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1
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Nishida H, Ando K, Kaimori R, Kawamura K, Daa T. Prognostic value of protein expression, tumor morphology and location within the pancreas in pancreatic ductal adenocarcinoma. Oncol Lett 2025; 29:288. [PMID: 40264825 PMCID: PMC12012415 DOI: 10.3892/ol.2025.15034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/24/2025] [Indexed: 04/24/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) of the head (hPDA) is more frequently diagnosed than PDA of the body/tail (btPDA) due to prevalent biliary obstruction symptoms, such as jaundice. hPDA is diagnosed and treated at an earlier stage than btPDA, leading to an improved prognosis. Data from 60 patients with PDA (30 patients with hPDA and 30 patients with btPDA) were analyzed, investigating tumor location (hPDA/btPDA) and clinical information [tumor size, lymph node metastasis, tumor stage and overall survival (OS)] depending on histological patterns [large duct pattern (PDA-L) and small duct pattern (PDA-S)], fibrotic focus (FF) and protein expression [GATA binding protein 6 (GATA6), cytokeratin 5/6, hepatocyte nuclear factor-1β (HNF1β), S100 calcium binding protein A4 (S-100A4), keratin 81 and transforming growth factor-β]. hPDA was significantly associated with tumor size, lymph node metastasis and more advanced stage. The worse OS was not related to tumor location, tumor size, lymph node metastasis or more advanced stage; however, GATA6 positivity was related to poor OS. Except for FF, PDA-L/PDA-S and immunostaining results were not associated with tumor location. PDA-L was related to S-100A4low, GATA6+ and HNF1β+. In the present study, tumor location did not influence tumor prognosis and histological pattern; otherwise, protein expression could influence PDA-L/PDA-S and OS. Therefore, histological classification may be useful in hPDA treatment.
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Affiliation(s)
- Haruto Nishida
- Department of Diagnostic Pathology, Faculty of Medicine, Oita University and Oita University Hospital, Yufu, Oita 879-5593, Japan
| | - Kengo Ando
- Department of Diagnostic Pathology, Faculty of Medicine, Oita University and Oita University Hospital, Yufu, Oita 879-5593, Japan
| | - Ryo Kaimori
- Department of Diagnostic Pathology, Faculty of Medicine, Oita University and Oita University Hospital, Yufu, Oita 879-5593, Japan
| | - Kazuhiro Kawamura
- Department of Diagnostic Pathology, Faculty of Medicine, Oita University and Oita University Hospital, Yufu, Oita 879-5593, Japan
| | - Tsutomu Daa
- Department of Diagnostic Pathology, Faculty of Medicine, Oita University and Oita University Hospital, Yufu, Oita 879-5593, Japan
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2
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Rotti PG, Yi Y, Gasser G, Yuan F, Sun X, Apak-Evans I, Wu P, Liu G, Choi S, Reeves R, Scioneaux AE, Zhang Y, Winter M, Liang B, Cunicelli N, Uc A, Norris AW, Sussel L, Wells KL, Engelhardt JF. CFTR represses a PDX1 axis to govern pancreatic ductal cell fate. iScience 2024; 27:111393. [PMID: 39687022 PMCID: PMC11647141 DOI: 10.1016/j.isci.2024.111393] [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: 04/29/2024] [Revised: 07/29/2024] [Accepted: 11/11/2024] [Indexed: 12/18/2024] Open
Abstract
Inflammation, acinar atrophy, and ductal hyperplasia drive pancreatic remodeling in newborn cystic fibrosis (CF) ferrets lacking a functional cystic fibrosis conductance regulator (CFTR) channel. These changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. The phenotypic changes in CF ductal epithelium and their impact on islet function are unknown. Using bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3β activation. In the absence of CFTR protein, centroacinar cells adopted a bipotent progenitor-like state associated with enhanced WNT/β-Catenin, transforming growth factor β (TGF-β), and AKT signaling. We show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.
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Affiliation(s)
| | - Yaling Yi
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Grace Gasser
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Feng Yuan
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Xingshen Sun
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Idil Apak-Evans
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Peipei Wu
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Guangming Liu
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Soon Choi
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Rosie Reeves
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Attilina E. Scioneaux
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Yulong Zhang
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Michael Winter
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Bo Liang
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Nathan Cunicelli
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Aliye Uc
- Stead Family Department of Pediatrics, Carver College of Medicine, Iowa City, IA, USA
| | - Andrew W. Norris
- Center for Gene Therapy, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Lori Sussel
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz, Medical Campus, Aurora, CO, USA
| | - Kristen L. Wells
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz, Medical Campus, Aurora, CO, USA
| | - John F. Engelhardt
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
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3
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Ahmed I, Chakraborty R, Faizy AF, Moin S. Exploring the key role of DNA methylation as an epigenetic modulator in oxidative stress related islet cell injury in patients with type 2 diabetes mellitus: a review. J Diabetes Metab Disord 2024; 23:1699-1718. [PMID: 39610516 PMCID: PMC11599646 DOI: 10.1007/s40200-024-01496-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/21/2024] [Indexed: 11/30/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterised by impaired insulin secretion and action, often exacerbated by oxidative stress. Recent research has highlighted the intricate involvement of epigenetic mechanisms, particularly DNA methylation, in the pathogenesis of T2DM. This review aims to elucidate the role of DNA methylation as an epigenetic modifier in oxidative stress-mediated beta cell dysfunction, a key component of T2DM pathophysiology. Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defence mechanisms, is a hallmark feature of T2DM. Beta cells, responsible for insulin secretion, are particularly vulnerable to oxidative damage due to their low antioxidant capacity. Emerging evidence suggests that oxidative stress can induce aberrant DNA methylation patterns in beta cells, leading to altered gene expression profiles associated with insulin secretion and cell survival. Furthermore, studies have identified specific genes involved in beta cell function and survival that undergo DNA methylation changes in response to oxidative stress in T2DM. These epigenetic modifications can perpetuate beta cell dysfunction by dysregulating key pathways essential for insulin secretion, such as the insulin signalling cascade and mitochondrial function. Understanding the interplay between DNA methylation, oxidative stress, and beta cell dysfunction holds promise for developing novel therapeutic strategies for T2DM. Targeting aberrant DNA methylation patterns may offer new avenues for restoring beta cell function and improving glycemic control in patients with T2DM. However, further research is needed to elucidate the complex mechanisms underlying epigenetic regulation in T2DM and to translate these findings into clinical interventions.
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Affiliation(s)
- Istiaque Ahmed
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Ritoja Chakraborty
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Abul Faiz Faizy
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Shagufta Moin
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
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4
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Rezaei N, Dormiani K, Kiani-Esfahani A, Mirdamadian S, Rahmani M, Jafarpour F, Nasr-Esfahani MH. Characterization and functional evaluation of goat PDX1 regulatory modules through comparative analysis of conserved interspecies homologs. Sci Rep 2024; 14:26755. [PMID: 39500950 PMCID: PMC11538457 DOI: 10.1038/s41598-024-77614-0] [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: 07/13/2024] [Accepted: 10/23/2024] [Indexed: 11/08/2024] Open
Abstract
PDX1 is a crucial transcription factor in pancreas development and mature β-cell function. However, the regulation of PDX1 expression in larger animals mirroring human pancreas morphogenesis and endocrine maturation remains poorly understood. Therefore, we conducted a comparative analysis to characterize regulatory regions of goat PDX1 gene and assessed their transcriptional activity by transient transfection of several transgenic EGFP constructs in β- and non-β cell lines. We recognized several highly conserved regions encompassing the promoter and cis-regulatory elements (Area I-IV) at 5' flanking sequence of the genes. Within the promoter, we identified that a key E-box and nearby CAAT element synergistically drive transcription, constituting the basal promoter of goat PDX1 gene. Furthermore, each recognized regulatory area separately enhances this basal promoter activity in β-cells compared to non-β cells; however, cooperatively, they exhibit a bifunctional regulatory effect on transcription. Additionally, the intact ~ 3 kb upstream region (Area I-III) functions as the most efficient reporter transgene in vitro and shows islet-specific expression in native rat pancreas. Together, our findings suggest that the regulation of goat PDX1 gene is governed by conserved regions similar to other mammals, while both structurally and functionally, these regions exhibit a closer resemblance to those found in humans.
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Affiliation(s)
- Naeimeh Rezaei
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Kianoush Dormiani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Abbas Kiani-Esfahani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Somayeh Mirdamadian
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Mohsen Rahmani
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Farnoosh Jafarpour
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Mohammad Hossein Nasr-Esfahani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
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5
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Benitz S, Steep A, Nasser MM, Preall J, Mahajan UM, McQuithey H, Loveless I, Davis ET, Wen HJ, Long DW, Metzler T, Zwernik S, Louw M, Rempinski D, Salas-Escabillas DJ, Brender SM, Song L, Huang L, Theisen BK, Zhang Z, Steele NG, Regel I, Bednar F, Crawford HC. ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma. Cancer Discov 2024; 14:2162-2182. [PMID: 38975886 PMCID: PMC11528200 DOI: 10.1158/2159-8290.cd-24-0137] [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: 01/25/2024] [Revised: 05/06/2024] [Accepted: 06/20/2024] [Indexed: 07/09/2024]
Abstract
Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions, to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor PDX1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in a mouse and human. We identified the receptor tyrosine kinase ROR2 as marker of a gastric metaplasia-like identity in pancreas neoplasms. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition. Significance: We discovered the receptor tyrosine kinase ROR2 as an important regulator of cellular identity in pancreatic precancerous lesions and pancreatic cancer. ROR2 drives an aggressive PDAC phenotype and confers resistance to KRAS inhibitors, suggesting that targeting ROR2 will enhance sensitivity to this new generation of targeted therapies. See related commentary by Marasco and Misale, p. 2018.
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Affiliation(s)
- Simone Benitz
- Department of Surgery, Henry Ford Health, Detroit, Michigan
| | - Alec Steep
- Center of Translational Data Science, University of Chicago, Chicago, Illinois
| | | | - Jonathan Preall
- Cold Spring Harbor Laboratory Cancer Center, Cold Spring Harbor, New York
| | | | | | - Ian Loveless
- Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan
| | - Erick T. Davis
- Department of Surgery, Henry Ford Health, Detroit, Michigan
| | - Hui-Ju Wen
- Department of Surgery, Henry Ford Health, Detroit, Michigan
| | - Daniel W. Long
- Department of Surgery, Henry Ford Health, Detroit, Michigan
| | - Thomas Metzler
- Comparative Experimental Pathology (CEP), Institute of Pathology, School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Samuel Zwernik
- Department of Surgery, Henry Ford Health, Detroit, Michigan
| | - Michaela Louw
- Department of Surgery, Henry Ford Health, Detroit, Michigan
| | | | | | | | - Linghao Song
- Center of Translational Data Science, University of Chicago, Chicago, Illinois
| | - Ling Huang
- Department of Surgery, Henry Ford Health, Detroit, Michigan
| | | | - Zhenyu Zhang
- Center of Translational Data Science, University of Chicago, Chicago, Illinois
| | - Nina G. Steele
- Department of Surgery, Henry Ford Health, Detroit, Michigan
- Department of Pathology, Wayne State University, Detroit, Michigan
- Department of Pharmacology and Toxicology, Michigan State University, Lansing, Michigan
- Department of Oncology, Wayne State University, Detroit, Michigan
| | - Ivonne Regel
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Howard C. Crawford
- Department of Surgery, Henry Ford Health, Detroit, Michigan
- Department of Pharmacology and Toxicology, Michigan State University, Lansing, Michigan
- Department of Oncology, Wayne State University, Detroit, Michigan
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6
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Swain S, Narayan RK, Mishra PR. Unraveling the interplay: exploring signaling pathways in pancreatic cancer in the context of pancreatic embryogenesis. Front Cell Dev Biol 2024; 12:1461278. [PMID: 39239563 PMCID: PMC11374643 DOI: 10.3389/fcell.2024.1461278] [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: 07/08/2024] [Accepted: 08/13/2024] [Indexed: 09/07/2024] Open
Abstract
Pancreatic cancer continues to be a deadly disease because of its delayed diagnosis and aggressive tumor biology. Oncogenes and risk factors are being reported to influence the signaling pathways involved in pancreatic embryogenesis leading to pancreatic cancer genesis. Although studies using rodent models have yielded insightful information, the scarcity of human pancreatic tissue has made it difficult to comprehend how the human pancreas develops. Transcription factors like IPF1/PDX1, HLXB9, PBX1, MEIS, Islet-1, and signaling pathways, including Hedgehog, TGF-β, and Notch, are directing pancreatic organogenesis. Any derangements in the above pathways may lead to pancreatic cancer. TP53: and CDKN2A are tumor suppressor genes, and the mutations in TP53 and somatic loss of CDKN2A are the drivers of pancreatic cancer. This review clarifies the complex signaling mechanism involved in pancreatic cancer, the same signaling pathways in pancreas development, the current therapeutic approach targeting signaling molecules, and the mechanism of action of risk factors in promoting pancreatic cancer.
