Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression
The sparse vascularity of Pancreatic Ductal Adenocarcinoma (PDAC) presents a mystery: what prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cell...
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Published in | bioRxiv |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Paper |
Language | English |
Published |
Cold Spring Harbor
Cold Spring Harbor Laboratory Press
02.03.2023
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Subjects | |
Online Access | Get full text |
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Summary: | The sparse vascularity of Pancreatic Ductal Adenocarcinoma (PDAC) presents a mystery: what prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote Hedgehog signaling in fibroblasts, leading to inhibition of WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues.Competing Interest StatementA.C. is founder, equity holder, consultant, and director of DarwinHealth Inc., which has licensed IP related to these algorithms from Columbia University. Columbia University is an equity holder in DarwinHealth Inc.Footnotes* https://github.com/califano-lab/Olive_926-mouse-screen |
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DOI: | 10.1101/2023.03.02.529724 |