TGF-β signaling and the miR-200-ZEB1/2 feedback loop plays a central role, important functions for lncRNAs and circRNAs are also now emerging. This review will summarise our current understanding of the roles of non-coding RNAs in EMT and TGF-β signaling with a focus on their functions in cancer progression.
Collapse
Affiliation(s)
- Cameron P Bracken
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; School of Biological Sciences, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, SA 5000, Australia.
| | - Gregory J Goodall
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; School of Biological Sciences, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, SA 5000, Australia.
| | - Philip A Gregory
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia.
| |
Collapse
|
|
10
|
Zhang YE, Stuelten CH. Alternative splicing in EMT and TGF-β signaling during cancer progression. Semin Cancer Biol 2024; 101:1-11. [PMID: 38614376 PMCID: PMC11180579 DOI: 10.1016/j.semcancer.2024.04.001] [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: 05/26/2023] [Revised: 11/20/2023] [Accepted: 04/04/2024] [Indexed: 04/15/2024]
Abstract
Epithelial to mesenchymal transition (EMT) is a physiological process during development where epithelial cells transform to acquire mesenchymal characteristics, which allows them to migrate and colonize secondary tissues. Many cellular signaling pathways and master transcriptional factors exert a myriad of controls to fine tune this vital process to meet various developmental and physiological needs. Adding to the complexity of this network are post-transcriptional and post-translational regulations. Among them, alternative splicing has been shown to play important roles to drive EMT-associated phenotypic changes, including actin cytoskeleton remodeling, cell-cell junction changes, cell motility and invasiveness. In advanced cancers, transforming growth factor-β (TGF-β) is a major inducer of EMT and is associated with tumor cell metastasis, cancer stem cell self-renewal, and drug resistance. This review aims to provide an overview of recent discoveries regarding alternative splicing events and the involvement of splicing factors in the EMT and TGF-β signaling. It will emphasize the importance of various splicing factors involved in EMT and explore their regulatory mechanisms.
Collapse
Affiliation(s)
- Ying E Zhang
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
| | - Christina H Stuelten
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| |
Collapse
|
|
11
|
Geng DY, Chen QS, Chen WX, Zhou LS, Han XS, Xie QH, Guo GH, Chen XF, Chen JS, Zhong XP. Molecular targets and mechanisms of different aberrant alternative splicing in metastatic liver cancer. World J Clin Oncol 2024; 15:531-539. [PMID: 38689626 PMCID: PMC11056863 DOI: 10.5306/wjco.v15.i4.531] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/29/2024] [Accepted: 03/07/2024] [Indexed: 04/22/2024] Open
Abstract
Metastasis remains a major challenge in the successful management of malignant diseases. The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon, stomach, and pancreatic cancers, as well as melanoma, breast cancer, and sarcoma. As an important factor that influences the development of metastatic liver cancer, alternative splicing drives the diversity of RNA transcripts and protein subtypes, which may provide potential to broaden the target space. In particular, the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence, progression, aggressiveness, and drug resistance of cancers caused by the selective splicing of specific genes. This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer. It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes, abnormal splicing, and the contribution of hypoxia to these changes during metastasis.
Collapse
Affiliation(s)
- De-Yi Geng
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Qing-Shan Chen
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Wan-Xian Chen
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Lin-Sa Zhou
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Xiao-Sha Han
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Qi-Hu Xie
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Geng-Hong Guo
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Xue-Fen Chen
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Jia-Sheng Chen
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Xiao-Ping Zhong
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| |
Collapse
|
|
12
|
den Hollander P, Maddela JJ, Mani SA. Spatial and Temporal Relationship between Epithelial-Mesenchymal Transition (EMT) and Stem Cells in Cancer. Clin Chem 2024; 70:190-205. [PMID: 38175600 PMCID: PMC11246550 DOI: 10.1093/clinchem/hvad197] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 11/02/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) is often linked with carcinogenesis. However, EMT is also important for embryo development and only reactivates in cancer. Connecting how EMT occurs during embryonic development and in cancer could help us further understand the root mechanisms of cancer diseases. CONTENT There are key regulatory elements that contribute to EMT and the induction and maintenance of stem cell properties during embryogenesis, tissue regeneration, and carcinogenesis. Here, we explore the implications of EMT in the different stages of embryogenesis and tissue development. We especially highlight the necessity of EMT in the mesodermal formation and in neural crest cells. Through EMT, these cells gain epithelial-mesenchymal plasticity (EMP). With this transition, crucial morphological changes occur to progress through the metastatic cascade as well as tissue regeneration after an injury. Stem-like cells, including cancer stem cells, are generated from EMT and during this process upregulate factors necessary for stem cell maintenance. Hence, it is important to understand the key regulators allowing stem cell awakening in cancer, which increases plasticity and promotes treatment resistance, to develop strategies targeting this cell population and improve patient outcomes. SUMMARY EMT involves multifaceted regulation to allow the fluidity needed to facilitate adaptation. This regulatory mechanism, plasticity, involves many cooperating transcription factors. Additionally, posttranslational modifications, such as splicing, activate the correct isoforms for either epithelial or mesenchymal specificity. Moreover, epigenetic regulation also occurs, such as acetylation and methylation. Downstream signaling ultimately results in the EMT which promotes tissue generation/regeneration and cancer progression.
Collapse
Affiliation(s)
- Petra den Hollander
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, United States
| | - Joanna Joyce Maddela
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, United States
| | - Sendurai A Mani
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, United States
| |
Collapse
|
|
13
|
Liu YN, Tsai MF, Wu SG, Chang TH, Shih JY. CD44s and CD44v8-10 isoforms confer acquired resistance to osimertinib by activating the ErbB3/STAT3 signaling pathway. Life Sci 2024; 336:122345. [PMID: 38092140 DOI: 10.1016/j.lfs.2023.122345] [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: 10/01/2023] [Revised: 11/24/2023] [Accepted: 12/06/2023] [Indexed: 12/17/2023]
Abstract
AIMS Although epidermal growth factor receptor (EGFR)-mutant lung cancers respond well to osimertinib, acquired resistance to osimertinib eventually develops through EGFR-dependent and EGFR-independent resistance mechanisms. CD44 splicing variants are widely expressed in lung cancer tissues. However, it remains unclear whether specific splicing variants are involved in acquired resistance to osimertinib. MAIN METHODS The real-time PCR was performed to measure the expression levels of total CD44 and specific CD44 splicing variants (CD44s or CD44v). Gene knockdown and restoration were performed to investigate the effects of CD44 splicing variants on osimertinib sensitivity. Activation of the signaling pathway was evaluated using receptor-tyrosine-kinase phosphorylation membrane arrays, co-immunoprecipitation, and western blotting. KEY FINDINGS Clinical analysis demonstrated that the expression level of total CD44 increased in primary cancer cells from lung adenocarcinomas patients after the development of acquired resistance to osimertinib. Furthermore, osimertinib-resistant cells showed elevated levels of either the CD44s variant or CD44v variants. Manipulations of CD44s or CD44v8-10 were performed to investigate their effects on treatment sensitivity to osimertinib. Knockdown of CD44 increased osimertinib-induced cell death in osimertinib-resistant cells. However, restoration of CD44s or CD44v8-10 in CD44-knockdown H1975/AZD-sgCD44 cells induced osimertinib resistance. Mechanically, we showed that ErbB3 interacted with CD44 and was transactivated by CD44, that consequently triggered activation of the ErbB3/STAT3 signaling pathway and led to CD44s- or CD44v8-10-mediated osimertinib resistance. SIGNIFICANCE CD44 is a co-receptor for ErbB3 and triggers activation of the ErbB3 signaling axis, leading to acquired resistance to osimertinib. CD44/ErbB3 signaling may represent a therapeutic target for overcoming osimertinib resistance.
Collapse
Affiliation(s)
- Yi-Nan Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Meng-Feng Tsai
- Department of Biomedical Sciences, Da-Yeh University, Changhua, Taiwan
| | - Shang-Gin Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Tzu-Hua Chang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jin-Yuan Shih
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
| |
Collapse
|
|
14
|
Merckens A, Sieler M, Keil S, Dittmar T. Altered Phenotypes of Breast Epithelial × Breast Cancer Hybrids after ZEB1 Knock-Out. Int J Mol Sci 2023; 24:17310. [PMID: 38139138 PMCID: PMC10744253 DOI: 10.3390/ijms242417310] [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: 10/30/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
ZEB1 plays a pivotal role in epithelial-to-mesenchymal transition (EMT), (cancer) cell stemness and cancer therapy resistance. The M13HS tumor hybrids, which were derived from spontaneous fusion events between the M13SV1-EGFP-Neo breast epithelial cells and HS578T-Hyg breast cancer cells, express ZEB1 and exhibit prospective cancer stem cell properties. To explore a possible correlation between the ZEB1 and stemness/ EMT-related properties in M13HS tumor hybrids, ZEB1 was knocked-out by CRISPR/Cas9. Colony formation, mammosphere formation, cell migration, invasion assays, flow cytometry and Western blot analyses were performed for the characterization of ZEB1 knock-out cells. The ZEB1 knock-out in M13HS tumor cells was not correlated with the down-regulation of the EMT-related markers N-CADHERIN (CDH2) and VIMENTIN and up-regulation of miR-200c-3p. Nonetheless, both the colony formation and mammosphere formation capacities of the M13HS ZEB1 knock-out cells were markedly reduced. Interestingly, the M13HS-2 ZEB1-KO cells harbored a markedly higher fraction of ALDH1-positive cells. The Transwell/ Boyden chamber migration assay data indicated a reduced migratory activity of the M13HS ZEB1-knock-out tumor hybrids, whereas in scratch/ wound-healing assays only the M13SH-8 ZEB1-knock-out cells possessed a reduced locomotory activity. Similarly, only the M13HS-8 ZEB1-knock-out tumor hybrids showed a reduced invasion capacity. Although the ZEB1 knock-out resulted in only moderate phenotypic changes, our data support the role of ZEB1 in EMT and stemness.