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7
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Bardaweel SK, Al-salamat H, Hajjo R, Sabbah D, Almutairi S. Unveiling the Intricacies of Monoamine Oxidase-A (MAO-A) Inhibition in Colorectal Cancer: Computational Systems Biology, Expression Patterns, and the Anticancer Therapeutic Potential. ACS OMEGA 2024; 9:35703-35717. [PMID: 39184489 PMCID: PMC11339988 DOI: 10.1021/acsomega.4c04100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 08/27/2024]
Abstract
Colorectal cancer (CRC) remains a significant health burden globally, necessitating a deeper understanding of its molecular intricacies for effective therapeutic interventions. Elevated monoamine oxidase-A (MAO-A) expression has been consistently observed in CRC tissues, correlating with advanced disease stages and a poorer prognosis. This research explores the systems biology effects of MAO-A inhibition with small molecule inhibitor clorgyline regarding CRC. The applied systems biology approach starts with a chemocentric informatics approach to derive high-confidence hypotheses regarding the antiproliferative effects of MAO-A inhibitors and ends with experimental validation. Our computational results emphasized the anticancer effects of MAO-A inhibition and the chemogenomics similarities between clorgyline and structurally diverse groups of apoptosis inducers in addition to highlighting apoptotic, DNA-damage, and microRNAs in cancer pathways. Experimental validation results revealed that MAO inhibition results in antiproliferative antimigratory activities in addition to synergistic effects with doxorubicin. Moreover, the results demonstrated a putative role of MAO-A inhibition in commencing CRC cellular death by potentially mediating the induction of apoptosis.
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Affiliation(s)
- Sanaa K. Bardaweel
- Department
of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman - 11942, Jordan
| | - Husam Al-salamat
- Department
of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman - 11942, Jordan
| | - Rima Hajjo
- Department
of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah
University of Jordan, P.O. Box 130, Amman - 11733, Jordan
- Laboratory
for Molecular Modeling, Division of Chemical Biology and Medicinal
Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Board
Member, Jordan CDC, Amman - 11183, Jordan
| | - Dima Sabbah
- Department
of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah
University of Jordan, P.O. Box 130, Amman - 11733, Jordan
| | - Shriefa Almutairi
- Department
of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman - 11942, Jordan
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Bertonnier‐Brouty L, Andersson J, Kaprio T, Hagström J, Bsharat S, Asplund O, Hatem G, Haglund C, Seppänen H, Prasad RB, Artner I. E2F transcription factors promote tumorigenicity in pancreatic ductal adenocarcinoma. Cancer Med 2024; 13:e7187. [PMID: 38686617 PMCID: PMC11058697 DOI: 10.1002/cam4.7187] [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: 09/18/2023] [Revised: 03/14/2024] [Accepted: 04/02/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs. OBJECTIVE Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we aimed to identify and characterize embryonic signaling pathways that were reinitiated during tumor formation and expansion. METHODS AND RESULTS Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells. CONCLUSION Our findings illustrate that E2F1 and E2F8 transcription factors are expressed in pancreatic progenitor and PDAC cells, where they contribute to tumor cell expansion by regulation of cell proliferation, viability, and cell migration making these genes attractive therapeutic targets and potential prognostic markers for pancreatic cancer.
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Affiliation(s)
- Ludivine Bertonnier‐Brouty
- Lund Stem Cell CenterLund UniversityLundSweden
- Lund University Diabetes Center, Lund UniversityMalmöSweden
| | | | - Tuomas Kaprio
- Department of SurgeryHelsinki University HospitalHelsinkiFinland
- Translational Cancer Medicine Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- iCAN, Digital Cancer Precision MedicineUniversity of Helsinki and HUS Helsinki University HospitalHelsinkiFinland
| | - Jaana Hagström
- Department of SurgeryHelsinki University HospitalHelsinkiFinland
- Translational Cancer Medicine Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- iCAN, Digital Cancer Precision MedicineUniversity of Helsinki and HUS Helsinki University HospitalHelsinkiFinland
- Department of Oral Pathology and RadiologyUniversity of TurkuTurkuFinland
| | - Sara Bsharat
- Lund Stem Cell CenterLund UniversityLundSweden
- Lund University Diabetes Center, Lund UniversityMalmöSweden
| | - Olof Asplund
- Lund University Diabetes Center, Lund UniversityMalmöSweden
| | - Gad Hatem
- Lund University Diabetes Center, Lund UniversityMalmöSweden
| | - Caj Haglund
- Department of SurgeryHelsinki University HospitalHelsinkiFinland
- Translational Cancer Medicine Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- iCAN, Digital Cancer Precision MedicineUniversity of Helsinki and HUS Helsinki University HospitalHelsinkiFinland
| | - Hanna Seppänen
- Department of SurgeryHelsinki University HospitalHelsinkiFinland
- Translational Cancer Medicine Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- iCAN, Digital Cancer Precision MedicineUniversity of Helsinki and HUS Helsinki University HospitalHelsinkiFinland
| | | | - Isabella Artner
- Lund Stem Cell CenterLund UniversityLundSweden
- Lund University Diabetes Center, Lund UniversityMalmöSweden
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9
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Wiley MB, Bauer J, Alvarez V, Mehrotra K, Cheng W, Kolics Z, Giarrizzo M, Ingle K, Bialkowska AB, Jung B. Activin A signaling stimulates neutrophil activation and macrophage migration in pancreatitis. Sci Rep 2024; 14:9382. [PMID: 38654064 PMCID: PMC11039671 DOI: 10.1038/s41598-024-60065-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/18/2024] [Indexed: 04/25/2024] Open
Abstract
Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in mice improves outcomes in two murine models of AP. To test the hypothesis that activin is produced early in response to pancreatitis and is maintained throughout disease progression to stimulate immune cells, we first performed digital spatial profiling (DSP) of human chronic pancreatitis (CP) patient tissue. Then, transwell migration assays using RAW264.7 mouse macrophages and qPCR analysis of "neutrophil-like" HL-60 cells were used for functional correlation. Immunofluorescence and western blots on cerulein-induced pancreatitis samples from pancreatic acinar cell-specific Kras knock-in (Ptf1aCreER™; LSL-KrasG12D) and functional WT Ptf1aCreER™ mouse lines mimicking AP and CP to allow for in vivo confirmation. Our data suggest activin promotes neutrophil and macrophage activation both in situ and in vitro, while pancreatic activin production is increased as early as 1 h in response to pancreatitis and is maintained throughout CP in vivo. Taken together, activin is produced early in response to pancreatitis and is maintained throughout disease progression to promote neutrophil and macrophage activation.
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Affiliation(s)
- Mark B Wiley
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Jessica Bauer
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Valentina Alvarez
- Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA
| | - Kunaal Mehrotra
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Wenxuan Cheng
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Zoe Kolics
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Michael Giarrizzo
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, 11794, USA
| | - Komala Ingle
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, 11794, USA
| | - Agnieszka B Bialkowska
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, 11794, USA
| | - Barbara Jung
- Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
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10
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Oropeza D, Herrera PL. Glucagon-producing α-cell transcriptional identity and reprogramming towards insulin production. Trends Cell Biol 2024; 34:180-197. [PMID: 37626005 DOI: 10.1016/j.tcb.2023.07.004] [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: 04/27/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 08/27/2023]
Abstract
β-Cell replacement by in situ reprogramming of non-β-cells is a promising diabetes therapy. Following the observation that near-total β-cell ablation in adult mice triggers the reprogramming of pancreatic α-, δ-, and γ-cells into insulin (INS)-producing cells, recent studies are delving deep into the mechanisms controlling adult α-cell identity. Systematic analyses of the α-cell transcriptome and epigenome have started to pinpoint features that could be crucial for maintaining α-cell identity. Using different transgenic and chemical approaches, significant advances have been made in reprogramming α-cells in vivo into INS-secreting cells in mice. The recent reprogramming of human α-cells in vitro is an important step forward that must now be complemented with a comprehensive molecular dissection of the mechanisms controlling α-cell identity.
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Affiliation(s)
- Daniel Oropeza
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Pedro Luis Herrera
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
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11
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Liu S, Zhong H, Zhu J, Wu Y, Deng Y, Wu L. Regulome-wide association study identifies genetically driven accessible regions associated with pancreatic cancer risk. Int J Cancer 2024; 154:670-678. [PMID: 37850323 PMCID: PMC10842605 DOI: 10.1002/ijc.34761] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 09/04/2023] [Accepted: 09/21/2023] [Indexed: 10/19/2023]
Abstract
Genome-wide association studies (GWAS) have identified two dozen genetic variants that are associated with the risk of pancreatic ductal adenocarcinoma (PDAC), a deadly malignancy. However, a majority of these variants are located in noncoding regions of the genome, which limits the translation of GWAS findings into clinical applications. The regulome-wide association study (RWAS) is a recently developed method for identifying TF binding-induced accessibility regions for diseases. However, their potential connection to PDAC has yet to be fully explored. We evaluated the associations between genetically predicted levels of chromatin accessibility and risk of PDAC by using pan-cancer chromatin accessibility genetic prediction models. Our analysis included 8275 cases and 6723 controls from the PanScan (I, II, and III) and PanC4 consortia. To further refine our results, we also integrated genes associated to allele-specific accessibility quantitative trait loci (as-aQTL) and TF motifs located in the as-aQTL. We found that 50 chromatin accessibility features were associated with PDAC risk at a false discovery rate (FDR) of less than 0.05. A total of 28 RWAS peaks were identified as conditionally significant. By integrating the results from as-aQTL, motif analysis, and RWAS, we identified candidate causal regulatory elements for two potential chromatin accessibility regions (THCA_89956 and ESCA_89167) that are associated with PDAC risk. Our study identified chromatin accessibility features in noncoding genomic regions that are associated with PDAC risk. We also predicted the associated genes and disrupt motifs. Our findings provide new insights into the regulatory mechanisms of noncoding regions for pancreatic tumorigenesis.
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Affiliation(s)
- Shuai Liu
- Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Hua Zhong
- Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Jingjing Zhu
- Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Yong Wu
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen School of Medicine at UCLA
| | - Youping Deng
- Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Lang Wu
- Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
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12
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Benitz S, Steep A, Nasser M, Preall J, Mahajan UM, McQuithey H, Loveless I, Davis ET, Wen HJ, Long DW, Metzler T, Zwernik S, Louw M, Rempinski D, Salas-Escabillas D, Brender S, Song L, Huang L, Zhang Z, Steele NG, Regel I, Bednar F, Crawford HC. ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.12.13.571566. [PMID: 38168289 PMCID: PMC10760092 DOI: 10.1101/2023.12.13.571566] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity in the pancreas. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.
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Affiliation(s)
- Simone Benitz
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
| | - Alec Steep
- Center of Translational Data Science, University of Chicago, Chicago, Illinois, USA
| | - Malak Nasser
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
| | - Jonathan Preall
- Cold Spring Harbor Laboratory Cancer Center, Cold Spring Harbor, New York, USA
| | - Ujjwal M. Mahajan
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Holly McQuithey
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
| | - Ian Loveless
- Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, USA
| | - Erick T. Davis
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
| | - Hui-Ju Wen
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
| | - Daniel W. Long
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
| | - Thomas Metzler
- Comparative Experimental Pathology (CEP), Institute of Pathology, School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Samuel Zwernik
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
| | - Michaela Louw
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
| | - Donald Rempinski
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
| | | | - Sydney Brender
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
| | - Linghao Song
- Center of Translational Data Science, University of Chicago, Chicago, Illinois, USA
| | - Ling Huang
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
| | - Zhenyu Zhang
- Center of Translational Data Science, University of Chicago, Chicago, Illinois, USA
| | - Nina G. Steele
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
- Department of Pathology, Wayne State University, Detroit, Michigan, USA
- Department of Pharmacology and Toxicology, Michigan State University, Lansing, Michigan, USA
- Department of Oncology, Wayne State University, Detroit, Michigan, USA
| | - Ivonne Regel
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Howard C. Crawford
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
- Department of Pharmacology and Toxicology, Michigan State University, Lansing, Michigan, USA
- Department of Oncology, Wayne State University, Detroit, Michigan, USA
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13
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Pan Z, Van den Bossche JL, Rodriguez-Aznar E, Janssen P, Lara O, Ates G, Massie A, De Paep DL, Houbracken I, Mambretti M, Rooman I. Pancreatic acinar cell fate relies on system x C- to prevent ferroptosis during stress. Cell Death Dis 2023; 14:536. [PMID: 37604805 PMCID: PMC10442358 DOI: 10.1038/s41419-023-06063-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 07/28/2023] [Accepted: 08/14/2023] [Indexed: 08/23/2023]
Abstract
Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer development. In the present study, we further decipher the precise mechanisms and regulation using primary human cells and murine experimental models. Our RNAseq analysis indicates that, in both species, early acinar cell dedifferentiation is accompanied by multiple pathways related to cell survival that are highly enriched, and where SLC7A11 (xCT) is transiently upregulated. xCT is the specific subunit of the cystine/glutamate antiporter system xC-. To decipher its role, gene silencing, pharmacological inhibition and a knock-out mouse model were used. Acinar cells with depleted or reduced xCT function show an increase in ferroptosis relating to lipid peroxidation. Lower glutathione levels and more lipid ROS accumulation could be rescued by the antioxidant N-acetylcysteine or the ferroptosis inhibitor ferrostatin-1. In caerulein-induced acute pancreatitis in mice, xCT also prevents lipid peroxidation in acinar cells. In conclusion, during stress, acinar cell fate seems to be poised for avoiding several forms of cell death. xCT specifically prevents acinar cell ferroptosis by fueling the glutathione pool and maintaining ROS balance. The data suggest that xCT offers a druggable tipping point to steer the acinar cell fate in stress conditions.
