Genetic screens identify a context-specific PI3K/p27Kip1 node driving extrahepatic biliary cancer

Falcomata, C. et al. (2021) Genetic screens identify a context-specific PI3K/p27Kip1 node driving extrahepatic biliary cancer. Cancer Discovery, 11(12), pp. 3158-3177. (doi: 10.1158/2159-8290.CD-21-0209) (PMID:34282029) (PMCID:PMC7612573)

Abstract

Biliary tract cancer ranks among the most lethal human malignancies, representing an unmet clinical need. Its abysmal prognosis is tied to an increasing incidence and a fundamental lack of mechanistic knowledge regarding the molecular basis of the disease. Here, we show that the Pdx1-positive extrahepatic biliary epithelium is highly susceptible toward transformation by activated PIK3CAH1047R but refractory to oncogenic KrasG12D. Using genome-wide transposon screens and genetic loss-of-function experiments, we discover context-dependent genetic interactions that drive extrahepatic cholangiocarcinoma (ECC) and show that PI3K signaling output strength and repression of the tumor suppressor p27Kip1 are critical context-specific determinants of tumor formation. This contrasts with the pancreas, where oncogenic Kras in concert with p53 loss is a key cancer driver. Notably, inactivation of p27Kip1 permits KrasG12D-driven ECC development. These studies provide a mechanistic link between PI3K signaling, tissue-specific tumor suppressor barriers, and ECC pathogenesis, and present a novel genetic model of autochthonous ECC and genes driving this highly lethal tumor subtype.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Morton, Professor Jen and Sansom, Professor Owen and Solar Abboud, Dr Myriam

Creator Roles

Solar, M.: Resources, Investigation
Sansom, O. J.: Resources, Data curation, Investigation
Morton, J. P.: Resources, Data curation, Investigation

• Authors: Falcomata, C., Barthel, S., Ulrich, A., Diersch, S., Veltkamp, C., Rad, L., Boniolo, F., Solar, M., Steiger, K., Seidler, B., Zukowska, M., Madej, J., Wang, M., Ollinger, R., Maresch, R., Barenboim, M., Eser, S., Tschurtschenthaler, M., Mehrabi, A., Roessler, S., Goeppert, B., Kind, A., Schnieke, A., Robles, M. S., Bradley, A., Schmid, R. M., Schmidt-Supprian, M., Reichert, M., Weichert, W., Sansom, O. J., Morton, J. P., Rad, R., Schneider, G., and Saur, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Discovery
• Publisher: American Association for Cancer Research
• ISSN: 2159-8274
• ISSN (Online): 2159-8290
• Published Online: 19 July 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Cancer Discovery 11(12): 3158-3177
• Publisher Policy: Reproduced under a Creative Commons License