Journal
CANCER RESEARCH
Volume 80, Issue 13, Pages 2804-2817Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-19-1523
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Funding
- American Cancer Society [RSG-18-143-01-CSM]
- NIH/NCI [P50 CA62924, U01CA217846, U54 CA2101732]
- NIH/NIDDK [K08 DK107781]
- Sol Goldman Pancreatic Cancer Research Center
- Buffone Family Gastrointestinal Cancer Research Fund
- Carol S. and Robert M. Long Pancreatic Cancer Research Fund
- Kaya Tuncer Career Development Award in Gastrointestinal Cancer Prevention
- AGA-Bernard Lee Schwartz Foundation Research Scholar Award in Pancreatic Cancer
- Sidney Kimmel Foundation for Cancer Research Kimmel Scholar Award
- AACR-Incyte Corporation Career Development Award for Pancreatic Cancer Research [16-20-46-WOOD]
- Gerald O Mann Charitable Foundation
- Joseph C Monastra Foundation
- Susan Wojcicki and Denis Troper
- Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through Government of Ontario
- Wallace McCain Centre for Pancreatic Cancer - Princess Margaret Cancer Foundation
- Terry Fox Research Institute
- Canadian Cancer Society Research Institute
- Pancreatic Cancer Canada Foundation
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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 L 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 TGF beta, suggesting that invasion in SMAD4-mutant organoids is mediated through noncanonical TGF beta signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGF beta-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.
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