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Affiliation(s)
- Zhaolong Pan
- Laboratory for Medical and Molecular Oncology, Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Jan-Lars Van den Bossche
- Laboratory for Medical and Molecular Oncology, Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Eva Rodriguez-Aznar
- Laboratory for Medical and Molecular Oncology, Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Pauline Janssen
- Laboratory for Medical and Molecular Oncology, Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
- Neuro-Aging & Viro-Immunotherapy Research Group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Olaya Lara
- Laboratory for Medical and Molecular Oncology, Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
- Neuro-Aging & Viro-Immunotherapy Research Group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Gamze Ates
- Neuro-Aging & Viro-Immunotherapy Research Group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Ann Massie
- Neuro-Aging & Viro-Immunotherapy Research Group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Diedert Luc De Paep
- Beta Cell Bank, Universitair Ziekenhuis Brussel and Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Isabelle Houbracken
- Laboratory for Medical and Molecular Oncology, Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Marco Mambretti
- Laboratory for Medical and Molecular Oncology, Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Ilse Rooman
- Laboratory for Medical and Molecular Oncology, Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
- Visual and Spatial Tissue Analysis (VSTA) Core Facility, Vrije Universiteit Brussel, Brussels, Belgium.
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14
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Davies A, Zoubeidi A, Beltran H, Selth LA. The Transcriptional and Epigenetic Landscape of Cancer Cell Lineage Plasticity. Cancer Discov 2023; 13:1771-1788. [PMID: 37470668 PMCID: PMC10527883 DOI: 10.1158/2159-8290.cd-23-0225] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/25/2023] [Accepted: 06/09/2023] [Indexed: 07/21/2023]
Abstract
Lineage plasticity, a process whereby cells change their phenotype to take on a different molecular and/or histologic identity, is a key driver of cancer progression and therapy resistance. Although underlying genetic changes within the tumor can enhance lineage plasticity, it is predominantly a dynamic process controlled by transcriptional and epigenetic dysregulation. This review explores the transcriptional and epigenetic regulators of lineage plasticity and their interplay with other features of malignancy, such as dysregulated metabolism, the tumor microenvironment, and immune evasion. We also discuss strategies for the detection and treatment of highly plastic tumors. SIGNIFICANCE Lineage plasticity is a hallmark of cancer and a critical facilitator of other oncogenic features such as metastasis, therapy resistance, dysregulated metabolism, and immune evasion. It is essential that the molecular mechanisms of lineage plasticity are elucidated to enable the development of strategies to effectively target this phenomenon. In this review, we describe key transcriptional and epigenetic regulators of cancer cell plasticity, in the process highlighting therapeutic approaches that may be harnessed for patient benefit.
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Affiliation(s)
- Alastair Davies
- Oncology Research Discovery, Pfizer Worldwide Research and Development, San Diego, CA, USA
| | - Amina Zoubeidi
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
- Vancouver Prostate Centre, Vancouver, British Columbia, Canada
| | - Himisha Beltran
- Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Luke A. Selth
- Flinders Health and Medical Research Institute and Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, South Australia, 5042 Australia
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, 5005 Australia
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15
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Marui S, Nishikawa Y, Shiokawa M, Yokode M, Matsumoto S, Muramoto Y, Ota S, Nakamura T, Yoshida H, Okada H, Kuwada T, Matsumori T, Kuriyama K, Fukuda A, Saur D, Aoi T, Uza N, Kodama Y, Chiba T, Seno H. Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation. Gastroenterology 2022; 163:1613-1629.e12. [PMID: 36075324 DOI: 10.1053/j.gastro.2022.08.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 07/23/2022] [Accepted: 08/30/2022] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS The Notch signaling pathway is an important pathway in the adult pancreas and in pancreatic ductal adenocarcinoma (PDAC), with hairy and enhancer of split-1 (HES1) as the core molecule in this pathway. However, the roles of HES1 in the adult pancreas and PDAC formation remain controversial. METHODS We used genetically engineered dual-recombinase mouse models for inducing Hes1 deletion under various conditions. RESULTS The loss of Hes1 expression in the adult pancreas did not induce phenotypic alterations. However, regeneration was impaired after caerulein-induced acute pancreatitis. In a pancreatic intraepithelial neoplasia (PanIN) mouse model, PanINs rarely formed when Hes1 deletion preceded PanIN formation, whereas more PanINs were formed when Hes1 deletion succeeded PanIN formation. In a PDAC mouse model, PDAC formation was also enhanced by Hes1 deletion after PanIN/PDAC development; therefore, Hes1 promotes PanIN initiation but inhibits PanIN/PDAC progression. RNA sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction revealed that Hes1 deletion enhanced epithelial-to-mesenchymal transition via Muc5ac up-regulation in PDAC progression. The results indicated that HES1 is not required for maintaining the adult pancreas under normal conditions, but is important for regeneration during recovery from pancreatitis; moreover, Hes1 plays different roles, depending on the tumor condition. CONCLUSIONS Our findings highlight the context-dependent roles of HES1 in the adult pancreas and pancreatic cancer.
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Affiliation(s)
- Saiko Marui
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshihiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Hyogo, Japan; Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Masahiro Shiokawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
| | - Masataka Yokode
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shimpei Matsumoto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuya Muramoto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Sakiko Ota
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeharu Nakamura
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroyuki Yoshida
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirokazu Okada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeshi Kuwada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomoaki Matsumori
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Katsutoshi Kuriyama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Akihisa Fukuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Dieter Saur
- Department of Internal Medicine II, Klinikum rechts der Isar Technische Universität München, München, Bayern, Germany; Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Baden-Württemberg, Germany
| | - Takashi Aoi
- Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Hyogo, Japan
| | - Norimitsu Uza
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuzo Kodama
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Kansai Electric Power Hospital, Osaka, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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16
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Li F, Niu Y, Zhao W, Yan C, Qi Y. Construction and validation of a prognostic model for lung adenocarcinoma based on endoplasmic reticulum stress-related genes. Sci Rep 2022; 12:19857. [PMID: 36400857 PMCID: PMC9674626 DOI: 10.1038/s41598-022-23852-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 11/07/2022] [Indexed: 11/19/2022] Open
Abstract
Lung adenocarcinoma (LUAD) is one of the most universal types of cancer all over the world and its morbidity continues to rise year by year. Growing evidence has demonstrated that endoplasmic reticulum stress is highly activated in cancer cells and plays a key role in regulating the fate of cancer cells. However, the role and mechanism of endoplasmic reticulum stress in lung adenocarcinoma genesis and development remains unclear. In this research, we developed a prognostic model to predict the overall survival of patients with LUAD utilizing endoplasmic reticulum stress-related genes and screened out potential small molecular compounds, which could assist the clinician in making accurate decisions and better treat LUAD patients. Firstly, we downloaded 419 endoplasmic reticulum stress-related genes (ERSRGs) from Molecular Signatures Database (MSigDB). Secondly, we obtained information about the transcriptome profiling and corresponding clinical data of 59 normal samples and 535 lung adenocarcinoma samples from The Cancer Genome Atlas (TCGA) database. Next, we used the DESeq2 package to identify differentially expressed genes related to endoplasmic reticulum stress. We performed univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis to establish a prognostic model for LUAD patients based on ERSRGs. Then, we carried out univariate and multivariate independent prognostic analysis of endoplasmic reticulum stress-related gene (ERSRG) score and some clinical traits of lung adenocarcinoma. Additionally, we developed a clinically applicable nomogram for predicting survival for LUAD patients over one, three, and five years. Moreover, we carried out a drug sensitivity analysis to identify novel small molecule compounds for LUAD treatment. Finally, we examined the tumor microenvironment (TME) and immune cell infiltrating analysis to explore the interactions between immune and cancer cells. 142 differentially expressed ERSRGs were identified by using the DESeq2 package. A prognostic model was built based on 7 differentially expressed ERSRGs after performing univariate Cox regression, LASSO regression, and multivariate Cox regression analysis. According to the results of univariate and multivariate independent prognostic analysis, we found ERSRG score can be used as an independent prognostic maker. Using the Kaplan-Meier curves, we found low-risk patients had higher survival probability than high-risk patients in both training set and test set. A nomogram was drawn to predict 1-, 3-, and 5-year survival probability. The calibration curves explained good performance of the model for the prediction of survival. Phenformin, OSU-03012, GSK-650394 and KIN001-135 were identified as the drugs most likely to provide important information to clinicians about the treatment of LUAD patients. A prognostic prediction model was established based on 7 differentially expressed ERSRGs (PDX1, IGFBP1, DDIT4, PPP1R3G, CFTR, DERL3 and NUPR1), which could effectively predict the prognosis of LUAD patients and give a reference for clinical doctors to help LUAD patients to make better treatment tactics. Based on the 4 small molecule compounds (Phenformin, OSU-03012, GSK-650394 and KIN001-135) we discovered, targeting endoplasmic reticulum stress-related genes may also be a therapeutic approach for LUAD patients.
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Affiliation(s)
- Feng Li
- grid.495434.b0000 0004 1797 4346School of Pharmacy, Key Laboratory of Nano-Carbon Modified Film Technology of Henan Province, Diagnostic Laboratory of Animal Diseases, Xinxiang University, Xinxiang, China
| | - Yandie Niu
- grid.495434.b0000 0004 1797 4346School of Pharmacy, Key Laboratory of Nano-Carbon Modified Film Technology of Henan Province, Diagnostic Laboratory of Animal Diseases, Xinxiang University, Xinxiang, China
| | - Wei Zhao
- grid.495434.b0000 0004 1797 4346School of Pharmacy, Key Laboratory of Nano-Carbon Modified Film Technology of Henan Province, Diagnostic Laboratory of Animal Diseases, Xinxiang University, Xinxiang, China
| | - Cheng Yan
- grid.495434.b0000 0004 1797 4346School of Pharmacy, Key Laboratory of Nano-Carbon Modified Film Technology of Henan Province, Diagnostic Laboratory of Animal Diseases, Xinxiang University, Xinxiang, China
| | - Yonghua Qi
- grid.495434.b0000 0004 1797 4346School of Pharmacy, Key Laboratory of Nano-Carbon Modified Film Technology of Henan Province, Diagnostic Laboratory of Animal Diseases, Xinxiang University, Xinxiang, China
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17
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Usher ET, Showalter SA. Biophysical insights into glucose-dependent transcriptional regulation by PDX1. J Biol Chem 2022; 298:102623. [PMID: 36272648 PMCID: PMC9691942 DOI: 10.1016/j.jbc.2022.102623] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/22/2022] Open
Abstract
The pancreatic and duodenal homeobox 1 (PDX1) is a central regulator of glucose-dependent transcription of insulin in pancreatic β cells. PDX1 transcription factor activity is integral to the development and sustained health of the pancreas; accordingly, deciphering the complex network of cellular cues that lead to PDX1 activation or inactivation is an important step toward understanding the etiopathologies of pancreatic diseases and the development of novel therapeutics. Despite nearly 3 decades of research into PDX1 control of Insulin expression, the molecular mechanisms that dictate the function of PDX1 in response to glucose are still elusive. The transcriptional activation functions of PDX1 are regulated, in part, by its two intrinsically disordered regions, which pose a barrier to its structural and biophysical characterization. Indeed, many studies of PDX1 interactions, clinical mutations, and posttranslational modifications lack molecular level detail. Emerging methods for the quantitative study of intrinsically disordered regions and refined models for transactivation now enable us to validate and interrogate the biochemical and biophysical features of PDX1 that dictate its function. The goal of this review is to summarize existing PDX1 studies and, further, to generate a comprehensive resource for future studies of transcriptional control via PDX1.
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Affiliation(s)
- Emery T Usher
- Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Scott A Showalter
- Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, USA; Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, USA.
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18
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Repositioning of Old Drugs for Novel Cancer Therapies: Continuous Therapeutic Perfusion of Aspirin and Oseltamivir Phosphate with Gemcitabine Treatment Disables Tumor Progression, Chemoresistance, and Metastases. Cancers (Basel) 2022; 14:cancers14153595. [PMID: 35892853 PMCID: PMC9331689 DOI: 10.3390/cancers14153595] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 07/18/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Repositioning old drugs in combination with clinical standard chemotherapeutics opens a promising clinical treatment approach for patients with pancreatic cancer. This report presents a therapeutic repositioning of continuous perfusion of aspirin and oseltamivir phosphate in combination with gemcitabine treatment as an effective treatment option for pancreatic cancer. The data suggest that repositioning these drugs with continuous perfusion with gemcitabine disables chemoresistance, tumor progression, EMT program, cancer stem cells, and metastases in a preclinical mouse model of human pancreatic cancer. These promising results warrant additional investigation to assess the potential of translating into the clinical setting to improve the cancer patient prognosis for an otherwise fatal disease. Abstract Metastatic pancreatic cancer has an invariably fatal outcome, with an estimated median progression-free survival of approximately six months employing our best combination chemotherapeutic regimens. Once drug resistance develops, manifested by increased primary tumor size and new and growing metastases, patients often die rapidly from their disease. Emerging evidence indicates that chemotherapy may contribute to the development of drug resistance through the upregulation of epithelial–mesenchymal transition (EMT) pathways and subsequent cancer stem cell (CSC) enrichment. Neuraminidase-1 (Neu-1) regulates the activation of several receptor tyrosine kinases implicated in EMT induction, angiogenesis, and cellular proliferation. Here, continuous therapeutic targeting of Neu-1 using parenteral perfusion of oseltamivir phosphate (OP) and aspirin (ASA) with gemcitabine (GEM) treatment significantly disrupts tumor progression, critical compensatory signaling mechanisms, EMT program, CSC, and metastases in a preclinical mouse model of human pancreatic cancer. ASA- and OP-treated xenotumors significantly inhibited the metastatic potential when transferred into animals.
