Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome.

Autor:	Huang W; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Hepatic Surgery Center, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China., Navarro-Serer B; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Jeong YJ; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Chianchiano P; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Xia L; Department of Gastroenterology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Luchini C; Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy., Veronese N; National Institute of Gastroenterology-Research Hospital, IRCCS 'S. de Bellis', Castellana Grotte, Bari, Italy., Dowiak C; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Ng T; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Trujillo MA; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Huang B; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Pflüger MJ; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Macgregor-Das AM; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Lionheart G; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Jones D; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Fujikura K; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Nguyen-Ngoc KV; Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Neumann NM; Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland., Groot VP; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Surgery, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands., Hasanain A; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., van Oosten AF; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Fischer SE; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, Canada., Gallinger S; Department of Surgery, University of Toronto, University Health Network, Toronto, Canada., Singhi AD; Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania., Zureikat AH; Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania., Brand RE; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania., Gaida MM; Institute of Pathology, University Medical Center Mainz, JGU-Mainz, Germany., Heinrich S; General, Visceral and Transplantation Surgery, University Hospital of Mainz, Mainz, Germany., Burkhart RA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., He J; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Wolfgang CL; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Goggins MG; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Thompson ED; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Roberts NJ; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Ewald AJ; Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Wood LD; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. ldwood@jhmi.edu.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Jul 01; Vol. 80 (13), pp. 2804-2817. Date of Electronic Publication: 2020 May 06.
DOI:	10.1158/0008-5472.CAN-19-1523
Abstrakt:	Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by extensive local invasion and systemic spread. In this study, we employed a three-dimensional organoid model of human pancreatic cancer to characterize the molecular alterations critical for invasion. Time-lapse microscopy was used to observe invasion in organoids from 25 surgically resected human PDAC samples in collagen I. Subsequent lentiviral modification and small-molecule inhibitors were used to investigate the molecular programs underlying invasion in PDAC organoids. When cultured in collagen I, PDAC organoids exhibited two distinct, morphologically defined invasive phenotypes, mesenchymal and collective. Each individual PDAC gave rise to organoids with a predominant phenotype, and PDAC that generated organoids with predominantly mesenchymal invasion showed a worse prognosis. Collective invasion predominated in organoids from cancers with somatic mutations in the driver gene SMAD4 (or its signaling partner TGFBR2 ). Reexpression of SMAD4 abrogated the collective invasion phenotype in SMAD4 -mutant PDAC organoids, indicating that SMAD4 loss is required for collective invasion in PDAC organoids. Surprisingly, invasion in passaged SMAD4 -mutant PDAC organoids required exogenous TGFβ, suggesting that invasion in SMAD4 -mutant organoids is mediated through noncanonical TGFβ signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGFβ-stimulated invasion in SMAD4 -mutant PDAC organoids, as inhibition of these GTPases suppressed collective invasion in our model. These data suggest that PDAC utilizes different invasion programs depending on SMAD4 status, with collective invasion uniquely present in PDAC with SMAD4 loss. SIGNIFICANCE: Organoid models of PDAC highlight the importance of SMAD4 loss in invasion, demonstrating that invasion programs in SMAD4 -mutant and SMAD4 wild-type tumors are different in both morphology and molecular mechanism. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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