Collapse
Affiliation(s)
| | | | | | - Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58448 Witten, Germany; (A.M.); (M.S.); (S.K.)
| |
Collapse
|
|
15
|
Deng H, Gao J, Cao B, Qiu Z, Li T, Zhao R, Li H, Wei B. LncRNA CCAT2 promotes malignant progression of metastatic gastric cancer through regulating CD44 alternative splicing. Cell Oncol (Dordr) 2023; 46:1675-1690. [PMID: 37354353 DOI: 10.1007/s13402-023-00835-4] [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] [Accepted: 05/30/2023] [Indexed: 06/26/2023] Open
Abstract
OBJECTIVE Gastric cancer (GC) is one of the most malignant tumors worldwide. Thus, it is necessary to explore the underlying mechanisms of GC progression and develop novel therapeutic regimens. Long non-coding RNAs (lncRNAs) have been demonstrated to be abnormally expressed and regulate the malignant behaviors of cancer cells. Our previous research demonstrated that lncRNA colon cancer-associated transcript 2 (CCAT2) has potential value for GC diagnosis and discrimination. However, the functional mechanisms of lncRNA CCAT2 in GC development remain to be explored. METHODS GC and normal adjacent tissues were collected to detect the expression of lncRNA CCAT2, ESRP1 and CD44 in clinical specimens and their clinical significance for GC patients. Cell counting kit-8, wound healing and transwell assays were conducted to investigate the malignant behaviors in vitro. The generation of nude mouse xenografts by subcutaneous, intraperitoneal and tail vein injection was performed to examine GC growth and metastasis in vivo. Co-immunoprecipitation, RNA-binding protein pull-down assay and fluorescence in situ hybridization were performed to reveal the binding relationships between ESRP1 and CD44. RESULTS In the present study, lncRNA CCAT2 was overexpressed in GC tissues compared to adjacent normal tissues and correlated with short survival time of patients. lncRNA CCAT2 promoted the proliferation, migration and invasion of GC cells. Its overexpression modulates alternative splicing of Cluster of differentiation 44 (CD44) variants and facilitates the conversion from the standard form to variable CD44 isoform 6 (CD44v6). Mechanistically, lncRNA CCAT2 upregulated CD44v6 expression by binding to epithelial splicing regulatory protein 1 (ESRP1), which subsequently mediates CD44 alternative splicing. The oncogenic role of the lncRNA CCAT2/ESRP1/CD44 axis in the promotion of malignant behaviors was verified by both in vivo and in vitro experiments. CONCLUSIONS Our findings identified a novel mechanism by which lncRNA CCAT2, as a type of protein-binding RNA, regulates alternative splicing of CD44 and promotes GC progression. This axis may become an effective target for clinical diagnosis and treatment.
Collapse
Affiliation(s)
- Huan Deng
- Department of Gastrointestinal Surgery, Peking University First Hospital, Beijing, 100034, China
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Jingwang Gao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Bo Cao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Ziyu Qiu
- Health Service Department of the Guard Bureau of the General Office of the Central Committee of the Communist Party of China, Beijing, 100091, China
| | - Tian Li
- School of Basic Medicine, The Fourth Military Medical University, Xi'an, 710021, China
| | - Ruiyang Zhao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Hanghang Li
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Bo Wei
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China.
- Medical School of Chinese PLA, Beijing, 100853, China.
| |
Collapse
|
|
16
|
Maltseva D, Tonevitsky A. RNA-binding proteins regulating the CD44 alternative splicing. Front Mol Biosci 2023; 10:1326148. [PMID: 38106992 PMCID: PMC10722200 DOI: 10.3389/fmolb.2023.1326148] [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: 10/22/2023] [Accepted: 11/15/2023] [Indexed: 12/19/2023] Open
Abstract
Alternative splicing is often deregulated in cancer, and cancer-specific isoform switches are part of the oncogenic transformation of cells. Accumulating evidence indicates that isoforms of the multifunctional cell-surface glycoprotein CD44 play different roles in cancer cells as compared to normal cells. In particular, the shift of CD44 isoforms is required for epithelial to mesenchymal transition (EMT) and is crucial for the maintenance of pluripotency in normal human cells and the acquisition of cancer stem cells phenotype for malignant cells. The growing and seemingly promising use of splicing inhibitors for treating cancer and other pathologies gives hope for the prospect of using such an approach to regulate CD44 alternative splicing. This review integrates current knowledge about regulating CD44 alternative splicing by RNA-binding proteins.
Collapse
Affiliation(s)
- Diana Maltseva
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia
| | - Alexander Tonevitsky
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| |
Collapse
|
|
17
|
Doustmihan A, Fathi M, Mazloomi M, Salemi A, Hamblin MR, Jahanban-Esfahlan R. Molecular targets, therapeutic agents and multitasking nanoparticles to deal with cancer stem cells: A narrative review. J Control Release 2023; 363:57-83. [PMID: 37739017 DOI: 10.1016/j.jconrel.2023.09.029] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 09/08/2023] [Accepted: 09/17/2023] [Indexed: 09/24/2023]
Abstract
There is increasing evidence that malignant tumors are initiated and maintained by a sub-population of tumor cells that have similar biological properties to normal adult stem cells. This very small population of Cancer Stem Cells (CSC) comprises tumor initiating cells responsible for cancer recurrence, drug resistance and metastasis. Conventional treatments such as chemotherapy, radiotherapy and surgery, in addition to being potentially toxic and non-specific, may paradoxically increase the population, spread and survival of CSCs. Next-generation sequencing and omics technologies are increasing our understanding of the pathways and factors involved in the development of CSCs, and can help to discover new therapeutic targets against CSCs. In addition, recent advances in nanomedicine have provided hope for the development of optimal specific therapies to eradicate CSCs. Moreover, the use of artificial intelligence and nano-informatics can elucidate new drug targets, and help to design drugs and nanoparticles (NPs) to deal with CSCs. In this review, we first summarize the properties of CSCs and describe the signaling pathways and molecular characteristics responsible for the emergence and survival of CSCs. Also, the location of CSCs within the tumor and the effect of host factors on the creation and maintenance of CSCs are discussed. Newly discovered molecular targets involved in cancer stemness and some novel therapeutic compounds to combat CSCs are highlighted. The optimum properties of anti-CSC NPs, including blood circulation and stability, tumor accumulation and penetration, cellular internalization, drug release, endosomal escape, and aptamers designed for specific targeting of CSCs are covered. Finally, some recent smart NPs designed for therapeutic and theranostic purposes to overcome CSCs are discussed.
Collapse
Affiliation(s)
- Abolfazl Doustmihan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marziyeh Fathi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - MirAhmad Mazloomi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysan Salemi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
| | - Rana Jahanban-Esfahlan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
18
|
Genetta T, Hurwitz J, Clark E, Herold B, Khalil S, Abbas T, Larner J. ZEB1 promotes non-homologous end joining double-strand break repair. Nucleic Acids Res 2023; 51:9863-9879. [PMID: 37665026 PMCID: PMC10570029 DOI: 10.1093/nar/gkad723] [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: 07/20/2022] [Revised: 07/31/2023] [Accepted: 08/21/2023] [Indexed: 09/05/2023] Open
Abstract
Repair of DSB induced by IR is primarily carried out by Non-Homologous End Joining (NHEJ), a pathway in which 53BP1 plays a key role. We have discovered that the EMT-inducing transcriptional repressor ZEB1 (i) interacts with 53BP1 and that this interaction occurs rapidly and is significantly amplified following exposure of cells to IR; (ii) is required for the localization of 53BP1 to a subset of double-stranded breaks, and for physiological DSB repair; (iii) co-localizes with 53BP1 at IR-induced foci (IRIF); (iv) promotes NHEJ and inhibits Homologous Recombination (HR); (v) depletion increases resection at DSBs and (vi) confers PARP inhibitor (PARPi) sensitivity on BRCA1-deficient cells. Lastly, ZEB1's effects on repair pathway choice, resection, and PARPi sensitivity all rely on its homeodomain. In contrast to the well-characterized therapeutic resistance of high ZEB1-expressing cancer cells, the novel ZEB1-53BP1-shieldin resection axis described here exposes a therapeutic vulnerability: ZEB1 levels in BRCA1-deficient tumors may serve as a predictive biomarker of response to PARPis.
Collapse
Affiliation(s)
- Thomas L Genetta
- Dept. of Radiation Oncology, University of Virginia School of Medicine, PO Box 800383, Charlottesville, VA 22908, USA
| | - Joshua C Hurwitz
- Dept. of Radiation Oncology, University of Virginia School of Medicine, PO Box 800383, Charlottesville, VA 22908, USA
| | - Evan A Clark
- Dept. of Radiation Oncology, University of Virginia School of Medicine, PO Box 800383, Charlottesville, VA 22908, USA
| | - Benjamin T Herold
- Dept. of Radiation Oncology, University of Virginia School of Medicine, PO Box 800383, Charlottesville, VA 22908, USA
| | - Shadi Khalil
- Dept. of Radiation Oncology, University of Virginia School of Medicine, PO Box 800383, Charlottesville, VA 22908, USA
| | - Tarek Abbas
- Dept. of Radiation Oncology, University of Virginia School of Medicine, PO Box 800383, Charlottesville, VA 22908, USA
- Dept. of Biochemistry and Molecular Genetics University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - James M Larner
- Dept. of Radiation Oncology, University of Virginia School of Medicine, PO Box 800383, Charlottesville, VA 22908, USA
| |
Collapse
|
|
19
|
Radhakrishnan K, Truong L, Carmichael CL. An "unexpected" role for EMT transcription factors in hematological development and malignancy. Front Immunol 2023; 14:1207360. [PMID: 37600794 PMCID: PMC10435889 DOI: 10.3389/fimmu.2023.1207360] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 07/14/2023] [Indexed: 08/22/2023] Open
Abstract
The epithelial to mesenchymal transition (EMT) is a fundamental developmental process essential for normal embryonic development. It is also important during various pathogenic processes including fibrosis, wound healing and epithelial cancer cell metastasis and invasion. EMT is regulated by a variety of cell signalling pathways, cell-cell interactions and microenvironmental cues, however the key drivers of EMT are transcription factors of the ZEB, TWIST and SNAIL families. Recently, novel and unexpected roles for these EMT transcription factors (EMT-TFs) during normal blood cell development have emerged, which appear to be largely independent of classical EMT processes. Furthermore, EMT-TFs have also begun to be implicated in the development and pathogenesis of malignant hematological diseases such as leukemia and lymphoma, and now present themselves or the pathways they regulate as possible new therapeutic targets within these malignancies. In this review, we discuss the ZEB, TWIST and SNAIL families of EMT-TFs, focusing on what is known about their normal roles during hematopoiesis as well as the emerging and "unexpected" contribution they play during development and progression of blood cancers.