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19
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De Angelis ML, Francescangeli F, Nicolazzo C, Signore M, Giuliani A, Colace L, Boe A, Magri V, Baiocchi M, Ciardi A, Scarola F, Spada M, La Torre F, Gazzaniga P, Biffoni M, De Maria R, Zeuner A. An organoid model of colorectal circulating tumor cells with stem cell features, hybrid EMT state and distinctive therapy response profile. J Exp Clin Cancer Res 2022; 41:86. [PMID: 35260172 PMCID: PMC8903172 DOI: 10.1186/s13046-022-02263-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 01/18/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Circulating tumor cells (CTCs) are responsible for the metastatic dissemination of colorectal cancer (CRC) to the liver, lungs and lymph nodes. CTCs rarity and heterogeneity strongly limit the elucidation of their biological features, as well as preclinical drug sensitivity studies aimed at metastasis prevention. METHODS We generated organoids from CTCs isolated from an orthotopic CRC xenograft model. CTCs-derived organoids (CTCDOs) were characterized through proteome profiling, immunohistochemistry, immunofluorescence, flow cytometry, tumor-forming capacity and drug screening assays. The expression of intra- and extracellular markers found in CTCDOs was validated on CTCs isolated from the peripheral blood of CRC patients. RESULTS CTCDOs exhibited a hybrid epithelial-mesenchymal transition (EMT) state and an increased expression of stemness-associated markers including the two homeobox transcription factors Goosecoid and Pancreatic Duodenal Homeobox Gene-1 (PDX1), which were also detected in CTCs from CRC patients. Functionally, CTCDOs showed a higher migratory/invasive ability and a different response to pathway-targeted drugs as compared to xenograft-derived organoids (XDOs). Specifically, CTCDOs were more sensitive than XDOs to drugs affecting the Survivin pathway, which decreased the levels of Survivin and X-Linked Inhibitor of Apoptosis Protein (XIAP) inducing CTCDOs death. CONCLUSIONS These results indicate that CTCDOs recapitulate several features of colorectal CTCs and may be used to investigate the features of metastatic CRC cells, to identify new prognostic biomarkers and to devise new potential strategies for metastasis prevention.
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Affiliation(s)
- Maria Laura De Angelis
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
| | - Federica Francescangeli
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Chiara Nicolazzo
- Department of Molecular Medicine, Liquid Biopsy Unit, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy
| | - Michele Signore
- RPPA Unit, Proteomics Area, Core Facilities, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Alessandro Giuliani
- Environment and Health Department, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Lidia Colace
- Department of Surgical Sciences, Policlinico Umberto I/Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Alessandra Boe
- Core Facilities, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Valentina Magri
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University, Viale del Policlinico 155, 00161, Rome, Italy
| | - Marta Baiocchi
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Antonio Ciardi
- Department of Surgery "Pietro Valdoni", Policlinico Umberto I/Sapienza University, Viale del Policlinico 155, 00161, Rome, Italy
| | - Francesco Scarola
- Department of Surgery "Pietro Valdoni", Policlinico Umberto I/Sapienza University, Viale del Policlinico 155, 00161, Rome, Italy
| | - Massimo Spada
- Center of Animal Research and Welfare, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Filippo La Torre
- Surgical Sciences and Emergency Department, Policlinico Umberto I/Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Paola Gazzaniga
- Department of Molecular Medicine, Liquid Biopsy Unit, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy
| | - Mauro Biffoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Ruggero De Maria
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Rome, Italy.
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy.
| | - Ann Zeuner
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
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20
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Velez-Delgado A, Donahue KL, Brown KL, Du W, Irizarry-Negron V, Menjivar RE, Lasse Opsahl EL, Steele NG, The S, Lazarus J, Sirihorachai VR, Yan W, Kemp SB, Kerk SA, Bollampally M, Yang S, Scales MK, Avritt FR, Lima F, Lyssiotis CA, Rao A, Crawford HC, Bednar F, Frankel TL, Allen BL, Zhang Y, Pasca di Magliano M. Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming. Cell Mol Gastroenterol Hepatol 2022; 13:1673-1699. [PMID: 35245687 PMCID: PMC9046274 DOI: 10.1016/j.jcmgh.2022.02.016] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIMS Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although the tumor cell-intrinsic effects of oncogenic Kras expression have been widely studied, its role in regulating the extensive pancreatic tumor microenvironment is less understood. METHODS Using a genetically engineered mouse model of inducible and reversible oncogenic Kras expression and a combination of approaches that include mass cytometry and single-cell RNA sequencing we studied the effect of oncogenic KRAS in the tumor microenvironment. RESULTS We have discovered that non-cell autonomous (ie, extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, and the main source of cytokines mediating the polarization of protumorigenic macrophages while also preventing tissue repair. CONCLUSIONS Our study provides fundamental knowledge on the mechanisms underlying the formation of the fibroinflammatory stroma in pancreatic cancer and highlights stromal pathways with the potential to be exploited therapeutically.
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Affiliation(s)
| | | | | | - Wenting Du
- Department of Surgery, Ann Arbor, Michigan
| | | | | | | | - Nina G Steele
- Department of Cell and Developmental Biology, Ann Arbor, Michigan
| | - Stephanie The
- Department of Computational Medicine and Bioinformatics, Ann Arbor, Michigan
| | | | | | - Wei Yan
- Department of Surgery, Ann Arbor, Michigan
| | - Samantha B Kemp
- Molecular and Cellular Pathology Program, Ann Arbor, Michigan
| | | | | | - Sion Yang
- Life Sciences and Arts College, Ann Arbor, Michigan
| | - Michael K Scales
- Department of Cell and Developmental Biology, Ann Arbor, Michigan
| | | | | | - Costas A Lyssiotis
- Cancer Biology Program, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, Michigan
| | - Arvind Rao
- Cancer Biology Program, Ann Arbor, Michigan; Department of Computational Medicine and Bioinformatics, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan; Michigan Institute of Data Science, Ann Arbor, Michigan; Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
| | - Howard C Crawford
- Cancer Biology Program, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, Michigan
| | - Filip Bednar
- Department of Surgery, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan
| | - Timothy L Frankel
- Department of Surgery, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan
| | - Benjamin L Allen
- Department of Cell and Developmental Biology, Ann Arbor, Michigan
| | - Yaqing Zhang
- Department of Surgery, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan.
| | - Marina Pasca di Magliano
- Department of Cell and Developmental Biology, Ann Arbor, Michigan; Cancer Biology Program, Ann Arbor, Michigan; Department of Surgery, Ann Arbor, Michigan; Cellular and Molecular Biology Program, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan.
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21
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Parte S, Nimmakayala RK, Batra SK, Ponnusamy MP. Acinar to ductal cell trans-differentiation: A prelude to dysplasia and pancreatic ductal adenocarcinoma. Biochim Biophys Acta Rev Cancer 2022; 1877:188669. [PMID: 34915061 DOI: 10.1016/j.bbcan.2021.188669] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer (PC) is the deadliest neoplastic epithelial malignancies and is projected to be the second leading cause of cancer-related mortality by 2024. Five years overall survival being ~10%, mortality and incidence rates are disturbing. Acinar to ductal cell metaplasia (ADM) encompasses cellular reprogramming and phenotypic switch-over, making it a cardinal event in tumor initiation. Differential cues and varied regulatory factors drive synchronous functions of metaplastic cell populations leading to multiple cell fates and physiological outcomes. ADM is a precursor for developing early pre-neoplastic lesions further progressing into PC due to oncogenic signaling. Hence delineating molecular events guiding tumor initiation may provide cues for regenerative medicine and precision onco-medicine. Therefore, understanding PC pathogenesis and early diagnosis are crucial. We hereby provide a timely overview of the current progress in this direction and future perspectives we foresee unfolding in the best interest of patient well-being and better clinical management of PC.
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Affiliation(s)
- Seema Parte
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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22
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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.
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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
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23
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Kim J, Ekstrom T, Yang W, Donahue G, Grygoryev D, Ngo TT, Muschler JL, Morgan T, Zaret KS. Longitudinal Analysis of Human Pancreatic Adenocarcinoma Development Reveals Transient Gene Expression Signatures. Mol Cancer Res 2021; 19:1854-1867. [PMID: 34330844 PMCID: PMC9398181 DOI: 10.1158/1541-7786.mcr-21-0483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/17/2021] [Accepted: 07/26/2021] [Indexed: 01/07/2023]
Abstract
Previous transcriptome studies of human pancreatic ductal adenocarcinoma (PDAC) compare non-cancerous pancreatic intraepithelial neoplasias (PanIN) with late-stage PDAC obtained from different patients, thus have limited ability to discern network dynamics that contribute to the disease progression. We demonstrated previously that the 10-22 cell line, an induced pluripotent stem cell-like line reprogrammed from late-stage human PDAC cells, recapitulated the progression from PanINs to PDAC upon transplantation into NOD/LtSz-scid/IL2R-gammanull mice. Herein, we investigated the transition from precursor to PDAC using the isogenic model. We analyzed transcriptomes of genetically tagged 10-22 cells progressing from PanINs to PDAC in mice and validated the results using The Cancer Genome Atlas PDAC dataset, human clinical PanIN and PDAC tissues, and a well-established murine PDAC model. We functionally studied candidate proteins using human normal (H6C7) and cancerous (Miapaca2, Aspc1) pancreatic ductal epithelial cell lines. 10-22 cell-derived PDAC displayed the molecular signature of clinical human PDAC. Expression changes of many genes were transient during PDAC progression. Pathways for extracellular vesicle transport and neuronal cell differentiation were derepressed in the progression of PanINs to PDAC. HMG-box transcription factor 1 (HBP1) and BTB domain and CNC homolog 1 (BACH1) were implicated in regulating dynamically expressed genes during PDAC progression, and their expressions inversely correlated with PDAC patients' prognosis. Ectopic expression of HBP1 increased proliferation and migration of normal and cancerous pancreatic cells, indicating that HBP1 may confer the cell dissemination capacity in early PDAC progression. This unique longitudinal analysis provides insights into networks underlying human PDAC progression and pathogenesis. IMPLICATIONS: Manipulation of HBP1, BACH1, and RUN3 networks during PDAC progression can be harnessed to develop new targets for treating PDAC.
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Affiliation(s)
- Jungsun Kim
- Department of Molecular and Medical Genetics, Oregon Health & Science University School of Medicine, Portland, Oregon.,Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, Oregon.,Knight Cancer Institute (Cancer Biology Research Program), Oregon Health & Science University School of Medicine, Portland, Oregon.,Corresponding Author: Jungsun Kim, Department of Molecular & Medical Genetics, Cancer Early Detection Advanced Research Center, Knight Cancer Institute. Oregon Health & Science University, Portland, OR 97239. Phone: 503-346-1967; E-mail:
| | - Taelor Ekstrom
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, Oregon
| | - Wenli Yang
- Department of Medicine, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Greg Donahue
- Institute for Regenerative Medicine, Department of Cell and Developmental Biology, Abramson Cancer Center (Tumor Biology Program), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Dmytro Grygoryev
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, Oregon
| | - Thuy T.M. Ngo
- Department of Molecular and Medical Genetics, Oregon Health & Science University School of Medicine, Portland, Oregon.,Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, Oregon.,Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon
| | - John L. Muschler
- Knight Cancer Institute (Cancer Biology Research Program), Oregon Health & Science University School of Medicine, Portland, Oregon.,Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon
| | - Terry Morgan
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, Oregon.,Department of Pathology, Oregon Health & Science University, Portland, Oregon
| | - Kenneth S. Zaret
- Institute for Regenerative Medicine, Department of Cell and Developmental Biology, Abramson Cancer Center (Tumor Biology Program), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
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24
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Dey S, Udari LM, RiveraHernandez P, Kwon JJ, Willis B, Easler JJ, Fogel EL, Pandol S, Kota J. Loss of miR-29a/b1 promotes inflammation and fibrosis in acute pancreatitis. JCI Insight 2021; 6:e149539. [PMID: 34464354 PMCID: PMC8525644 DOI: 10.1172/jci.insight.149539] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 08/25/2021] [Indexed: 12/15/2022] Open
Abstract
MicroRNA-29 (miR-29) is a critical regulator of fibroinflammatory processes in human diseases. In this study, we found a decrease in miR-29a in experimental and human chronic pancreatitis, leading us to investigate the regulatory role of the miR-29a/b1 cluster in acute pancreatitis (AP) utilizing a conditional miR-29a/b1-KO mouse model. miR-29a/b1-sufficient (WT) and -deficient (KO) mice were administered supramaximal caerulein to induce AP and characterized at different time points, utilizing an array of IHC and biochemical analyses for AP parameters. In caerulein-induced WT mice, miR-29a remained dramatically downregulated at injury. Despite high-inflammatory milieu, fibrosis, and parenchymal disarray in the WT mice during early AP, the pancreata fully restored during recovery. miR-29a/b1-KO mice showed significantly greater inflammation, lymphocyte infiltration, macrophage polarization, and ECM deposition, continuing until late recovery with persistent parenchymal disorganization. The increased pancreatic fibrosis was accompanied by enhanced TGFβ1 coupled with persistent αSMA+ PSC activation. Additionally, these mice exhibited higher circulating IL-6 and inflammation in lung parenchyma. Together, this collection of studies indicates that depletion of miR-29a/b1 cluster impacts the fibroinflammatory mechanisms of AP, resulting in (a) aggravated pathogenesis and (b) delayed recovery from the disease, suggesting a protective role of the molecule against AP.
