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 col-lective invasion phenotype in SMAD4-mutant PDAC organoids, indicating that SMAD4 loss is required for collective invasion in PDAC organoids. Surprisingly, invasion in passaged SMAD4mutant PDAC organoids required exogenous TGFb, suggesting that invasion in SMAD4-mutant organoids is mediated through noncanonical TGFb signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGFb-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.
Introduction: Recurrence of hepatocellular carcinoma (rHCC) after liver transplantation (LT) is associated with limited survival. Therefore, identification of factors that prolong survival in these patients is of great interest. Surgical resection, radiotherapy, and transarterial chemoembolization (TACE) are established interventions to improve outcomes in these patients; however, the impact of immunosuppression is unknown. Methods: All patients diagnosed with rHCC in the follow-up after LT were identified from a database of liver recipients transplanted between 1988 and 2019 at our institution (Charité Universitätsmedizin Berlin, Germany). Based on the immunosuppressive regimen following diagnosis of rHCC and the oncological treatment approach, survival analysis was performed. Results: Among 484 patients transplanted for HCC, 112 (23.1%) developed rHCC in the follow-up. Recurrent HCC was diagnosed at a median interval of 16.0 months (range 1.0–203.0), with the majority presenting early after transplantation (63.0%, <2 years). Median survival after rHCC diagnosis was 10.6 months (0.3–228.7). Reduction of immunosuppression was associated with improved survival, particularly in patients with palliative treatment (8.4 versus 3.0 months). In addition, greater reduction of immunosuppression seemed to be associated with greater prolongation of survival. Graft rejection after reduction was uncommon (n = 7, 6.8%) and did not result in any graft loss. Patients that underwent surgical resection showed improved survival rates (median 19.5 vs. 8.7 months). Conclusion: Reduction of immunosuppressive therapy after rHCC diagnosis is associated with prolonged survival in LT patients. Therefore, reduction of immunosuppression should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful.
Intraductal tubulopapillary neoplasm (ITPN) is a distinct precancerous lesion in the pancreas with unique clinical and molecular features. Although in vitro studies in two-dimensional culture have led to numerous important insights in pancreatic cancer, such models are currently lacking for precancerous lesions. In this study, we report the generation and characterization of a cell line from a human pancreatic ITPN. Neoplastic cells were initially cultured in a three-dimensional organoid system, followed by transfer to two-dimensional culture. RNA sequencing revealed a gene expression profile consistent with pancreatic ductal origin, and whole genome sequencing identified many somatic mutations (including in genes involved in DNA repair and WNT signaling) and structural rearrangements. In vitro characterization of the tumorigenic potential demonstrated a phenotype between that of normal pancreatic ductal cells and cancer cell lines. This cell line represents a valuable resource for interrogation of unique ITPN biology, as well as precancerous pancreatic lesions more generally.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.