Collapse
Affiliation(s)
- Karthika Radhakrishnan
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Lynda Truong
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Catherine L. Carmichael
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Monash University, Faculty of Medicine, Nursing and Health Sciences, Clayton, VIC, Australia
| |
Collapse
|
|
20
|
Saini M, Schmidleitner L, Moreno HD, Donato E, Falcone M, Bartsch JM, Klein C, Vogel V, Würth R, Pfarr N, Espinet E, Lehmann M, Königshoff M, Reitberger M, Haas S, Graf E, Schwarzmayr T, Strom TM, Spaich S, Sütterlin M, Schneeweiss A, Weichert W, Schotta G, Reichert M, Aceto N, Sprick MR, Trumpp A, Scheel CH. Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer. Cell Rep 2023; 42:112533. [PMID: 37257449 DOI: 10.1016/j.celrep.2023.112533] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 10/04/2022] [Accepted: 05/03/2023] [Indexed: 06/02/2023] Open
Abstract
The acquisition of mesenchymal traits is considered a hallmark of breast cancer progression. However, the functional relevance of epithelial-to-mesenchymal transition (EMT) remains controversial and context dependent. Here, we isolate epithelial and mesenchymal populations from human breast cancer metastatic biopsies and assess their functional potential in vivo. Strikingly, progressively decreasing epithelial cell adhesion molecule (EPCAM) levels correlate with declining disease propagation. Mechanistically, we find that persistent EPCAM expression marks epithelial clones that resist EMT induction and propagate competitively. In contrast, loss of EPCAM defines clones arrested in a mesenchymal state, with concomitant suppression of tumorigenicity and metastatic potential. This dichotomy results from distinct clonal trajectories impacting global epigenetic programs that are determined by the interplay between human ZEB1 and its target GRHL2. Collectively, our results indicate that susceptibility to irreversible EMT restrains clonal propagation, whereas resistance to mesenchymal reprogramming sustains disease spread in multiple models of human metastatic breast cancer, including patient-derived cells in vivo.
Collapse
Affiliation(s)
- Massimo Saini
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany; Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
| | - Laura Schmidleitner
- Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany; Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Center for Functional Protein Assemblies (CPA), Technical University of Munich (TUM), Garching, Germany; Center for Organoid Systems (COS), Technical University of Munich (TUM), Garching, Germany; Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), Garching, Germany
| | - Helena Domínguez Moreno
- Division of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilian University of Munich (LMU), Munich, Germany
| | - Elisa Donato
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Mattia Falcone
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Johanna M Bartsch
- Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany
| | - Corinna Klein
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Vanessa Vogel
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Roberto Würth
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Nicole Pfarr
- Institute of Pathology, Technical University of Munich (TUM), Munich, Germany
| | - Elisa Espinet
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Mareike Lehmann
- Institute for Lung Health and Immunity (LHI) and Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Germany; Institute for Lung Research, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany
| | - Melanie Königshoff
- Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Member of the German Center of Lung Research (DZL), Munich, Germany
| | - Manuel Reitberger
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Simon Haas
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Elisabeth Graf
- Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany
| | - Thomas Schwarzmayr
- Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany
| | - Tim-Matthias Strom
- Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany
| | - Saskia Spaich
- Department of Gynaecology and Obstetrics, University Women's Clinic, University Medical Centre Mannheim, Mannheim, Germany
| | - Marc Sütterlin
- Department of Gynaecology and Obstetrics, University Women's Clinic, University Medical Centre Mannheim, Mannheim, Germany
| | - Andreas Schneeweiss
- National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Wilko Weichert
- Institute of Pathology, Technical University of Munich (TUM), Munich, Germany; German Cancer Consortium (DKTK), Germany
| | - Gunnar Schotta
- Division of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilian University of Munich (LMU), Munich, Germany
| | - Maximilian Reichert
- Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Center for Functional Protein Assemblies (CPA), Technical University of Munich (TUM), Garching, Germany; Center for Organoid Systems (COS), Technical University of Munich (TUM), Garching, Germany; Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), Garching, Germany; German Cancer Consortium (DKTK), Germany
| | - Nicola Aceto
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Martin R Sprick
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; German Cancer Consortium (DKTK), Germany.
| | - Andreas Trumpp
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; German Cancer Consortium (DKTK), Germany.
| | - Christina H Scheel
- Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany.
| |
Collapse
|
|
21
|
Yehya A, Youssef J, Hachem S, Ismael J, Abou-Kheir W. Tissue-specific cancer stem/progenitor cells: Therapeutic implications. World J Stem Cells 2023; 15:323-341. [PMID: 37342220 PMCID: PMC10277968 DOI: 10.4252/wjsc.v15.i5.323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/14/2023] [Accepted: 04/12/2023] [Indexed: 05/26/2023] Open
Abstract
Surgical resection, chemotherapy, and radiation are the standard therapeutic modalities for treating cancer. These approaches are intended to target the more mature and rapidly dividing cancer cells. However, they spare the relatively quiescent and intrinsically resistant cancer stem cells (CSCs) subpopulation residing within the tumor tissue. Thus, a temporary eradication is achieved and the tumor bulk tends to revert supported by CSCs' resistant features. Based on their unique expression profile, the identification, isolation, and selective targeting of CSCs hold great promise for challenging treatment failure and reducing the risk of cancer recurrence. Yet, targeting CSCs is limited mainly by the irrelevance of the utilized cancer models. A new era of targeted and personalized anti-cancer therapies has been developed with cancer patient-derived organoids (PDOs) as a tool for establishing pre-clinical tumor models. Herein, we discuss the updated and presently available tissue-specific CSC markers in five highly occurring solid tumors. Additionally, we highlight the advantage and relevance of the three-dimensional PDOs culture model as a platform for modeling cancer, evaluating the efficacy of CSC-based therapeutics, and predicting drug response in cancer patients.
Collapse
Affiliation(s)
- Amani Yehya
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Joe Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Sana Hachem
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Jana Ismael
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon.
| |
Collapse
|
|
22
|
Verstappe J, Berx G. A role for partial epithelial-to-mesenchymal transition in enabling stemness in homeostasis and cancer. Semin Cancer Biol 2023; 90:15-28. [PMID: 36773819 DOI: 10.1016/j.semcancer.2023.02.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/19/2023] [Accepted: 02/02/2023] [Indexed: 02/12/2023]
Abstract
Stem cells have self-renewal capacities and the ability to give rise to differentiated cells thereby sustaining tissues during homeostasis and injury. This structural hierarchy extends to tumours which harbor stem-like cells deemed cancer stem cells that propagate the tumour and drive metastasis and relapse. The process of epithelial-to-mesenchymal transition (EMT), which plays an important role in development and cancer cell migration, was shown to be correlated with stemness in both homeostasis and cancer indicating that stemness can be acquired and is not necessarily an intrinsic trait. Nowadays it is experimentally proven that the activation of an EMT program does not necessarily drive cells towards a fully mesenchymal phenotype but rather to hybrid E/M states. This review offers the latest advances in connecting the EMT status and stem-cell state of both non-transformed and cancer cells. Recent literature clearly shows that hybrid EMT states have a higher probability of acquiring stem cell traits. The position of a cell along the EMT-axis which coincides with a stem cell-like state is known as the stemness window. We show how the original EMT-state of a cell dictates the EMT/MET inducing programmes required to reach stemness. Lastly we present the mechanism of stemness regulation and the regulatory feedback loops which position cells at a certain EMT state along the EMT axis.
Collapse
Affiliation(s)
- Jeroen Verstappe
- Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Geert Berx
- Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
| |
Collapse
|
|
23
|
Fratini L, Dalmolin MGS, Sinigaglia M, da Silveira Perla A, de Farias CB, Brunetto AL, Brunetto AT, da Cunha Jaeger M, Roesler R. ZEB1 is a Subgroup-Specific Marker of Prognosis and Potential Drug Target in Medulloblastoma. Neuromolecular Med 2023; 25:64-74. [PMID: 35716340 DOI: 10.1007/s12017-022-08716-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: 01/20/2022] [Accepted: 05/02/2022] [Indexed: 10/18/2022]
Abstract
Medulloblastoma (MB) is a malignant brain tumor that afflicts mostly children and adolescents and presents four distinct molecular subgroups, known as WNT, SHH, Group 3, and Group 4. ZEB1 is a transcription factor that promotes the expression of mesenchymal markers while restraining expression of epithelial and polarity genes. Because of ZEB1 involvement in cerebellum development, here we investigated the role of ZEB1 in MB. We found increased expression of ZEB1 in MB tumor samples compared to normal cerebellar tissue. Expression was higher in the SHH subgroup when compared to all other MB molecular subgroups. High ZEB1 expression was associated with poor prognosis in Group 3 and Group 4, whereas in patients with WNT tumors poorer prognosis were related to lower ZEB1 expression. There was a moderate correlation between ZEB1 and MYC expression in Group 3 and Group 4 MB. Treatment with the immunomodulator and histone deacetylase (HDAC) inhibitor fingolimod (FTY720) reduced ZEB1 expression specifically in D283 cells, which are representative of Group 3 and Group 4 MB. These findings reveal novel subgroup-specific associations of ZEB1 expression with survival in patients with MB and suggest that ZEB1 expression can be reduced by pharmacological agents that target HDAC activity.
Collapse
Affiliation(s)
- Livia Fratini
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.
- Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90050-170, Brazil.
- Graduate Program in Cellular and Molecular Biology, Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, RS, 91501-970, Brazil.
| | - Matheus Gibeke Siqueira Dalmolin
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil
- Children's Cancer Institute, Porto Alegre, RS, 90620-110, Brazil
| | - Marialva Sinigaglia
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil
- Children's Cancer Institute, Porto Alegre, RS, 90620-110, Brazil
| | - Alexandre da Silveira Perla
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil
- Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90050-170, Brazil
- Neurology Service, São José Hospital, Santa Casa de Misericórdia Porto Alegre Hospital Complex, Porto Alegre, RS, 90020-090, Brazil
| | - Caroline Brunetto de Farias
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil
- Children's Cancer Institute, Porto Alegre, RS, 90620-110, Brazil
| | - Algemir L Brunetto
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil
- Children's Cancer Institute, Porto Alegre, RS, 90620-110, Brazil
| | - André T Brunetto
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil
- Children's Cancer Institute, Porto Alegre, RS, 90620-110, Brazil
| | - Mariane da Cunha Jaeger
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil
- Children's Cancer Institute, Porto Alegre, RS, 90620-110, Brazil
| | - Rafael Roesler
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.
- Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90050-170, Brazil.
- Graduate Program in Cellular and Molecular Biology, Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, RS, 91501-970, Brazil.
| |
Collapse
|
|
24
|
Antón-García P, Haghighi EB, Rose K, Vladimirov G, Boerries M, Hecht A. TGFβ1-Induced EMT in the MCF10A Mammary Epithelial Cell Line Model Is Executed Independently of SNAIL1 and ZEB1 but Relies on JUNB-Coordinated Transcriptional Regulation. Cancers (Basel) 2023; 15:558. [PMID: 36672507 PMCID: PMC9856774 DOI: 10.3390/cancers15020558] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 01/11/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) fosters cancer cell invasion and metastasis, the main cause of cancer-related mortality. Growing evidence that SNAIL and ZEB transcription factors, typically portrayed as master regulators of EMT, may be dispensable for this process, led us to re-investigate its mechanistic underpinnings. For this, we used an unbiased computational approach that integrated time-resolved analyses of chromatin structure and differential gene expression, to predict transcriptional regulators of TGFβ1-inducible EMT in the MCF10A mammary epithelial cell line model. Bioinformatic analyses indicated comparatively minor contributions of SNAIL proteins and ZEB1 to TGFβ1-induced EMT, whereas the AP-1 subunit JUNB was anticipated to have a much larger impact. CRISPR/Cas9-mediated loss-of-function studies confirmed that TGFβ1-induced EMT proceeded independently of SNAIL proteins and ZEB1. In contrast, JUNB was necessary and sufficient for EMT in MCF10A cells, but not in A549 lung cancer cells, indicating cell-type-specificity of JUNB EMT-regulatory capacity. Nonetheless, the JUNB-dependence of EMT-associated transcriptional reprogramming in MCF10A cells allowed to define a gene expression signature which was regulated by TGFβ1 in diverse cellular backgrounds, showed positively correlated expression with TGFβ signaling in multiple cancer transcriptomes, and was predictive of patient survival in several cancer types. Altogether, our findings provide novel mechanistic insights into the context-dependent control of TGFβ1-driven EMT and thereby may lead to improved diagnostic and therapeutic options.
Collapse
Affiliation(s)
- Pablo Antón-García
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Elham Bavafaye Haghighi
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Katja Rose
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Georg Vladimirov
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Andreas Hecht
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
- BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
| |
Collapse
|
|
25
|
Underlying mechanisms of epithelial splicing regulatory proteins in cancer progression. J Mol Med (Berl) 2022; 100:1539-1556. [PMID: 36163376 DOI: 10.1007/s00109-022-02257-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/31/2022] [Accepted: 09/12/2022] [Indexed: 12/14/2022]
Abstract
Cancer is the second-leading disease-related cause of global mortality after cardiovascular disease. Despite significant advances in cancer therapeutic strategies, cancer remains one of the major obstacles to human life extension. Cancer pathogenesis is extremely complicated and not fully understood. Epithelial splicing regulatory proteins (ESRPs), including ESRP1 and ESRP2, belong to the heterogeneous nuclear ribonucleoprotein family of RNA-binding proteins and are crucial regulators of the alternative splicing of messenger RNAs (mRNAs). The expression and activity of ESRPs are modulated by various mechanisms, including post-translational modifications and non-coding RNAs. Although a growing body of evidence suggests that ESRP dysregulation is closely associated with cancer progression, the detailed mechanisms remain inconclusive. In this review, we summarize recent findings on the structures, functions, and regulatory mechanisms of ESRPs and focus on their underlying mechanisms in cancer progression. We also highlight the clinical implications of ESRPs as prognostic biomarkers and therapeutic targets in cancer treatment. The information reviewed herein could be extremely beneficial to the development of individualized therapeutic strategies for cancer patients.
Collapse
|
|
26
|
ZEB1: Catalyst of immune escape during tumor metastasis. Biomed Pharmacother 2022; 153:113490. [DOI: 10.1016/j.biopha.2022.113490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/23/2022] [Accepted: 07/27/2022] [Indexed: 11/20/2022] Open
|
|
27
|
Wang D, Li Y, Ge H, Ghadban T, Reeh M, Güngör C. The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC. Cancers (Basel) 2022; 14:cancers14163998. [PMID: 36010993 PMCID: PMC9406497 DOI: 10.3390/cancers14163998] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is rich in dense fibrotic stroma that are composed of extracellular matrix (ECM) proteins. A disruption of the balance between ECM synthesis and secretion and the altered expression of matrix remodeling enzymes lead to abnormal ECM dynamics in PDAC. This pathological ECM promotes cancer growth, survival, invasion, and alters the behavior of fibroblasts and immune cells leading to metastasis formation and chemotherapy resistance, which contribute to the high lethality of PDAC. Additionally, recent evidence highlights that ECM, as a major structural component of the tumor microenvironment, is a highly dynamic structure in which ECM proteins establish a physical and biochemical niche for cancer stem cells (CSCs). CSCs are characterized by self-renewal, tumor initiation, and resistance to chemotherapeutics. In this review, we will discuss the effects of the ECM on tumor biological behavior and its molecular impact on the fundamental signaling pathways in PDAC. We will also provide an overview of how the different ECM components are able to modulate CSCs properties and finally discuss the current and ongoing therapeutic strategies targeting the ECM. Given the many challenges facing current targeted therapies for PDAC, a better understanding of molecular events involving the interplay of ECM and CSC will be key in identifying more effective therapeutic strategies to eliminate CSCs and ultimately to improve survival in patients that are suffering from this deadly disease.
Collapse
|
|
28
|
N6-methyladenosine-mediated CELF2 regulates CD44 alternative splicing affecting tumorigenesis via ERAD pathway in pancreatic cancer. Cell Biosci 2022; 12:125. [PMID: 35941702 PMCID: PMC9361702 DOI: 10.1186/s13578-022-00844-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 07/07/2022] [Indexed: 11/10/2022] Open
Abstract
Background Alternative splicing (AS) of genes has been found to affect gene stability, and its abnormal regulation can lead to tumorigenesis. CELF2 is a vital splicing factor to participate in mRNA alternative splicing. Its downregulation has been confirmed to promote the occurrence and development of pancreatic cancer (PC). However, the regulatory role and mechanisms in PC has not been elucidated. Results CELF2 was downregulated in PC tissues, which affected tumor TNM stage and tumor size, and low expression of CELF2 indicated a poor prognosis of PC. In vivo and in vitro experiments showed that abnormal expression of CELF2 affected the stemness, apoptosis, and proliferation of PC cells. Furthmore, we also found that CELF2 was targeted by ALKBH5 for m6A modification, leading to CELF2 degradation by YTHDF2. Bioinformatic analysis of AS model based on the TCGA database indicated that CELF2 could target CD44 to form different spliceosomes, thereby affecting the biological behavior of PC cells. The conversion of CD44s to CD44V is the key to tumorigenesis. Transcriptomic analysis was conducted to reveal the mechanism of CELF2-mediated CD44 AS in PC. We found that CELF2-mediated splicing of CD44 led to changes in the level of endoplasmic reticulum stress, further regulating the endoplasmic reticulum-associated degradation (ERAD) signaling pathway, thereby affecting apoptosis and cell stemness. In addition, ERAD signaling pathway inhibitor, EerI, could effectively reverse the effect of CD44 on tumors. Conclusions This study indicates that N6-methyladenosine-mediated CELF2 promotes AS of CD44, affecting the ERAD pathway and regulating the biological behavior of PC cells. CELF2 is expected to be a new target for targeted-drug development. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00844-0.
Collapse
|
|
29
|
Poodineh J, Sirati-Sabet M, Rajabibazl M, Ghasemian M, Mohammadi-Yeganeh S. Downregulation of NRARP exerts anti-tumor activities in the breast tumor cells depending on Wnt/ꞵ-catenin mediated signals; the role of miR-130a-3p. Chem Biol Drug Des 2022; 100:334-345. [PMID: 35797350 DOI: 10.1111/cbdd.14113] [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: 04/09/2022] [Revised: 06/12/2022] [Accepted: 07/03/2022] [Indexed: 12/01/2022]
Abstract
OBJECTIVES The Notch-regulated ankyrin repeat protein (NRARP) functions as a molecular link between Notch and Wnt signaling pathways. Although it has recently been identified to be overexpressed in breast cancer (BC), the molecular mechanisms that regulate NRARP remain unknown. Since microRNAs (miRNAs) regulate gene expression post-transcriptionally, miRNA dysregulation could explain the abnormal gene expression. Here, we identified miR-130a-3p as an NRARP regulator and evaluated its effects on the behavior of BC cells. METHODS Quantitative real-time PCR (qRT-PCR) was performed to assess the transcriptional levels of miR-130a-3p and NRARP in BC cells. Next, miR-130a-3p was transiently transfected into BC cells to assess its influence on NRARP expression. Owing to the positive regulatory effects of NRARP on the Wnt/β-catenin signaling pathway, we also analyzed the expression levels of five Wnt/β-catenin pathway genes and one downstream target gene in BC cells. We then assessed anti-tumor activities of miR-130a-3p in BC cells using the MTT proliferation assay, the soft agar colony formation assay for anchorage-independent growth (AIG), as well as scratch and transwell assays for cell migration. RESULTS miR-130a-3p was found to be downregulated in BC cells, whereas NRARP was upregulated. Overexpression of miR-130a-3p inhibited the expression of NRARP and some Wnt/β-catenin signaling pathway genes, as well as exerted anti-tumor effects as evidenced by decreased cell proliferation, AIG, and migration of BC cells. CONCLUSION In conclusion, the tumor suppressive function of miR-130a-3p in BC may be mediated by inhibiting NRARP and Wnt/β-catenin signaling pathway. As a result, miR-130a-3p could be introduced as a therapeutic target for miRNA therapy in BC.