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Affiliation(s)
- Shatovisha Dey
- Department of Medical and Molecular Genetics, Indiana University (IU) School of Medicine, Indianapolis, Indiana, USA
| | - Lata M Udari
- Department of Medical and Molecular Genetics, Indiana University (IU) School of Medicine, Indianapolis, Indiana, USA
| | - Primavera RiveraHernandez
- Department of Medical and Molecular Genetics, Indiana University (IU) School of Medicine, Indianapolis, Indiana, USA
| | - Jason J Kwon
- Department of Medical and Molecular Genetics, Indiana University (IU) School of Medicine, Indianapolis, Indiana, USA
| | | | - Jeffrey J Easler
- Department of Medicine, Division of Gastroenterology/Hepatology, IU Health, IU School of Medicine, Indianapolis, Indiana, USA.,The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, Indiana, USA
| | - Evan L Fogel
- Department of Medicine, Division of Gastroenterology/Hepatology, IU Health, IU School of Medicine, Indianapolis, Indiana, USA.,The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, Indiana, USA
| | - Stephen Pandol
- Department of Medicine, Cedar-Sinai Medical Center, Los Angeles, California, USA
| | - Janaiah Kota
- Department of Medical and Molecular Genetics, Indiana University (IU) School of Medicine, Indianapolis, Indiana, USA.,The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, Indiana, USA
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25
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Voutsadakis IA. Mutations of p53 associated with pancreatic cancer and therapeutic implications. Ann Hepatobiliary Pancreat Surg 2021; 25:315-327. [PMID: 34402431 PMCID: PMC8382872 DOI: 10.14701/ahbps.2021.25.3.315] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/19/2021] [Accepted: 05/31/2021] [Indexed: 12/30/2022] Open
Abstract
Pancreatic adenocarcinoma is a malignancy with rising incidence and grim prognosis. Despite improvements in therapeutics for treating metastatic pancreatic cancer, this disease is invariably fatal with survival time less than a few years. New molecular understanding of the pathogenesis of pancreatic adenocarcinoma based on efforts led by The Cancer Genome Atlas and other groups has elucidated the landscape of this disease and started to produce therapeutic results, leading to the first introduction of targeted therapies for subsets of pancreatic cancers bearing specific molecular lesions such as BRCA mutations. These efforts have highlighted that subsets of pancreatic cancers are particularly sensitive to chemotherapy. The most common molecular lesions in pancreatic adenocarcinomas are mutations in an oncogene KRAS and the TP53 gene that encodes for tumor suppressor protein p53. This paper will review the landscape of pancreatic cancers, focusing on mutations of p53, a major tumor suppressor protein, in pancreatic cancers and possible therapeutic repercussions.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, ON, Canada.,Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON, Canada
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26
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Kondratyeva L, Chernov I, Kopantzev E, Didych D, Kuzmich A, Alekseenko I, Kostrov S, Sverdlov E. Pancreatic Lineage Specifier PDX1 Increases Adhesion and Decreases Motility of Cancer Cells. Cancers (Basel) 2021; 13:cancers13174390. [PMID: 34503200 PMCID: PMC8430990 DOI: 10.3390/cancers13174390] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 12/16/2022] Open
Abstract
Intercellular interactions involving adhesion factors are key operators in cancer progression. In particular, these factors are responsible for facilitating cell migration and metastasis. Strengthening of adhesion between tumor cells and surrounding cells or extracellular matrix (ECM), may provide a way to inhibit tumor cell migration. Recently, we demonstrated that PDX1 ectopic expression results in the reduction of pancreatic cancer line PANC-1 cell motility in vitro and in vivo, and we now provide experimental data confirming the hypothesis that suppression of migration may be related to the effect of PDX1 on cell adhesion. Cell migration analyses demonstrated decreased motility of pancreatic Colo357 and PANC-1 cell lines expressing PDX1. We observed decreased expression levels of genes associated with promoting cell migration and increased expression of genes negatively affecting cell motility. Expression of the EMT regulator genes was only mildly induced in cells expressing PDX1 during the simulation of the epithelial-mesenchymal transition (EMT) by the addition of TGFβ1 to the medium. PDX1-expressing cancer cell lines showed increased cell adhesion to collagen type I, fibronectin, and poly-lysine. We conclude that ectopic expression of PDX1 reduces the migration potential of cancer cells, by increasing the adhesive properties of cells and reducing the sensitivity to TGFβ1-induced EMT.
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Affiliation(s)
- Liya Kondratyeva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (I.C.); (E.K.); (D.D.); (A.K.); (I.A.)
- Correspondence: (L.K.); (E.S.)
| | - Igor Chernov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (I.C.); (E.K.); (D.D.); (A.K.); (I.A.)
| | - Eugene Kopantzev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (I.C.); (E.K.); (D.D.); (A.K.); (I.A.)
| | - Dmitry Didych
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (I.C.); (E.K.); (D.D.); (A.K.); (I.A.)
| | - Alexey Kuzmich
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (I.C.); (E.K.); (D.D.); (A.K.); (I.A.)
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, Ploshchad’ Akademika Kurchatova, 123182 Moscow, Russia;
| | - Irina Alekseenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (I.C.); (E.K.); (D.D.); (A.K.); (I.A.)
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, Ploshchad’ Akademika Kurchatova, 123182 Moscow, Russia;
| | - Sergey Kostrov
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, Ploshchad’ Akademika Kurchatova, 123182 Moscow, Russia;
| | - Eugene Sverdlov
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, Ploshchad’ Akademika Kurchatova, 123182 Moscow, Russia;
- Correspondence: (L.K.); (E.S.)
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27
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Milan M, Diaferia GR, Natoli G. Tumor cell heterogeneity and its transcriptional bases in pancreatic cancer: a tale of two cell types and their many variants. EMBO J 2021; 40:e107206. [PMID: 33844319 PMCID: PMC8246061 DOI: 10.15252/embj.2020107206] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), one of the most highly lethal tumors, is characterized by complex histology, with a massive fibrotic stroma in which both pseudo-glandular structures and compact nests of abnormally differentiated tumor cells are embedded, in different proportions and with different mutual relationships in space. This complexity and the heterogeneity of the tumor component have hindered the development of a broadly accepted, clinically actionable classification of PDACs, either on a morphological or a molecular basis. Here, we discuss evidence suggesting that such heterogeneity can to a large extent, albeit not exclusively, be traced back to two main classes of PDAC cells that commonly coexist in the same tumor: cells that maintained their ability to differentiate toward endodermal, mucin-producing epithelia and epithelial cells unable to form glandular structures and instead characterized by various levels of squamous differentiation and the expression of mesenchymal lineage genes. The underlying gene regulatory networks and how they are controlled by distinct transcription factors, as well as the practical implications of these two different populations of tumor cells, are discussed.
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Affiliation(s)
- Marta Milan
- Department of Experimental OncologyEuropean Institute of Oncology (IEO) IRCCSMilanItaly
- Present address:
The Francis Crick InstituteLondonUK
| | - Giuseppe R Diaferia
- Department of Experimental OncologyEuropean Institute of Oncology (IEO) IRCCSMilanItaly
| | - Gioacchino Natoli
- Department of Experimental OncologyEuropean Institute of Oncology (IEO) IRCCSMilanItaly
- Humanitas UniversityMilanItaly
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28
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REST Inhibits Direct Reprogramming of Pancreatic Exocrine to Endocrine Cells by Preventing PDX1-Mediated Activation of Endocrine Genes. Cell Rep 2021; 31:107591. [PMID: 32375045 DOI: 10.1016/j.celrep.2020.107591] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 01/29/2020] [Accepted: 04/09/2020] [Indexed: 12/13/2022] Open
Abstract
The emerging appreciation of plasticity among pancreatic lineages has created interest in harnessing cellular reprogramming for β cell replacement therapy of diabetes. Current reprogramming methodologies are inefficient, largely because of a limited understanding of the underlying mechanisms. Using an in vitro reprogramming system, we reveal the transcriptional repressor RE-1 silencing transcription factor (REST) as a barrier for β cell gene expression in the reprogramming of pancreatic exocrine cells. We observe that REST-bound loci lie adjacent to the binding sites of multiple key β cell transcription factors, including PDX1. Accordingly, a loss of REST function combined with PDX1 expression results in the synergistic activation of endocrine genes. This is accompanied by increased histone acetylation and PDX1 binding at endocrine gene loci. Collectively, our data identify a mechanism for REST activity involving the prevention of PDX1-mediated activation of endocrine genes and uncover REST downregulation and the resulting chromatin alterations as key events in β cell reprogramming.
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29
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Camolotto SA, Belova VK, Torre-Healy L, Vahrenkamp JM, Berrett KC, Conway H, Shea J, Stubben C, Moffitt R, Gertz J, Snyder EL. Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4. Gut 2021; 70:900-914. [PMID: 32826305 PMCID: PMC7945295 DOI: 10.1136/gutjnl-2020-321316] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/17/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: classical and basal-like. The classical subtype is characterised by a more favourable prognosis and better response to chemotherapy than the basal-like subtype. The classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor hepatocyte nuclear factor 4 α (HNF4α). The objective of this study is to evaluate the role of HNF4α, SIX4 and SIX1 in regulating the growth and molecular subtype of PDAC. DESIGN We manipulate the expression of HNF4α, SIX4 and SIX1 in multiple in vitro and in vivo PDAC models. We determine the consequences of manipulating these genes on PDAC growth, differentiation and molecular subtype using functional assays, gene expression analysis and cross-species comparisons with human datasets. RESULTS We show that HNF4α restrains tumour growth and drives tumour cells toward an epithelial identity. Gene expression analysis of murine models and human tumours shows that HNF4α activates expression of genes associated with the classical subtype. HNF4α also directly represses SIX4 and SIX1, two mesodermal/neuronal lineage specifiers expressed in the basal-like subtype. Finally, SIX4 and SIX1 drive proliferation and regulate differentiation in HNF4α-negative PDAC. CONCLUSION Our data show that HNF4α regulates the growth and molecular subtype of PDAC by multiple mechanisms, including activation of the classical gene expression programme and repression of SIX4 and SIX1, which may represent novel dependencies of the basal-like subtype.
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Affiliation(s)
- Soledad A Camolotto
- Department of Pathology, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Veronika K Belova
- Department of Pathology, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Luke Torre-Healy
- Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York, USA
| | - Jeffery M Vahrenkamp
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Kristofer C Berrett
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Hannah Conway
- HCI Clinical Trials Operations, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Jill Shea
- Department of Surgery, University of Utah, Salt Lake City, Utah, USA
| | - Chris Stubben
- Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Richard Moffitt
- Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York, USA
| | - Jason Gertz
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Eric L Snyder
- Department of Pathology, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
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Liang Z, Zhao B, Hou J, Zheng J, Xin G. CircRNA circ-OGDH (hsa_circ_0003340) Acts as a ceRNA to Regulate Glutamine Metabolism and Esophageal Squamous Cell Carcinoma Progression by the miR-615-5p/PDX1 Axis. Cancer Manag Res 2021; 13:3041-3053. [PMID: 33854374 PMCID: PMC8039021 DOI: 10.2147/cmar.s290088] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/01/2021] [Indexed: 01/17/2023] Open
Abstract
Background Circular RNA hsa_circ_0003340 (circ-OGDH) has been uncovered to be involved in esophageal squamous cell carcinoma (ESCC) progression. However, the mechanism by which circ-OGDH regulates ESCC progression is unclear. Methods Expression levels of circ-OGDH, microRNA (miR)-615-5p, and PDX1 (pancreatic and duodenal homeobox 1) mRNA were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, apoptosis, migration, invasion, and cell cycle progression of ESCC cells were analyzed by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), colony formation, flow cytometry, and transwell assays. Measurement of glutamine consumption, α-KG (α-ketoglutarate) production, and ATP (Adenosine Triphosphate) content using corresponding kits. Protein levels were analyzed by Western blotting. The targeting relationship between circ-OGDH or PDX1 and miR-615-5p was verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The function of circ-OGDH in ESCC was confirmed by animal experiments. Results Circ-OGDH was upregulated in ESCC. Circ-OGDH inhibition reduced ESCC growth in vivo and accelerated cell apoptosis, cell cycle arrest, repressed cell proliferation, migration, invasion, and reduced cell glutamine metabolism in ESCC cells in vitro. MiR-615-5p was downregulated in ESCC, while PDX1 had an opposite result. Circ-OGDH sponged miR-615-5p to regulate PDX1 expression. MiR-615-5p inhibitor neutralized the repressive effect of circ-OGDH knockdown on malignancy and glutamine metabolism of ESCC cells. PDX1 overexpression counteracted the inhibitory impact of miR-615-5p mimic on malignancy and glutamine metabolism of ESCC cells. Conclusion Circ-OGDH sponged miR-615-5p to elevate PDX1 expression, thus elevating glutamine metabolism and promoting tumor growth in ESCC. The study offered evidence to support circ-OGDH as a promising target for ESCC therapy.
