
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.30.610360
preprint
1
Article
Distinct phenotypic consequences of cholangiocarcinoma-associated FGFR2 alterations depend on biliary epithelial maturity
O'Loughlin Evan http://orcid.org/0000-0001-5940-6150

Zhang Youwen
Chiasson-MacKenzie Christine http://orcid.org/0000-0002-4820-9765

Dave Preshita
Rheinbay Esther http://orcid.org/0000-0002-5566-6729

Stott Shannon L http://orcid.org/0000-0002-0349-0522

McClatchey Andrea I http://orcid.org/0000-0002-6150-3619

02 9 2024
2024.08.30.610360https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.30.610360
nihpp-2024.08.30.610360.pdf
Epithelial cancers disrupt tissue architecture and are often driven by mutations in genes that normally play important roles in epithelial morphogenesis. The intrahepatic biliary system is an epithelial tubular network that forms within the developing liver via the de novo initiation and expansion of apical lumens. Intrahepatic biliary tumors are often driven by different types of mutations in the FGFR2 receptor tyrosine kinase which plays important roles in epithelial morphogenesis in other developmental settings. Using a physiologic and quantitative 3D model we have found that FGFR signaling is important for biliary morphogenesis and that oncogenic FGFR2 mutants disrupt biliary architecture. Importantly, we found that both the trafficking and signaling of normal FGFR2 and the phenotypic consequences of FGFR2 mutants are influenced by the epithelial state of the cell. Unexpectedly, we found that different tumor-driving FGFR2 mutants disrupt biliary morphogenesis in completely different and clinically relevant ways, informing our understanding of morphogenesis and tumorigenesis and highlighting the importance of convergent studies of both.
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pmc