Collapse
Affiliation(s)
- Jafar Poodineh
- Department of Clinical Biochemistry, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Majid Sirati-Sabet
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoumeh Rajabibazl
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Ghasemian
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samira Mohammadi-Yeganeh
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
30
|
Regulation of Tissue Factor by CD44 Supports Coagulant Activity in Breast Tumor Cells. Cancers (Basel) 2022; 14:cancers14133288. [PMID: 35805061 PMCID: PMC9266039 DOI: 10.3390/cancers14133288] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 06/29/2022] [Accepted: 07/01/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Metastasis and thromboembolic complications are the main cause of cancer-associated death. An overexpression of coagulation factors, and particularly Tissue factor, by tumor cells is a key event implicated in this observed hypercoagulability. Tissue Factor is indeed a cellular initiator of the coagulation cascade which has been associated with aggressive tumor phenotypes such as those characteristic of Epithelial-Mesenchymal Transitions (EMTs) and Cancer Stem Cells (CSCs). Understanding molecular mechanisms controlling Tissue Factor overexpression in those tumor phenotypes is thus an important aspect of cancer research. We show here that CD44 (a transmembrane marker of CSC and EMT phenotypes) contributes to regulate TF expression at a transcriptional level, thereby supporting procoagulant properties in tumor cells that facilitate their metastatic spread. Abstract Previous work identified Tissue Factor (TF), a key activator of the coagulation cascade, as a gene induced in cellular contexts of Epithelial-Mesenchymal Transitions (EMTs), providing EMT+ Circulating Tumor Cells (CTCs) with coagulant properties that facilitate their metastatic seeding. Deciphering further molecular aspects of TF regulation in tumor cells, we report here that CD44 and TF coexpress in EMT contexts, and that CD44 acts as a regulator of TF expression supporting procoagulant properties and metastatic seeding. A transcriptional regulatory mechanism bridging CD44 to TF expression was further evidenced. Comparing different TF –promoter luciferase reporter constructs, we indeed found that the shortest -111 pb TF promoter fragment harboring three Specificity Protein 1 (Sp1) binding sites is still responsive to CD44 silencing. The observation that (i) mutation within Sp1 binding sites decreased the basal activity of the -111 pb TF promoter construct, (ii) CD44 silencing decreased Sp1 protein and mRNA levels and (iii) Sp1 silencing diminished TF expression further points to Sp1 as a key mediator linking CD44 to TF regulation. All together, these data thus report a transcriptional regulatory mechanism of TF expression by CD44 supporting procoagulant activity and metastatic competence of CTCs.
Collapse
|
|
31
|
Role of CD44 isoforms in epithelial-mesenchymal plasticity and metastasis. Clin Exp Metastasis 2022; 39:391-406. [PMID: 35023031 PMCID: PMC10042269 DOI: 10.1007/s10585-022-10146-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/03/2022] [Indexed: 01/21/2023]
Abstract
Cellular plasticity lies at the core of cancer progression, metastasis, and resistance to treatment. Stemness and epithelial-mesenchymal plasticity in cancer are concepts that represent a cancer cell's ability to coopt and adapt normal developmental programs to promote survival and expansion. The cancer stem cell model states that a small subset of cancer cells with stem cell-like properties are responsible for driving tumorigenesis and metastasis while remaining especially resistant to common chemotherapeutic drugs. Epithelial-mesenchymal plasticity describes a cancer cell's ability to transition between epithelial and mesenchymal phenotypes which drives invasion and metastasis. Recent research supports the existence of stable epithelial/mesenchymal hybrid phenotypes which represent highly plastic states with cancer stem cell characteristics. The cell adhesion molecule CD44 is a widely accepted marker for cancer stem cells, and it lies at a functional intersection between signaling networks regulating both stemness and epithelial-mesenchymal plasticity. CD44 expression is complex, with alternative splicing producing many isoforms. Interestingly, not only does the pattern of isoform expression change during transitions between epithelial and mesenchymal phenotypes in cancer, but these isoforms have distinct effects on cell behavior including the promotion of metastasis and stemness. The role of CD44 both downstream and upstream of signaling pathways regulating epithelial-mesenchymal plasticity and stemness make this protein a valuable target for further research and therapeutic intervention.
Collapse
|
|
32
|
Gu W, Shen H, Xie L, Zhang X, Yang J. The Role of Feedback Loops in Targeted Therapy for Pancreatic Cancer. Front Oncol 2022; 12:800140. [PMID: 35651786 PMCID: PMC9148955 DOI: 10.3389/fonc.2022.800140] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 04/11/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic cancer is the leading cause of cancer-related deaths worldwide, with limited treatment options and low long-term survival rates. The complex and variable signal regulation networks are one of the important reasons why it is difficult for pancreatic cancer to develop precise targeted therapy drugs. Numerous studies have associated feedback loop regulation with the development and therapeutic response of cancers including pancreatic cancer. Therefore, we review researches on the role of feedback loops in the progression of pancreatic cancer, and summarize the connection between feedback loops and several signaling pathways in pancreatic cancer, as well as recent advances in the intervention of feedback loops in pancreatic cancer treatment, highlighting the potential of capitalizing on feedback loops modulation in targeted therapy for pancreatic cancer.
Collapse
Affiliation(s)
- Weigang Gu
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - HongZhang Shen
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lu Xie
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaofeng Zhang
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- *Correspondence: Xiaofeng Zhang, ; Jianfeng Yang,
| | - Jianfeng Yang
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Xiaofeng Zhang, ; Jianfeng Yang,
| |
Collapse
|
|
33
|
Perez-Oquendo M, Gibbons DL. Regulation of ZEB1 Function and Molecular Associations in Tumor Progression and Metastasis. Cancers (Basel) 2022; 14:cancers14081864. [PMID: 35454770 PMCID: PMC9031734 DOI: 10.3390/cancers14081864] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 02/08/2023] Open
Abstract
Zinc finger E-box binding homeobox 1 (ZEB1) is a pleiotropic transcription factor frequently expressed in carcinomas. ZEB1 orchestrates the transcription of genes in the control of several key developmental processes and tumor metastasis via the epithelial-to-mesenchymal transition (EMT). The biological function of ZEB1 is regulated through pathways that influence its transcription and post-transcriptional mechanisms. Diverse signaling pathways converge to induce ZEB1 activity; however, only a few studies have focused on the molecular associations or functional changes of ZEB1 by post-translational modifications (PTMs). Due to the robust effect of ZEB1 as a transcription repressor of epithelial genes during EMT, the contribution of PTMs in the regulation of ZEB1-targeted gene expression is an active area of investigation. Herein, we review the pivotal roles that phosphorylation, acetylation, ubiquitination, sumoylation, and other modifications have in regulating the molecular associations and behavior of ZEB1. We also outline several questions regarding the PTM-mediated regulation of ZEB1 that remain unanswered. The areas of research covered in this review are contributing to new treatment strategies for cancer by improving our mechanistic understanding of ZEB1-mediated EMT.
Collapse
Affiliation(s)
- Mabel Perez-Oquendo
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Don L. Gibbons
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence: ; Tel.: +1-713-792-6363
| |
Collapse
|
|
34
|
Gulla A, Andriusaityte U, Zdanys GT, Babonaite E, Strupas K, Kelly H. The Impact of Epithelial-Mesenchymal Transition and Metformin on Pancreatic Cancer Chemoresistance: A Pathway towards Individualized Therapy. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:467. [PMID: 35454306 PMCID: PMC9032206 DOI: 10.3390/medicina58040467] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/14/2022] [Accepted: 03/21/2022] [Indexed: 12/26/2022]
Abstract
Globally, pancreatic ductal adenocarcinoma remains among the most aggressive forms of neoplastic diseases, having a dismal prognostic outcome. Recent findings elucidated that epithelial-mesenchymal transition (EMT) can play an important role in pancreatic tumorigenic processes, as it contributes to the manifestation of malignant proliferative masses, which impede adequate drug delivery. An organized literature search with PubMed, Scopus, Microsoft Academic and the Cochrane library was performed for articles published in English from 2011 to 2021 to review and summarize the latest updates and knowledge on the current understanding of EMT and its implications for tumorigenesis and chemoresistance. Furthermore, in the present paper, we investigate the recent findings on metformin as a possible neoadjuvant chemotherapy agent, which affects EMT progression and potentially provides superior oncological outcomes for PDAC patients. Our main conclusions indicate that selectively suppressing EMT in pancreatic cancer cells has a promising therapeutic utility by selectively targeting the chemotherapy-resistant sub-population of cancer stem cells, inhibiting tumor growth via EMT pathways and thereby improving remission in PDAC patients. Moreover, given that TGF-β1-driven EMT generates the migration of tumor-initiating cells by directly linking the acquisition of abnormal cellular motility with the maintenance of tumor initiating potency, the chemoprevention of TGF-β1-induced EMT may have promising clinical applications in the therapeutic management of PDAC outcomes.