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Affiliation(s)
- Zongying Liang
- Department of Thoracic Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, 067000, People's Republic of China
| | - Baoshan Zhao
- Department of Thoracic Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, 067000, People's Republic of China
| | - Jishen Hou
- Department of Thoracic Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, 067000, People's Republic of China
| | - Jingxiong Zheng
- Department of Thoracic Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, 067000, People's Republic of China
| | - Guohua Xin
- Department of Thoracic Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, 067000, People's Republic of China
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Azizi N, Toma J, Martin M, Khalid MF, Mousavi F, Win PW, Borrello MT, Steele N, Shi J, di Magliano MP, Pin CL. Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer. Oncogene 2021; 40:3118-3135. [PMID: 33864001 PMCID: PMC8173475 DOI: 10.1038/s41388-021-01771-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/04/2021] [Accepted: 03/16/2021] [Indexed: 02/02/2023]
Abstract
The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, we examined activating transcription factor 3 (ATF3), a mediator of the UPR that promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized that ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germline mutation of Atf3 (Atf3-/-) combined with acinar-specific induction of oncogenic KRAS (Ptf1acreERT/+KrasG12D/+). Atf3-/- mice with (termed APK) and without KRASG12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3-/- mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia (PanIN) formation and PDAC in Ptf1acreERT/+KrasG12D/+ mice. In response to injury, KRASG12D bypassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. Compared to Ptf1acreERT/+KrasG12D/+ mice, APK mice exhibited a significant decrease in pancreatic and total body weight, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. These findings suggest a complex, multifaceted role for ATF3 in pancreatic cancer pathology.
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Affiliation(s)
- Nawab Azizi
- Children's Health Research Institute, London, ON, Canada
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
| | - Jelena Toma
- Children's Health Research Institute, London, ON, Canada
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
- Department of Oncology, University of Western Ontario, London, ON, Canada
| | - Mickenzie Martin
- Children's Health Research Institute, London, ON, Canada
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
- Department of Biology, University of Western Ontario, London, ON, Canada
| | - Muhammad Faran Khalid
- Children's Health Research Institute, London, ON, Canada
- Department of Paediatrics, University of Western Ontario, London, ON, Canada
| | - Fatemeh Mousavi
- Children's Health Research Institute, London, ON, Canada
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
| | - Phyo Wei Win
- Children's Health Research Institute, London, ON, Canada
- Department of Paediatrics, University of Western Ontario, London, ON, Canada
| | - Maria Teresa Borrello
- Centre for Cancer Research Marseille, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Nina Steele
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Jiaqi Shi
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | | | - Christopher L Pin
- Children's Health Research Institute, London, ON, Canada.
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
- Department of Oncology, University of Western Ontario, London, ON, Canada.
- Department of Paediatrics, University of Western Ontario, London, ON, Canada.
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Willmann SJ. Cutting the edge between cancerogenesis and organogenesis of the pancreatic endocrine lineage allocation-comprehensive review of the genes Synaptotagmin 13 and 533041C22 Rik in epithelial-to-mesenchymal transition. Cancer Metastasis Rev 2021; 39:953-958. [PMID: 32447478 PMCID: PMC8205884 DOI: 10.1007/s10555-020-09897-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
In the past years, a multitude of studies has been published in the field of pancreatic organogenesis to interrogate the critical regulators of endocrine lineage segregation. Preliminary, transcription factors are guiding the transcriptional hierarchy of the endocrine specified cells, underpinning the importance of open chromatin formation. Signaling pathways either inhibit or accelerate the transcriptional landscape of pancreatic organogenesis. Thus, the fine-tuned process in the former pancreatic multipotent progenitors in the mechanism of lineage segregation needs to be elucidated more precisely for unraveling the temporal-spatial lineage-determining factors. Previously, Willmann et al. described candidate gene regulators of lineage segregation during the secondary transition of pancreatic organogenesis. At embryonic stage (E) 12.5, the former multipotent pancreatic progenitor compartmentalizes into the acinar, ductal, and endocrine lineage. In the adult pancreatic gland, acinar cells secrete enzymes that are transported by the duct to the duodenum. In contrast, the endocrine cells are clustered within the acinar tissue in the Islets of Langerhans. These Islets of Langerhans consist of a subset of α, δ, ε, and PP cells and β cells, and the function of the α and β cells is predominantly described by regulating glucose homeostasis, contrary, the function of the additional subtypes in the Islets of Langerhans remains still unclear and is rather pointing to a supportive role for the α and β cells. The essential wave of endocrine precursor cells emerges at E 14.5 out of the ductal cord-like structure in a process called epithelial-to-mesenchymal transition (EMT). This EMT is a reversible and incomplete process that includes significant intermedia states. As EMT is in focus in the field of cancer research, missense in endocrine lineage segregation is linking to a progression of pancreatic cancer, to be more precise in adenocarcinoma, e.g., meaning pancreatic ductal adenocarcinoma. Thus, the previous review will further accelerate the understanding of EMT about endocrine lineage segregation, respective pancreatic ductal adenocarcinoma, and introduces factors previously only known for either lineage segregation or related in cancer disease into a complete picture.
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Pancreatic and duodenal homeobox-1 in pancreatic ductal adenocarcinoma and diabetes mellitus. Chin Med J (Engl) 2020; 133:344-350. [PMID: 31904730 PMCID: PMC7004619 DOI: 10.1097/cm9.0000000000000628] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Diabetes mellitus and pancreatic ductal adenocarcinoma are two common diseases worldwidely which are both derived from different components of pancreas. The pancreatic and duodenal homeobox-1 (PDX1) is an essential transcription factor for the early development of pancreas that is required for the differentiation of all pancreatic cell lineages. Current evidence suggests an important role of PDX1 in both the origin and progression of pancreatic diseases. In this review, we discussed recent studies of PDX1 in diabetes mellitus and pancreatic cancer, and the therapeutic strategies derived from this transcription factor.
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Creeden JF, Alganem K, Imami AS, Henkel ND, Brunicardi FC, Liu SH, Shukla R, Tomar T, Naji F, McCullumsmith RE. Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia. Int J Mol Sci 2020; 21:ijms21228823. [PMID: 33233470 PMCID: PMC7700673 DOI: 10.3390/ijms21228823] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/16/2020] [Accepted: 11/19/2020] [Indexed: 02/08/2023] Open
Abstract
Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.
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Affiliation(s)
- Justin F. Creeden
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 6038, USA
- Correspondence: ; Tel.: +1-419-383-6474
| | - Khaled Alganem
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
| | - Ali S. Imami
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
| | - Nicholas D. Henkel
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
| | - F. Charles Brunicardi
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 6038, USA
| | - Shi-He Liu
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 6038, USA
| | - Rammohan Shukla
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
| | - Tushar Tomar
- PamGene International BV, 5200 BJ’s-Hertogenbosch, The Netherlands; (T.T.); (F.N.)
| | - Faris Naji
- PamGene International BV, 5200 BJ’s-Hertogenbosch, The Netherlands; (T.T.); (F.N.)
| | - Robert E. McCullumsmith
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
- Neurosciences Institute, ProMedica, Toledo, OH 6038, USA
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Creeden JF, Alganem K, Imami AS, Brunicardi FC, Liu SH, Shukla R, Tomar T, Naji F, McCullumsmith RE. Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases. Int J Mol Sci 2020; 21:ijms21228679. [PMID: 33213062 PMCID: PMC7698519 DOI: 10.3390/ijms21228679] [Citation(s) in RCA: 25] [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: 09/29/2020] [Revised: 11/12/2020] [Accepted: 11/14/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.
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Affiliation(s)
- Justin F. Creeden
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (R.S.); (R.E.M.)
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
- Correspondence: ; Tel.: +1-419-383-6474
| | - Khaled Alganem
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (R.S.); (R.E.M.)
| | - Ali S. Imami
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (R.S.); (R.E.M.)
| | - F. Charles Brunicardi
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Shi-He Liu
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Rammohan Shukla
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (R.S.); (R.E.M.)
| | - Tushar Tomar
- PamGene International BV, 5200 BJ’s-Hertogenbosch, The Netherlands; (T.T.); (F.N.)
| | - Faris Naji
- PamGene International BV, 5200 BJ’s-Hertogenbosch, The Netherlands; (T.T.); (F.N.)
| | - Robert E. McCullumsmith
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (R.S.); (R.E.M.)
- Neurosciences Institute, ProMedica, Toledo, OH 43606, USA
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Paoli C, Carrer A. Organotypic Culture of Acinar Cells for the Study of Pancreatic Cancer Initiation. Cancers (Basel) 2020; 12:E2606. [PMID: 32932616 PMCID: PMC7564199 DOI: 10.3390/cancers12092606] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/02/2020] [Accepted: 09/09/2020] [Indexed: 12/17/2022] Open
Abstract
The carcinogenesis of pancreatic ductal adenocarcinoma (PDA) progresses according to multi-step evolution, whereby the disease acquires increasingly aggressive pathological features. On the other hand, disease inception is poorly investigated. Decoding the cascade of events that leads to oncogenic transformation is crucial to design strategies for early diagnosis as well as to tackle tumor onset. Lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a highly specialized cell type in the pancreatic epithelium. Primary acinar cells can survive in vitro as organoid-like 3D spheroids, which can transdifferentiate into cells with a clear ductal morphology in response to different cell- and non-cell-autonomous stimuli. This event, termed acinar-to-ductal metaplasia, recapitulates the histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary pancreatic acinar cells, providing a historical and technical perspective. The impact of pancreatic cancer research will also be debated. In particular, we will dissect the roles of transcriptional, epigenetic, and metabolic reprogramming for tumor initiation and we will show how that can be modeled using ex vivo acinar cell cultures. Finally, mechanisms of PDA initiation described using organotypical cultures will be reviewed.
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Affiliation(s)
- Carlotta Paoli
- Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy;
- Department of Biology, University of Padova, 35129 Padova, Italy
| | - Alessandro Carrer
- Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy;
- Department of Biology, University of Padova, 35129 Padova, Italy
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Hoffman MT, Kemp SB, Salas-Escabillas DJ, Zhang Y, Steele NG, The S, Long D, Benitz S, Yan W, Margolskee RF, Bednar F, Pasca di Magliano M, Wen HJ, Crawford HC. The Gustatory Sensory G-Protein GNAT3 Suppresses Pancreatic Cancer Progression in Mice. Cell Mol Gastroenterol Hepatol 2020; 11:349-369. [PMID: 32882403 PMCID: PMC7779788 DOI: 10.1016/j.jcmgh.2020.08.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDA) initiation and progression are accompanied by an immunosuppressive inflammatory response. Here, we evaluated the immunomodulatory role of chemosensory signaling in metaplastic tuft cells (MTCs) by analyzing the role of GNAT3, a gustatory pathway G-protein expressed by MTCs, during PDA progression. METHODS Gnat3-null (Gnat3-/-) mice were crossbred with animals harboring a Cre-inducible KrasLSL-G12D/+ allele with either Ptf1aCre/+ (KC) or tamoxifen-inducible Ptf1aCreERT/+ (KCERT) mice to drive oncogenic KRAS expression in the pancreas. Ex vivo organoid conditioned medium generated from KC and Gnat3-/-;KC acinar cells was analyzed for cytokine secretion. Experimental pancreatitis was induced in KCERT and Gnat3-/-;KCERT mice to accelerate tumorigenesis, followed by analysis using mass cytometry and single-cell RNA sequencing. To study PDA progression, KC and Gnat3-/-;KC mice were aged to morbidity or 52 weeks. RESULTS Ablation of Gnat3 in KC organoids increased release of tumor-promoting cytokines in conditioned media, including CXCL1 and CXCL2. Analysis of Gnat3-/-;KCERT pancreata found altered expression of immunomodulatory genes in Cxcr2 expressing myeloid-derived suppressor cells (MDSCs) and an increased number of granulocytic MDSCs, a subset of tumor promoting MDSCs. Importantly, expression levels of CXCL1 and CXCL2, known ligands for CXCR2, were also elevated in Gnat3-/-;KCERT pancreata. Consistent with the tumor-promoting role of MDSCs, aged Gnat3-/-;KC mice progressed more rapidly to metastatic carcinoma compared with KC controls. CONCLUSIONS Compromised gustatory sensing, achieved by Gnat3 ablation, enhanced the CXCL1/2-CXCR2 axis to alter the MDSC population and promoted the progression of metastatic PDA.
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Affiliation(s)
- Megan T Hoffman
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Samantha B Kemp
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Pathology, University of Michigan, Ann Arbor, Michigan
| | - Daniel J Salas-Escabillas
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Yaqing Zhang
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Nina G Steele
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| | - Stephanie The
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Daniel Long
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Simone Benitz
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Wei Yan
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | | | - Filip Bednar
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Marina Pasca di Magliano
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| | - Hui-Ju Wen
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Howard C Crawford
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
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Nguyen AP, Nicoletti P, Arnol D, Califano A, Rodríguez Martínez M. Identifying the Potential Mechanism of Action of SNPs Associated With Breast Cancer Susceptibility With GVITamIN. Front Bioeng Biotechnol 2020; 8:798. [PMID: 32850701 PMCID: PMC7417307 DOI: 10.3389/fbioe.2020.00798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 06/22/2020] [Indexed: 11/24/2022] Open
Abstract
In the last decade, a large number of genome-wide association studies have uncovered many single-nucleotide polymorphisms (SNPs) that are associated with complex traits and confer susceptibility to diseases, such as cancer. However, so far only a few heritable traits with medium-to-high penetrance have been identified. The vast majority of the discovered variants only leads to disease in combination with other still unknown factors. Furthermore, while many studies aimed to link the effect of SNPs to changes in molecular phenotypes, the analysis has been often focused on testing associations between a single SNP and a transcript, hence disregarding the dysregulation of gene regulatory networks that has been shown to play an essential role in disease onset, notably in cancer. Here we take a systems biology approach and develop GVITamIN (Genetic VarIaTIoN functional analysis tool), a new statistical and computational approach to characterize the effect of a SNP on both genes and transcriptional regulatory programs. GVITamIN exploits a novel statistical approach to combine the usually small effect of disease-susceptibility SNPs, and reveals important potential oncogenic mechanisms, hence taking one step further in the direction of understanding the SNP mechanism of action. We apply GVITamIN on a breast cancer cohort and identify well-known cancer-related transcription factors, such as CTCF, LEF1, and FOXA1, as TFs dysregulated by breast cancer-associated SNPs. Furthermore, our results reveal that SNPs located on the RAD51B gene are significantly associated with an abnormal regulatory activity, suggesting a pivotal role for homologous recombination repair mechanisms in breast cancer.
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Affiliation(s)
- An-Phi Nguyen
- IBM Research-Zurich, Zurich, Switzerland.,ETH-Zürich, Zurich, Switzerland
| | - Paola Nicoletti
- Herbert Irving Cancer Research Center, Columbia University Medical Center, New York, NY, United States
| | | | - Andrea Califano
- Herbert Irving Cancer Research Center, Columbia University Medical Center, New York, NY, United States.,Department of Systems Biology, Columbia University, New York, NY, United States.,Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, United States.,Department of Biomedical Informatics, Columbia University, New York, NY, United States.,Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, United States.,Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States.,J.P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, United States
| | - María Rodríguez Martínez
- Herbert Irving Cancer Research Center, Columbia University Medical Center, New York, NY, United States
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Zhu B, Wu Y, Luo J, Zhang Q, Huang J, Li Q, Xu L, Lu E, Ren B. MNX1 Promotes Malignant Progression of Cervical Cancer via Repressing the Transcription of p21 cip1. Front Oncol 2020; 10:1307. [PMID: 32850410 PMCID: PMC7431913 DOI: 10.3389/fonc.2020.01307] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/23/2020] [Indexed: 01/08/2023] Open
Abstract
Motor neuron and pancreas homeobox 1 (MNX1) is a development-related genes and has been found to be highly expressed in several cancers. However, its biological function in cervical cancer remains largely unexplored. QRT-PCR, western blot, and IHC showed that MNX1 was abnormally overexpressed in cervical cancer tissues and cell lines. The high expression level of MNX1 correlated with poorer clinicopathologic characteristics in cervical cancer patients. Evaluated by RTCA (Real Time Cellular Analysis) proliferation assay, colony formation assay, EdU assay, transwell assay, and matrigel assay, we found that knockdown of MNX1 inhibited proliferation, migration and invasion of cervical cancer in vitro, while overexpression of MNX1 promoted malignant phenotype of cervical cancer. And subcutaneous xenograft model confirmed the malignant phenotype of MNX1 in vivo. Furthermore, flow cytometry, chromatin immunoprecipitation, and luciferase reporter assay indicated that MNX1 accelerated cell cycle transition by transcriptionally downregulating cyclin-dependent kinases p21cip1. In summary, our study revealed that MNX1 exerted an oncogenic role in cervical cancer via repressing the transcription of p21cip1 and thus accelerating cell cycle progression. Our results suggested that MNX1 was a potential diagnostic marker and therapeutic target for cervical cancer patients.
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Affiliation(s)
- Biqing Zhu
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Yaqin Wu
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Jing Luo
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Quanli Zhang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, China
| | - Jian Huang
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Qian Li
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Lin Xu
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, China.,Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Emei Lu
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Binhui Ren
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, China.,Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
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40
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Ahmed SAH, Ansari SA, Mensah-Brown EPK, Emerald BS. The role of DNA methylation in the pathogenesis of type 2 diabetes mellitus. Clin Epigenetics 2020; 12:104. [PMID: 32653024 PMCID: PMC7353744 DOI: 10.1186/s13148-020-00896-4] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/30/2020] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic condition characterised by β cell dysfunction and persistent hyperglycaemia. The disorder can be due to the absence of adequate pancreatic insulin production or a weak cellular response to insulin signalling. Among the three types of DM, namely, type 1 DM (T1DM), type 2 DM (T2DM), and gestational DM (GDM); T2DM accounts for almost 90% of diabetes cases worldwide. Epigenetic traits are stably heritable phenotypes that result from certain changes that affect gene function without altering the gene sequence. While epigenetic traits are considered reversible modifications, they can be inherited mitotically and meiotically. In addition, epigenetic traits can randomly arise in response to environmental factors or certain genetic mutations or lesions, such as those affecting the enzymes that catalyse the epigenetic modification. In this review, we focus on the role of DNA methylation, a type of epigenetic modification, in the pathogenesis of T2DM.
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Affiliation(s)
- Sanabil Ali Hassan Ahmed
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, Abu Dhabi, United Arab Emirates
| | - Suraiya Anjum Ansari
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, Abu Dhabi, United Arab Emirates
| | - Eric P K Mensah-Brown
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, Abu Dhabi, United Arab Emirates
| | - Bright Starling Emerald
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, Abu Dhabi, United Arab Emirates.
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Zhang Y, Le Y, Bu P, Cheng X. Regulation of Hox and ParaHox genes by perfluorochemicals in mouse liver. Toxicology 2020; 441:152521. [PMID: 32534105 DOI: 10.1016/j.tox.2020.152521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/30/2020] [Accepted: 06/08/2020] [Indexed: 01/01/2023]
Abstract
Homeobox (Hox) genes encode homeodomain proteins, which play important roles in the development and morphological diversification of organisms including plants and animals. Perfluorinated chemicals (PFCs), which are well recognized industrial pollutants and universally detected in human and wildlife, interfere with animal development. In addition, PFCs produce a number of hepatic adverse effects, such as hepatomegaly and dyslipidemia. Homeodomain proteins profoundly contribute to liver regeneration. Hox genes serve as either oncogenes or tumor suppressor genes during target organ carcinogenesis. However, to date, no study investigated whether PFCs regulate expression of Hox genes. This study was designed to determine the regulation of Hox (including Hox-a to -d subfamily members) and paraHox [including GS homeobox (Gsx), pancreatic and duodenal homeobox (Pdx), and caudal-related homeobox (Cdx) family members] genes by PFCs including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) in mouse liver. 46.4 mg/kg PFNA induced mRNA expression of Hoxa5, b7, c5, d10 and Pdx1 in wild-type and CAR-null mouse livers, but not in PPARα-null mouse livers, indicating a PPARα-dependent manner. PFOA, PFNA, and PFDA all induced mRNA expression of Hoxa5, b7, c5, d10, Pdx1 and Zeb2 in wild-type but not PPARα-null mouse livers. In addition, in Nrf2-null mouse livers, PFNA continued to increase mRNA expression of Hoxa5 and Pdx1, but not Hoxb7, c5 or d10. Furthermore, Wy14643, a classical PPARα agonist, induced mRNA expression of Hoxb7 and c5 in wild-type but not PPARα-null mouse livers. However, Wy14643 did not induce mRNA expression of Hoxa5, d10 or Pdx1 in either wild-type or PPARα-null mouse livers. TCPOBOP, a classical mouse CAR agonist, increased mRNA expression of Hoxb7, c5 and d10 but not Hoxa5 or Pdx1 in mouse livers. Moreover, PFNA decreased cytoplasmic and nuclear Hoxb7 protein levels in mouse livers. However, PFNA increased cytoplasmic Hoxc5 protein level but decreased nuclear Hoxc5 protein level in mouse livers. In conclusion, PFCs induced mRNA expression of several Hox genes such as Hoxb7, c5 and d10, mostly through the activation of PPARα and/or Nrf2 signaling.
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Affiliation(s)
- Yue Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, United States
| | - Yuan Le
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, United States
| | - Pengli Bu
- Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, Chicago, IL, 60064, United States
| | - Xingguo Cheng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, United States.
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Shan YS, Chen LT, Wu JS, Chang YF, Lee CT, Wu CH, Chiang NJ, Huang HE, Yen CJ, Chao YJ, Tsai HJ, Chen CY, Kang JW, Kuo CF, Tsai CR, Weng YL, Yang HC, Liu HC, Chang JS. Validation of genome-wide association study-identified single nucleotide polymorphisms in a case-control study of pancreatic cancer from Taiwan. J Biomed Sci 2020; 27:69. [PMID: 32456644 PMCID: PMC7251895 DOI: 10.1186/s12929-020-00664-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 05/22/2020] [Indexed: 02/07/2023] Open
Abstract
Background Due to differences in genetic background, it is unclear whether the genetic loci identified by the previous genome-wide association studies (GWAS) of pancreatic cancer also play significant roles in the development of pancreatic cancer among the Taiwanese population. Methods This study aimed to validate the 25 pancreatic cancer GWAS-identified single nucleotide polymorphisms (SNPs) in a case-control study (278 cases and 658 controls) of pancreatic cancer conducted in Taiwan. Statistical analyses were conducted to determine the associations between the GWAS-identified SNPs and pancreatic cancer risk. Gene-environment interaction analysis was conducted to evaluate the interactions between SNPs and environmental factors on pancreatic cancer risk. Results Among the 25 GWAS-identified SNPs, 7 (rs2816938 (~ 11 kb upstream of NR5A2), rs10094872 (~ 28 kb upstream of MYC), rs9581943 (200 bp upstream of PDX1) and 4 chromosome 13q22.1 SNPs: rs4885093, rs9573163, rs9543325, rs9573166) showed a statistically significant association with pancreatic cancer risk in the current study. Additional analyses showed two significant gene-environment interactions (between poor oral hygiene and NR5A2 rs2816938 and between obesity and PDX1 rs9581943) on the risk of pancreatic cancer. Conclusions The current study confirmed the associations between 7 of the 25 GWAS-identified SNPs and pancreatic risk among the Taiwanese population. Furthermore, pancreatic cancer was jointly influenced by lifestyle and medical factors, genetic polymorphisms, and gene-environment interaction. Additional GWAS is needed to determine the genetic polymorphisms that are more relevant to the pancreatic cancer cases occurring in Taiwan.
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Affiliation(s)
- Yan-Shen Shan
- Department of Surgery, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.,Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Ziyou 1st Road, Sanmin District, Kaohsiung, 80756, Taiwan.,Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Jin-Shang Wu
- Department of Family Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Yin-Fan Chang
- Department of Family Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Chih-Ting Lee
- Department of Family Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Chih-Hsing Wu
- Department of Family Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Nai-Jung Chiang
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.,Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Hsin-En Huang
- Department of Family Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Chia-Jui Yen
- Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Ying-Jui Chao
- Department of Surgery, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Hui-Jen Tsai
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.,Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Chiung-Yu Chen
- Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Jui-Wen Kang
- Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Chin-Fu Kuo
- Preventive Medicine Center, Taichung Tzu Chi Hospital, 88 Section 1, Fengxing Road, Tanzi District, Taichung, 427, Taiwan
| | - Chia-Rung Tsai
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan
| | - Ya-Ling Weng
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan
| | - Han-Chien Yang
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan
| | - Hui-Chin Liu
- Department of Nursing, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Jeffrey S Chang
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.