Collapse
Affiliation(s)
- Aiste Gulla
- Institute of Clinical Medicine, Clinic of Gastroenterology, Surgery, Nephrology, Faculty of Medicine, Vilnius University, Santariskiu Str. 2, 08661 Vilnius, Lithuania;
- Center of Visceral Medicine and Translational Research, Department of Surgery, Georgetown University Hospital, 3800 Reservoir Road Northwest BLES Building 1st. Floor, Washington, DC 20007, USA
| | - Urte Andriusaityte
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Gabrielius Tomas Zdanys
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Elena Babonaite
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Kestutis Strupas
- Institute of Clinical Medicine, Clinic of Gastroenterology, Surgery, Nephrology, Faculty of Medicine, Vilnius University, Santariskiu Str. 2, 08661 Vilnius, Lithuania;
| | - Helena Kelly
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, 123 St. Stephen’s Green, D02 YN77 Dublin, Ireland;
| |
Collapse
|
|
35
|
Lyu J, Cheng C. Regulation of Alternative Splicing during Epithelial-Mesenchymal Transition. Cells Tissues Organs 2022; 211:238-251. [PMID: 34348273 PMCID: PMC8741878 DOI: 10.1159/000518249] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/28/2021] [Indexed: 01/03/2023] Open
Abstract
Alternative splicing is an essential mechanism of gene regulation, giving rise to remarkable protein diversity in higher eukaryotes. Epithelial-mesenchymal transition (EMT) is a developmental process that plays an essential role in metazoan embryogenesis. Recent studies have revealed that alternative splicing serves as a fundamental layer of regulation that governs cells to undergo EMT. In this review, we summarize recent findings on the functional impact of alternative splicing in EMT and EMT-associated activities. We then discuss the regulatory mechanisms that control alternative splicing changes during EMT.
Collapse
Affiliation(s)
- Jingyi Lyu
- Lester and Sue Smith Breast Center, Department of Molecular
& Human Genetics, Department of Molecular & Cellular Biology, Baylor College
of Medicine, Houston, TX 77030, USA,Integrative Molecular and Biomedical Sciences Graduate
Program, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chonghui Cheng
- Lester and Sue Smith Breast Center, Department of Molecular
& Human Genetics, Department of Molecular & Cellular Biology, Baylor College
of Medicine, Houston, TX 77030, USA,Integrative Molecular and Biomedical Sciences Graduate
Program, Baylor College of Medicine, Houston, TX 77030, USA.,To whom correspondence should be addressed:
| |
Collapse
|
|
36
|
van Roey R, Brabletz T, Stemmler MP, Armstark I. Deregulation of Transcription Factor Networks Driving Cell Plasticity and Metastasis in Pancreatic Cancer. Front Cell Dev Biol 2021; 9:753456. [PMID: 34888306 PMCID: PMC8650502 DOI: 10.3389/fcell.2021.753456] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/27/2021] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is a very aggressive disease with 5-year survival rates of less than 10%. The constantly increasing incidence and stagnant patient outcomes despite changes in treatment regimens emphasize the requirement of a better understanding of the disease mechanisms. Challenges in treating pancreatic cancer include diagnosis at already progressed disease states due to the lack of early detection methods, rapid acquisition of therapy resistance, and high metastatic competence. Pancreatic ductal adenocarcinoma, the most prevalent type of pancreatic cancer, frequently shows dominant-active mutations in KRAS and TP53 as well as inactivation of genes involved in differentiation and cell-cycle regulation (e.g. SMAD4 and CDKN2A). Besides somatic mutations, deregulated transcription factor activities strongly contribute to disease progression. Specifically, transcriptional regulatory networks essential for proper lineage specification and differentiation during pancreas development are reactivated or become deregulated in the context of cancer and exacerbate progression towards an aggressive phenotype. This review summarizes the recent literature on transcription factor networks and epigenetic gene regulation that play a crucial role during tumorigenesis.
Collapse
Affiliation(s)
- Ruthger van Roey
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Thomas Brabletz
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Marc P Stemmler
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Isabell Armstark
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| |
Collapse
|
|
37
|
Liu Y, Li J, Ding H, Ge D, Wang J, Xu C. Perfluorooctane sulfonate (PFOS) triggers migration and invasion of esophageal squamous cell carcinoma cells via regulation of Zeb1. Drug Chem Toxicol 2021; 45:2804-2813. [PMID: 34732098 DOI: 10.1080/01480545.2021.1991775] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent and deadly cancers worldwide, especially in Eastern Asia. As a potential endocrine-disrupting chemical (EDC), perfluorooctane sulfonate (PFOS) can mimic estrogen, disturb the estrogen signals, and then cause various diseases. Although ESCC can be directly exposed to PFOS during food digestion, the effects and mechanisms of PFOS on the development of ESCC are still not well illustrated. This study showed that PFOS can promote the migration and invasion of ESCC cells. Further, PFOS treatment can increase the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, while decreasing the expression of E-Cadherin (E-Cad). Zeb1, an important transcription factor for cell motility, was essential for PFOS induced migration and invasion of ESCC cells. PFOS can increase the expression of Zeb1 via upregulation of its transcription and proteins stability. A-kinase interacting protein 1 (AKIP1) and ataxia-telangiectasia mutated (ATM) were responsible for PFOS induced transcription and proteins stability of Zeb1 in ESCC cells, respectively. Collectively, our data indicated that environmental exposure and body accumulation of PFOS might be an important risk factor for ESCC progression.
Collapse
Affiliation(s)
- Yaqing Liu
- Internal Medicine Department, The First People's Hospital of Shangqiu, Shangqiu, P. R. China.,Department of Gastroenterology, Shangqiu Clinical College, Xuzhou Medical University, Shangqiu, P. R. China
| | - Jian Li
- Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou, P. R. China
| | - Hui Ding
- Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou, P. R. China
| | - Dahe Ge
- Internal Medicine Department, The First People's Hospital of Shangqiu, Shangqiu, P. R. China.,Department of Gastroenterology, Shangqiu Clinical College, Xuzhou Medical University, Shangqiu, P. R. China
| | - Juntao Wang
- Internal Medicine Department, The First People's Hospital of Shangqiu, Shangqiu, P. R. China
| | - Chunjin Xu
- Internal Medicine Department, The First People's Hospital of Shangqiu, Shangqiu, P. R. China.,Department of Gastroenterology, Shangqiu Clinical College, Xuzhou Medical University, Shangqiu, P. R. China
| |
Collapse
|
|
38
|
Osuna de la Peña D, Trabulo SMD, Collin E, Liu Y, Sharma S, Tatari M, Behrens D, Erkan M, Lawlor RT, Scarpa A, Heeschen C, Mata A, Loessner D. Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology. Nat Commun 2021; 12:5623. [PMID: 34561461 PMCID: PMC8463670 DOI: 10.1038/s41467-021-25921-9] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 08/25/2021] [Indexed: 12/11/2022] Open
Abstract
Patient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches.
Collapse
Affiliation(s)
- David Osuna de la Peña
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Institute of Bioengineering, Queen Mary University of London, London, UK
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK
| | | | - Estelle Collin
- Institute of Bioengineering, Queen Mary University of London, London, UK
| | - Ying Liu
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Institute of Bioengineering, Queen Mary University of London, London, UK
| | - Shreya Sharma
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, University of London, London, UK
| | - Marianthi Tatari
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Diana Behrens
- EPO - Experimental Pharmacology and Oncology GmbH, Berlin, Germany
| | - Mert Erkan
- Department of Surgery, Koç University School of Medicine, Istanbul, Turkey
- Koç University Translational Research Center - KUTTAM, Istanbul, Turkey
| | - Rita T Lawlor
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
- ARC-Net, Applied Research on Cancer Centre, University of Verona, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
- ARC-Net, Applied Research on Cancer Centre, University of Verona, Verona, Italy
| | - Christopher Heeschen
- Center for Single-Cell Omics, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Laboratory of Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.
| | - Alvaro Mata
- Institute of Bioengineering, Queen Mary University of London, London, UK.
- School of Pharmacy, University of Nottingham, Nottingham, UK.
- Department of Chemical and Environmental Engineering, University of Nottingham, Nottingham, UK.
- Biodiscovery Institute, University of Nottingham, Nottingham, UK.
| | - Daniela Loessner
- Barts Cancer Institute, Queen Mary University of London, London, UK.
- Department of Chemical Engineering, Faculty of Engineering, Monash University, Melbourne, VIC, Australia.
- Department of Materials Science and Engineering, Faculty of Engineering, Monash University, Melbourne, VIC, Australia.
- Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.
| |
Collapse
|
|
39
|
Na L, Wang Z, Bai Y, Sun Y, Dong D, Wang W, Zhao C. WNT7B represses epithelial-mesenchymal transition and stem-like properties in bladder urothelial carcinoma. Biochim Biophys Acta Mol Basis Dis 2021; 1868:166271. [PMID: 34562599 DOI: 10.1016/j.bbadis.2021.166271] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 09/01/2021] [Accepted: 09/15/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Recurrence and metastasis are the major problems of bladder urothelial carcinoma, which mainly attribute to tumor cell stemness, epithelial-mesenchymal transition (EMT) and chemoresistance. METHODS TCGA database was interrogated for gene mRNA expression in bladder urothelial carcinoma samples. CCLE database was interrogated for gene mRNA expression in bladder cancer cell lines. The correlation between two genes was analyzed by Pearson statistics. 37 human bladder urothelial carcinoma specimens were adopted for immunohistochemistry. Bladder cancer cells RT4, J82, and UM-UC-3 were used to carry out loss and gain of function studies. Kaplan-Meier method was performed to analyze the overall survival. FINDINGS WNT7B is downregulated in high-grade bladder urothelial carcinomas. Low WNT7B expression is associated with unfavorable prognosis. Loss and gain of function studies showed that WNT7B inhibits bladder urothelial carcinoma cell EMT, stem-like properties and chemoresistance. FZD5, a specific receptor for WNT7B, mediates WNT7B signaling. ELF3 is a downstream component of WNT7B signaling, which transcriptionally modulates NOTCH1, a tumor suppressor in bladder urothelial carcinoma. INTERPRETATION These data demonstrate that WNT7B/FZD5-ELF3-NOTCH1 signaling functions as a tumor-suppressing pathway in bladder urothelial carcinoma.
Collapse
Affiliation(s)
- Lei Na
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China; Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhuo Wang
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yu Bai
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China; Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu Sun
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Dan Dong
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Wei Wang
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China.
| | - Chenghai Zhao
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China.
| |
Collapse
|
|
40
|
Patil K, Khan FB, Akhtar S, Ahmad A, Uddin S. The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance. Cancer Metastasis Rev 2021; 40:691-720. [PMID: 34453639 PMCID: PMC8556195 DOI: 10.1007/s10555-021-09979-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ''tumor debulking'' rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting 'natural agents' that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.
Collapse
Affiliation(s)
- Kalyani Patil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Farheen B Khan
- Department of Biology, College of Science, The United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates
| | - Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
- Laboratory Animal Research Center, Qatar University, Doha, Qatar.
| |
Collapse
|
|
41
|
Lv D, Chen L, Du L, Zhou L, Tang H. Emerging Regulatory Mechanisms Involved in Liver Cancer Stem Cell Properties in Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:691410. [PMID: 34368140 PMCID: PMC8339910 DOI: 10.3389/fcell.2021.691410] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/01/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and one of the leading causes of cancer-related deaths worldwide. A growing body of evidence supports the hypothesis that HCC is driven by a population of cells called liver cancer stem cells (LCSCs). LCSCs have been proposed to contribute to malignant HCC progression, including promoting tumor occurrence and growth, mediating tumor metastasis, and treatment resistance, but the regulatory mechanism of LCSCs in HCC remains unclear. Understanding the signaling pathways responsible for LCSC maintenance and survival may provide opportunities to improve patient outcomes. Here, we review the current literature about the origin of LCSCs and the niche composition, describe the current evidence of signaling pathways that mediate LCSC stemness, then highlight several mechanisms that modulate LCSC properties in HCC progression, and finally, summarize the new developments in therapeutic strategies targeting LCSCs markers and regulatory pathways.
Collapse
Affiliation(s)
- Duoduo Lv
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Liyu Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lingyun Zhou
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy and Center of Infectious Diseases, Division of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| |
Collapse
|
|
42
|
Wu Y, Liu Z, Wei X, Feng H, Hu B, Liu B, Luan Y, Ruan Y, Liu X, Liu Z, Wang S, Liu J, Wang T. Identification of the Functions and Prognostic Values of RNA Binding Proteins in Bladder Cancer. Front Genet 2021; 12:574196. [PMID: 34239534 PMCID: PMC8258248 DOI: 10.3389/fgene.2021.574196] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 05/19/2021] [Indexed: 12/01/2022] Open
Abstract
Post-transcriptional regulation plays a leading role in gene regulation and RNA binding proteins (RBPs) are the most important posttranscriptional regulatory protein. RBPs had been found to be abnormally expressed in a variety of tumors and is closely related to its occurrence and progression. However, the exact mechanism of RBPs in bladder cancer (BC) is unknown. We downloaded transcriptomic data of BC from the Cancer Genome Atlas (TCGA) database and used bioinformatics techniques for subsequent analysis. A total of 116 differentially expressed RBPs were selected, among which 61 were up-regulated and 55 were down-regulated. We then identified 12 prognostic RBPs including CTIF, CTU1, DARS2, ENOX1, IGF2BP2, LIN28A, MTG1, NOVA1, PPARGC1B, RBMS3, TDRD1, and ZNF106, and constructed a prognostic risk score model. Based on this model we found that patients in the high-risk group had poorer overall survival (P < 0.001), and the area under the receiver operator characteristic curve for this model was 0.677 for 1 year, 0.697 for 3 years, and 0.709 for 5 years. Next, we drew a nomogram based on the risk score and other clinical variables, which showed better predictive performance. Our findings contribute to a better understanding of the pathogenesis, progression and metastasis of BC. The model of these 12 genes has good predictive value and may have good prospects for improving clinical treatment regimens and patient prognosis.
Collapse
Affiliation(s)
- Yue Wu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zheng Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xian Wei
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huan Feng
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bintao Hu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Luan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yajun Ruan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaming Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuo Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaogang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
43
|
Pancreas morphogenesis and homeostasis depends on tightly regulated Zeb1 levels in epithelial cells. Cell Death Discov 2021; 7:138. [PMID: 34112759 PMCID: PMC8192546 DOI: 10.1038/s41420-021-00522-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/26/2021] [Accepted: 05/13/2021] [Indexed: 02/08/2023] Open
Abstract
The pancreas is comprised of exocrine and endocrine compartments releasing digestive enzymes into the duodenum and regulating blood glucose levels by insulin and glucagon release. Tissue homeostasis is depending on transcription factor networks, involving Ptf1α, Ngn3, Nkx6.1, and Sox9, which are already activated during organogenesis. However, proper organ function is challenged by diets of high sugar and fat content, increasing the risk of type 2 diabetes and other disorders. A detailed understanding of processes that are important for homeostasis and are impaired during type 2 diabetes is lacking. Here, we show that Zeb1—a transcription factor known for its pivotal role in epithelial-mesenchymal transition, cell plasticity, and metastasis in cancer—is expressed at low levels in epithelial cells of the pancreas and is crucial for organogenesis and pancreas function. Loss of Zeb1 in these cells result in an increase of islet mass, impaired glucose tolerance, and sensitizes to develop liver and pancreas steatosis during diabetes and obesity. Interestingly, moderate overexpression of Zeb1 results in severe pancreas agenesis and lethality after birth, due to islet insufficiency and lack of acinar structures. We show that Zeb1 induction interferes with proper differentiation, cell survival, and proliferation during pancreas formation, due to deregulated expression of endocrine-specific transcription factors. In summary, our analysis suggests a novel role of Zeb1 for homeostasis in epithelial cells that is indispensable for pancreas morphogenesis and proper organ function involving a tight regulation of Zeb1 expression.
Collapse
|
|
44
|
Yang L, Xia H, Smith K, Gilbertsen A, Beisang D, Kuo J, Bitterman PB, Henke CA. A CD44/Brg1 nuclear complex confers mesenchymal progenitor cells with enhanced fibrogenicity in idiopathic pulmonary fibrosis. JCI Insight 2021; 6:144652. [PMID: 33822772 PMCID: PMC8262361 DOI: 10.1172/jci.insight.144652] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 03/25/2021] [Indexed: 12/22/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease. We previously identified fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of patients with IPF who serve as drivers of progressive fibrosis. Recent single-cell RNA sequencing work revealed that IPF MPCs with the highest transcriptomic network entropy differ the most from control MPCs and that increased CD44 was a marker of these IPF MPCs. We hypothesize that IPF MPCs with high CD44 (CD44hi) expression will display enhanced fibrogenicity. We demonstrate that CD44-expressing MPCs are present at the periphery of the IPF fibroblastic focus, placing them in regions of active fibrogenesis. In a humanized mouse xenograft model, CD44hi IPF MPCs are more fibrogenic than CD44lo IPF MPCs, and knockdown of CD44 diminishes their fibrogenicity. CD44hi IPF MPCs display increased expression of pluripotency markers and enhanced self-renewal compared with CD44lo IPF MPCs, properties potentiated by IL-8. The mechanism involves the accumulation of CD44 within the nucleus, where it associates with the chromatin modulator protein Brahma-related gene 1 (Brg1) and the zinc finger E-box binding homeobox 1 (Zeb1) transcription factor. This CD44/Brg1/Zeb1 nuclear protein complex targets the Sox2 gene, promoting its upregulation and self-renewal. Our data implicate CD44 interaction with the epigenetic modulator protein Brg1 in conveying IPF MPCs with cell-autonomous fibrogenicity.
Collapse
Affiliation(s)
| | | | | | | | - Daniel Beisang
- Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | | | | | | |
Collapse
|
|
45
|
Wu Y, Wei X, Feng H, Hu B, Liu B, Luan Y, Ruan Y, Liu X, Liu Z, Wang S, Liu J, Wang T. Transcriptome Analyses Identify an RNA Binding Protein Related Prognostic Model for Clear Cell Renal Cell Carcinoma. Front Genet 2021; 11:617872. [PMID: 33488680 PMCID: PMC7817999 DOI: 10.3389/fgene.2020.617872] [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] [Received: 10/15/2020] [Accepted: 12/07/2020] [Indexed: 01/16/2023] Open
Abstract
RNA binding proteins (RBPs) play a key role in post-transcriptional gene regulation. They have been shown to be dysfunctional in a variety of cancers and are closely related to the occurrence and progression of cancers. However, the biological function and clinical significance of RBPs in clear cell renal carcinoma (ccRCC) are unclear. In our current study, we downloaded the transcriptome data of ccRCC patients from The Cancer Genome Atlas (TCGA) database and identified differential expression of RBPs between tumor tissue and normal kidney tissue. Then the biological function and clinical value of these RBPs were explored by using a variety of bioinformatics techniques. We identified a total of 40 differentially expressed RBPs, including 10 down-regulated RBPs and 30 up-regulated RBPs. Eight RBPs (APOBEC3G, AUH, DAZL, EIF4A1, IGF2BP3, NR0B1, RPL36A, and TRMT1) and nine RBPs (APOBEC3G, AUH, DDX47, IGF2BP3, MOV10L1, NANOS1, PIH1D3, TDRD9, and TRMT1) were identified as prognostic related to overall survival (OS) and disease-free survival (DFS), respectively, and prognostic models for OS and DFS were constructed based on these RBPs. Further analysis showed that OS and DFS were worse in high-risk group than in the low-risk group. The area under the receiver operator characteristic curve of the model for OS was 0.702 at 3 years and 0.726 at 5 years in TCGA cohort and 0.783 at 3 years and 0.795 at 5 years in E-MTAB-1980 cohort, showing good predictive performance. Both models have been shown to independently predict the prognosis of ccRCC patients. We also established a nomogram based on these prognostic RBPs for OS and performed internal validation in the TCGA cohort, showing an accurate prediction of ccRCC prognosis. Stratified analysis showed a significant correlation between the prognostic model for OS and ccRCC progression.