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Niu N, Lu P, Yang Y, He R, Zhang L, Shi J, Wu J, Yang M, Zhang ZG, Wang LW, Gao WQ, Habtezion A, Xiao GG, Sun Y, Li L, Xue J. Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis. Gut 2020; 69:715-726. [PMID: 31300513 DOI: 10.1136/gutjnl-2019-318362] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 06/18/2019] [Accepted: 06/30/2019] [Indexed: 01/04/2023]
Abstract
OBJECTIVE SETD2, the sole histone H3K36 trimethyltransferase, is frequently mutated or deleted in human cancer, including pancreatic ductal adenocarcinoma (PDAC). However, whether SETD2/H3K36me3 alteration results in PDAC remains largely unknown. DESIGN TCGA(PAAD) public database and PDAC tissue array with SETD2/H3K36me3 staining were used to investigate the clinical relevance of SETD2 in PDAC. Furthermore, to define the role of SETD2 in the carcinogenesis of PDAC, we crossed conditional Setd2 knockout mice (PdxcreSetd2flox/flox) together with KrasG12D mice. Moreover, to examine the role of SETD2 after ductal metaplasia, Crisp/cas9 was used to deplete Setd2 in PDAC cells. RNA-seq and H3K36me3 ChIP-seq were performed to uncover the mechanism. RESULTS SETD2 mutant/low expression was correlated with poor prognosis in patients with PDAC. Next, we found that Setd2 acted as a putative tumour suppressor in Kras-driven pancreatic carcinogenesis. Mechanistically, Setd2 loss in acinar cells facilitated Kras-induced acinar-to-ductal reprogramming, mainly through epigenetic dysregulation of Fbxw7. Moreover, Setd2 ablation in pancreatic cancer cells enhanced epithelia-mesenchymal transition (EMT) through impaired epigenetic regulation of Ctnna1. In addition, Setd2 deficiency led to sustained Akt activation via inherent extracellular matrix (ECM) production, which would favour their metastasis. CONCLUSION Together, our findings highlight the function of SETD2 during pancreatic carcinogenesis, which would advance our understanding of epigenetic dysregulation in PDAC. Moreover, it may also pave the way for development of targeted, patients-tailored therapies for PDAC patients with SETD2 deficiency.
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Affiliation(s)
- Ningning Niu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Ping Lu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Yanlin Yang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Ruizhe He
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Li Zhang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Juanjuan Shi
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Jinghua Wu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Minwei Yang
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Zhi-Gang Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li-Wei Wang
- Department of Oncology, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China.,School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Gary Guishan Xiao
- School of pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China
| | - Yongwei Sun
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Li Li
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China.,School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Xue
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
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Nelson SR, Zhang C, Roche S, O'Neill F, Swan N, Luo Y, Larkin A, Crown J, Walsh N. Modelling of pancreatic cancer biology: transcriptomic signature for 3D PDX-derived organoids and primary cell line organoid development. Sci Rep 2020; 10:2778. [PMID: 32066753 PMCID: PMC7026166 DOI: 10.1038/s41598-020-59368-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 01/28/2020] [Indexed: 12/12/2022] Open
Abstract
With a five-year survival rate of 9%, pancreatic ductal adenocarcinoma (PDAC) is the deadliest of all cancers. The rapid mortality makes PDAC difficult to research, and inspires a resolve to create reliable, tractable cellular models for preclinical cancer research. Organoids are increasingly used to model PDAC as they maintain the differentiation status, molecular and genomic signatures of the original tumour. In this paper, we present novel methodologies and experimental approaches to develop PDAC organoids from PDX tumours, and the simultaneous development of matched primary cell lines. Moreover, we also present a method of recapitulating primary cell line cultures to organoids (CLOs). We highlight the usefulness of CLOs as PDAC organoid models, as they maintain similar transcriptomic signatures as their matched patient-derived organoids and patient derived xenografts (PDX)s. These models provide a manageable, expandable in vitro resource for downstream applications such as high throughput screening, functional genomics, and tumour microenvironment studies.
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Affiliation(s)
- Shannon R Nelson
- National Institute for Cellular Biotechnology, School of Biotechnology, Dublin City University, Dublin 9, Ireland
| | - Chenxi Zhang
- BGI Education Centre, University of Chinese Academy of Sciences, Shenzhen, 518083, China.,Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, BGI-Shenzhen, Qingdao, 266000, China
| | - Sandra Roche
- National Institute for Cellular Biotechnology, School of Biotechnology, Dublin City University, Dublin 9, Ireland
| | - Fiona O'Neill
- National Institute for Cellular Biotechnology, School of Biotechnology, Dublin City University, Dublin 9, Ireland
| | - Niall Swan
- St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - Yonglun Luo
- Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, BGI-Shenzhen, Qingdao, 266000, China.,Department of Biomedicine, Aarhus University, 8000, Aarhus, Denmark
| | - AnneMarie Larkin
- National Institute for Cellular Biotechnology, School of Biotechnology, Dublin City University, Dublin 9, Ireland.,Institute of Technology, Sligo, Ash Lane, Sligo, Ireland
| | - John Crown
- St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - Naomi Walsh
- National Institute for Cellular Biotechnology, School of Biotechnology, Dublin City University, Dublin 9, Ireland.
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Bulanenkova SS, Snezhkov EV, Akopov SB. SOX9 as One of the Central Units of Regulation Axis of Pancreas Embryogenesis and Cancer Progression. MOLECULAR GENETICS MICROBIOLOGY AND VIROLOGY 2020. [DOI: 10.3103/s0891416819030030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Monkman JH, Thompson EW, Nagaraj SH. Targeting Epithelial Mesenchymal Plasticity in Pancreatic Cancer: A Compendium of Preclinical Discovery in a Heterogeneous Disease. Cancers (Basel) 2019; 11:E1745. [PMID: 31703358 PMCID: PMC6896204 DOI: 10.3390/cancers11111745] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/30/2019] [Accepted: 10/30/2019] [Indexed: 12/13/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a particularly insidious and aggressive disease that causes significant mortality worldwide. The direct correlation between PDAC incidence, disease progression, and mortality highlights the critical need to understand the mechanisms by which PDAC cells rapidly progress to drive metastatic disease in order to identify actionable vulnerabilities. One such proposed vulnerability is epithelial mesenchymal plasticity (EMP), a process whereby neoplastic epithelial cells delaminate from their neighbours, either collectively or individually, allowing for their subsequent invasion into host tissue. This disruption of tissue homeostasis, particularly in PDAC, further promotes cellular transformation by inducing inflammatory interactions with the stromal compartment, which in turn contributes to intratumoural heterogeneity. This review describes the role of EMP in PDAC, and the preclinical target discovery that has been conducted to identify the molecular regulators and effectors of this EMP program. While inhibition of individual targets may provide therapeutic insights, a single 'master-key' remains elusive, making their collective interactions of greater importance in controlling the behaviours' of heterogeneous tumour cell populations. Much work has been undertaken to understand key transcriptional programs that drive EMP in certain contexts, however, a collaborative appreciation for the subtle, context-dependent programs governing EMP regulation is needed in order to design therapeutic strategies to curb PDAC mortality.
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Affiliation(s)
- James H. Monkman
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia;
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia
- Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Erik W. Thompson
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia;
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia
- Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Shivashankar H. Nagaraj
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia;
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia
- Translational Research Institute, Brisbane, QLD 4102, Australia
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48
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Zang HL, Huang GM, Ju HY, Tian XF. Integrative analysis of the inverse expression patterns in pancreas development and cancer progression. World J Gastroenterol 2019; 25:4727-4738. [PMID: 31528097 PMCID: PMC6718033 DOI: 10.3748/wjg.v25.i32.4727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 07/05/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND As the malignant tumor, pancreatic cancer with a meager 5-years survival rate has been widely concerning. However, the molecular mechanisms that result in malignant transformation of pancreatic cells remain elusive.
AIM To investigate the gene expression profiles in normal or malignant transformed pancreas development.
METHODS MaSigPro and ANOVA were performed on two pancreas development datasets downloaded from the Gene Expression Omnibus database. Six pancreatic cancer datasets collected from TCGA database were used to establish differentially expressed genes related to pancreas development and pancreatic cancer. Moreover, gene clusters with highly similar interpretation patterns between pancreas development and pancreatic cancer progression were established by self-organizing map and singular value decomposition. Additionally, the hypergeometric test was performed to compare the corresponding interpretation patterns. Abnormal regions of metabolic pathway were analyzed using the Sub-pathway-GM method.
RESULTS This study established the continuously upregulated and downregulated genes at different stages in pancreas development and progression of pancreatic cancer. Through analysis of the differentially expressed genes, we established the inverse and consistent direction development-cancer pattern associations. Based on the application of the Subpathway-GM analysis, we established 17 significant metabolic sub-pathways that were closely associated with pancreatic cancer. Of note, the most significant metabolites sub-pathway was related to glycerophospholipid metabolism.
CONCLUSION The inverse and consistent direction development-cancer pattern associations were established. There was a significant correlation in the inverse patterns, but not consistent direction patterns.
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Affiliation(s)
- Hong-Liang Zang
- Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Guo-Min Huang
- Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Hai-Ying Ju
- Department of Hematology, Jilin Province Blood Center, Changchun 130000, Jilin Province, China
| | - Xiao-Feng Tian
- Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
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Krah NM, Narayanan SM, Yugawa DE, Straley JA, Wright CVE, MacDonald RJ, Murtaugh LC. Prevention and Reversion of Pancreatic Tumorigenesis through a Differentiation-Based Mechanism. Dev Cell 2019; 50:744-754.e4. [PMID: 31422917 DOI: 10.1016/j.devcel.2019.07.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 05/25/2019] [Accepted: 07/07/2019] [Indexed: 02/06/2023]
Abstract
Activating mutations in Kras are nearly ubiquitous in human pancreatic cancer and initiate precancerous pancreatic intraepithelial neoplasia (PanINs) when induced in mouse acinar cells. PanINs normally take months to form but are accelerated by deletion of acinar cell differentiation factors such as Ptf1a, suggesting that loss of cell identity is rate limiting for pancreatic tumor initiation. Using a genetic mouse model that allows for independent control of oncogenic Kras and Ptf1a expression, we demonstrate that sustained Ptf1a is sufficient to prevent Kras-driven tumorigenesis, even in the presence of tumor-promoting inflammation. Furthermore, reintroducing Ptf1a into established PanINs reverts them to quiescent acinar cells in vivo. Similarly, Ptf1a re-expression in human pancreatic cancer cells inhibits their growth and colony-forming ability. Our results suggest that reactivation of an endogenous differentiation program can prevent and reverse oncogene-driven transformation in cells harboring tumor-driving mutations, introducing a potential paradigm for solid tumor prevention and treatment.
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Affiliation(s)
- Nathan M Krah
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Shuba M Narayanan
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Deanne E Yugawa
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Julie A Straley
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Christopher V E Wright
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
| | - Raymond J MacDonald
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - L Charles Murtaugh
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
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50
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Kondratyeva LG, Safina DR, Chernov IP, Kopantzev EP, Kostrov SV, Sverdlov ED. PDX1, a key factor in pancreatic embryogenesis, can exhibit antimetastatic activity in pancreatic ductal adenocarcinoma. Cancer Manag Res 2019; 11:7077-7087. [PMID: 31440095 PMCID: PMC6666369 DOI: 10.2147/cmar.s209940] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Abstract
Background: In cancer biology, metastasizing is one of the most poorly studied processes. Pancreatic ductal adenocarcinoma (PDAC) is characterized by early metastasis, which is the leading cause of death. The PDX1 protein is crucial for the development of cancer, and its low levels are characteristic of the most aggressive PDAC tumors. The PDX1 is a mediator of initiation and progression of PDAC. However, further studies are needed to elucidate the role of PDX1 in the cancer metastasis. Purpose: To confirm the hypothesis that PDX1 in PDAC plays suppressor role of epithelial–mesenchymal transition (EMT), and to study its possible ability to inhibit metastasis. Methods: A PDX1-overexpressing PDAC cell line was obtained by lentiviral transduction of PANC-1 cells. PDX1 overexpression was confirmed by RT-PCR and Western blotting. Effects of PDX1 ectopic expression on cell proliferation and motility were determined in PANC-1 cells using MTS, cell cycle analysis, transwell and wound-healing assay. EMT genes expression was analyzed in PDX1-overexpressing and Control PANC-1. Finally, the migration potential of pancreatic cancer cells expressing PDX1 was evaluated using a zebrafish embryo model. Results: The motility of human PDAC cells PANC-1 considerably decreased at ectopic expression of PDX1. The decreased expression of ZEB1, the key factor of EMT, and almost unchanged expression of the genes that characterize the epithelial state suggest a decrease in the EMT ability. Suppression of PDX1 expression by siRNA knockdown restored the PANC1 motility. Conclusion: The results obtained suggest a possible therapeutic use of PDX1 delivery into PDAC patients with a reduced or absent expression of PDX1 in the most aggressive tumors.
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Affiliation(s)
- Liya G Kondratyeva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Dina R Safina
- Institute of Molecular Genetics Russian Academy of Sciences, Moscow, Russia
| | - Igor P Chernov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Eugene P Kopantzev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Sergey V Kostrov
- Institute of Molecular Genetics Russian Academy of Sciences, Moscow, Russia
| | - Eugene D Sverdlov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia.,Institute of Molecular Genetics Russian Academy of Sciences, Moscow, Russia
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