Collapse
Affiliation(s)
- Yue Wu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xian Wei
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huan Feng
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bintao Hu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Luan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yajun Ruan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaming Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuo Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaogang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
46
|
Alternative splicing modulates cancer aggressiveness: role in EMT/metastasis and chemoresistance. Mol Biol Rep 2021; 48:897-914. [PMID: 33400075 DOI: 10.1007/s11033-020-06094-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 12/15/2020] [Indexed: 12/11/2022]
Abstract
Enhanced metastasis and disease recurrence accounts for the high mortality rates associated with cancer. The process of Epithelial-Mesenchymal Transition (EMT) contributes towards the augmentation of cancer invasiveness along with the gain of stem-like and the subsequent drug-resistant behavior. Apart from the well-established transcriptional regulation, EMT is also controlled post-transcriptionally by virtue of alternative splicing (AS). Numerous genes including Fibroblast Growth Factor receptor (FGFR) as well as CD44 are differentially spliced during this trans-differentiation process which, in turn, governs cancer progression. These splicing alterations are controlled by various splicing factors including ESRP, RBFOX2 as well as hnRNPs. Here, we have depicted the mechanisms governing the splice isoform switching of FGFR and CD44. Moreover, the role of the splice variants generated by AS of these gene transcripts in modulating the metastatic potential and stem-like/chemoresistant behavior of cancer cells has also been highlighted. Additionally, the involvement of splicing factors in regulating EMT/invasiveness along with drug-resistance as well as the metabolic properties of the cells has been emphasized. Tumorigenesis is accompanied by a remodeling of the cellular splicing profile generating diverse protein isoforms which, in turn, control the cancer-associated hallmarks. Therefore, we have also briefly discussed about a wide variety of genes which are differentially spliced in the tumor cells and promote cancer progression. We have also outlined different strategies for targeting the tumor-associated splicing events which have shown promising results and therefore this approach might be useful in developing therapies to reduce cancer aggressiveness in a more specific manner.
Collapse
|
|
47
|
Pasani S, Sahoo S, Jolly MK. Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology. J Clin Med 2020; 10:E60. [PMID: 33375334 PMCID: PMC7794989 DOI: 10.3390/jcm10010060] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/20/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023] Open
Abstract
Metastasis remains an unsolved clinical challenge. Two crucial features of metastasizing cancer cells are (a) their ability to dynamically move along the epithelial-hybrid-mesenchymal spectrum and (b) their tumor initiation potential or stemness. With increasing functional characterization of hybrid epithelial/mesenchymal (E/M) phenotypes along the spectrum, recent in vitro and in vivo studies have suggested an increasing association of hybrid E/M phenotypes with stemness. However, the mechanistic underpinnings enabling this association remain unclear. Here, we develop a mechanism-based mathematical modeling framework that interrogates the emergent nonlinear dynamics of the coupled network modules regulating E/M plasticity (miR-200/ZEB) and stemness (LIN28/let-7). Simulating the dynamics of this coupled network across a large ensemble of parameter sets, we observe that hybrid E/M phenotype(s) are more likely to acquire stemness relative to "pure" epithelial or mesenchymal states. We also integrate multiple "phenotypic stability factors" (PSFs) that have been shown to stabilize hybrid E/M phenotypes both in silico and in vitro-such as OVOL1/2, GRHL2, and NRF2-with this network, and demonstrate that the enrichment of hybrid E/M phenotype(s) with stemness is largely conserved in the presence of these PSFs. Thus, our results offer mechanistic insights into recent experimental observations of hybrid E/M phenotype(s) that are essential for tumor initiation and highlight how this feature is embedded in the underlying topology of interconnected EMT (Epithelial-Mesenchymal Transition) and stemness networks.
Collapse
Affiliation(s)
- Satwik Pasani
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India; (S.P.); (S.S.)
| | - Sarthak Sahoo
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India; (S.P.); (S.S.)
- Undergraduate Programme, Indian Institute of Science, Bangalore 560012, India
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India; (S.P.); (S.S.)
| |
Collapse
|
|
48
|
Hass R, von der Ohe J, Ungefroren H. The Intimate Relationship Among EMT, MET and TME: A T(ransdifferentiation) E(nhancing) M(ix) to Be Exploited for Therapeutic Purposes. Cancers (Basel) 2020; 12:3674. [PMID: 33297508 PMCID: PMC7762343 DOI: 10.3390/cancers12123674] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/03/2020] [Accepted: 12/03/2020] [Indexed: 12/12/2022] Open
Abstract
Intratumoral heterogeneity is considered the major cause of drug unresponsiveness in cancer and accumulating evidence implicates non-mutational resistance mechanisms rather than genetic mutations in its development. These non-mutational processes are largely driven by phenotypic plasticity, which is defined as the ability of a cell to reprogram and change its identity (phenotype switching). Tumor cell plasticity is characterized by the reactivation of developmental programs that are closely correlated with the acquisition of cancer stem cell properties and an enhanced potential for retrodifferentiation or transdifferentiation. A well-studied mechanism of phenotypic plasticity is the epithelial-mesenchymal transition (EMT). Current evidence suggests a complex interplay between EMT, genetic and epigenetic alterations, and clues from the tumor microenvironment in cell reprogramming. A deeper understanding of the connections between stem cell, epithelial-mesenchymal, and tumor-associated reprogramming events is crucial to develop novel therapies that mitigate cell plasticity and minimize the evolution of tumor heterogeneity, and hence drug resistance. Alternatively, vulnerabilities exposed by tumor cells when residing in a plastic or stem-like state may be exploited therapeutically, i.e., by converting them into less aggressive or even postmitotic cells. Tumor cell plasticity thus presents a new paradigm for understanding a cancer's resistance to therapy and deciphering its underlying mechanisms.
Collapse
Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Hendrik Ungefroren
- First Department of Medicine, UKSH, Campus Lübeck, 23538 Lübeck, Germany;
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, UKSH, Campus Kiel, 24105 Kiel, Germany
| |
Collapse
|
|
49
|
Tanabe A, Kimura K, Tazawa H, Maruo T, Taguchi M, Sahara H. Functional analysis of CD44 variants and xCT in canine tumours. Vet Med Sci 2020; 7:577-585. [PMID: 33210459 PMCID: PMC8025623 DOI: 10.1002/vms3.397] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 10/12/2020] [Accepted: 11/02/2020] [Indexed: 01/17/2023] Open
Abstract
The cell surface glycoprotein CD44 has various types of splicing variants, which contribute to its multiple distinct cellular functions. Recently, it was reported that the CD44v8‐10 isoform interacts with the system Xc(‐) transporter‐related protein (xCT), and inhibits the accumulation of reactive oxygen species by promoting the synthesis of the antioxidant glutathione in human tumour cells. In this study, we investigated the expression and function of CD44 variants and xCT in canine tumours. From semi‐quantitative reverse transcription polymerase chain reaction analysis, the mRNA expression of the CD44v8‐10 isoform was observed in canine tumour tissues as well as human cases. The overexpression of CD44v8‐10 may promote the synthesis of glutathione and enhance the resistance to radiation of canine breast tumour cells. Furthermore, canine xCT mRNA expression was significantly upregulated in the canine breast tumour tissues as compared to the normal tissues surrounding the tumours. To investigate the function of canine xCT, we treated canine tumour cells with the xCT inhibitor sulfasalazine. Consequently, the sulfasalazine‐treated cells were more sensitive to oxidative stress than the non‐treated cells. Taken together, these results suggested that CD44v8‐10 and xCT play important roles in the therapy resistance of canine tumours as well as human tumours.
Collapse
Affiliation(s)
- Atsushi Tanabe
- Laboratory of Biology, School of Veterinary Medicine, Azabu University, Kanagawa, Japan
| | - Kento Kimura
- Laboratory of Biology, School of Veterinary Medicine, Azabu University, Kanagawa, Japan
| | - Hana Tazawa
- Laboratory of Biology, School of Veterinary Medicine, Azabu University, Kanagawa, Japan
| | - Takuya Maruo
- Veterinary Teaching Hospital, Azabu University, Sagamihara, Japan
| | - Masayuki Taguchi
- Laboratory of Biology, School of Veterinary Medicine, Azabu University, Kanagawa, Japan
| | - Hiroeki Sahara
- Laboratory of Biology, School of Veterinary Medicine, Azabu University, Kanagawa, Japan
| |
Collapse
|
|
50
|
Saxena K, Jolly MK, Balamurugan K. Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis. Transl Oncol 2020; 13:100845. [PMID: 32781367 PMCID: PMC7419667 DOI: 10.1016/j.tranon.2020.100845] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/12/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a cellular biological process involved in migration of primary cancer cells to secondary sites facilitating metastasis. Besides, EMT also confers properties such as stemness, drug resistance and immune evasion which can aid a successful colonization at the distant site. EMT is not a binary process; recent evidence suggests that cells in partial EMT or hybrid E/M phenotype(s) can have enhanced stemness and drug resistance as compared to those undergoing a complete EMT. Moreover, partial EMT enables collective migration of cells as clusters of circulating tumor cells or emboli, further endorsing that cells in hybrid E/M phenotypes may be the 'fittest' for metastasis. Here, we review mechanisms and implications of hybrid E/M phenotypes, including their reported association with hypoxia. Hypoxia-driven activation of HIF-1α can drive EMT. In addition, cyclic hypoxia, as compared to acute or chronic hypoxia, shows the highest levels of active HIF-1α and can augment cancer aggressiveness to a greater extent, including enriching for a partial EMT phenotype. We also discuss how metastasis is influenced by hypoxia, partial EMT and collective cell migration, and call for a better understanding of interconnections among these mechanisms. We discuss the known regulators of hypoxia, hybrid EMT and collective cell migration and highlight the gaps which needs to be filled for connecting these three axes which will increase our understanding of dynamics of metastasis and help control it more effectively.
Collapse
Affiliation(s)
- Kritika Saxena
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India.
| | - Kuppusamy Balamurugan
- Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
| |
Collapse
|