@article{745888c9ca6e4e6b890e94c45e1d0980,
title = "Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity",
abstract = "Cancer heterogeneity impacts therapeutic response, driving efforts to discover over-arching rules that supersede variability. Here, we define pan-cancer binary classes based on distinct expression of YAP and YAP-responsive adhesion regulators. Combining informatics with in vivo and in vitro gain- and loss-of-function studies across multiple murine and human tumor types, we show that opposite pro- or anti-cancer YAP activity functionally defines binary YAPon or YAPoff cancer classes that express or silence YAP, respectively. YAPoff solid cancers are neural/neuroendocrine and frequently RB1−/−, such as retinoblastoma, small cell lung cancer, and neuroendocrine prostate cancer. YAP silencing is intrinsic to the cell of origin, or acquired with lineage switching and drug resistance. The binary cancer groups exhibit distinct YAP-dependent adhesive behavior and pharmaceutical vulnerabilities, underscoring clinical relevance. Mechanistically, distinct YAP/TEAD enhancers in YAPoff or YAPon cancers deploy anti-cancer integrin or pro-cancer proliferative programs, respectively. YAP is thus pivotal across cancer, but in opposite ways, with therapeutic implications.",
keywords = "RB1, TAZ/WWTR1, TEAD, YAP, cancer plasticity, cancer stratification, neuroendocrine cancer, retinoblastoma, retinoma, small cell cancers",
author = "Pearson, {Joel D.} and Katherine Huang and Marek Pacal and McCurdy, {Sean R.} and Suying Lu and Arthur Aubry and Tao Yu and Wadosky, {Kristine M.} and Letian Zhang and Tao Wang and Alex Gregorieff and Mohammad Ahmad and Helen Dimaras and Ellen Langille and Cole, {Susan P.C.} and Monnier, {Philippe P.} and Lok, {Benjamin H.} and Tsao, {Ming Sound} and Nagako Akeno and Daniel Schramek and Wikenheiser-Brokamp, {Kathryn A.} and Knudsen, {Erik S.} and Witkiewicz, {Agnieszka K.} and Wrana, {Jeffrey L.} and Goodrich, {David W.} and Rod Bremner",
note = "Funding Information: B.H.L. reports honoraria and non-financial support from AstraZeneca, and has received research funding from Pfizer and AstraZeneca not related to this work. Funding Information: We thank Pao-Tien Chuang for Cgrp CreER mice, Brenda Gallie for retinoblastoma samples, Meredith Irwin for neuroblastoma lines, Eldad Zacksenhaus for breast cancer lines, Todd McMullen for NE pancreatic lines, Rob Ingham for lymphoma cells lines, Mark Minden and Aaron Schimmer for leukemia cell lines, Charles M Rudin for SCLC PDXs, Ayla Pearson for assistance with data analysis, Hanna Rosenheck for help with multispectral imaging, Michael Parsons at the LTRI Flow Cytometry Core for help with flow cytometry, Louise Brown of the LTRI Imaging Core for assistance with imaging, Kin Chan at the LTRI Network Biology Collaborative Centre (nbcc.lunenfeld.ca) for RNA-seq and ChIP-seq services, and Rene Bernards, Dan Durocher, Helen McNeill, Jeremy Sivak and Valerie Wallace for helpful comments. The NBCC is supported by the Canada Foundation for Innovation , the Ontario Genomics , and Genome Canada and Ontario Genomics ( OGI-139 ). J.D.P. is a recipient of a post-doctoral fellowship from the Canadian Institutes of Health Research (CIHR). The project was supported by funding from the CIHR (grant no. 153128 ), The Cancer Research Society , and the Krembil Foundation (to R.B.); a CIHR Foundation Program Grant ( FDN 143252 ) and a Terry Fox Research Institute Program Project Grant (TFRI Project no. 1107 ) (to J.L.W.); and research in the lab of B.H.L. is supported by funding from the Conquer Cancer Foundation of ASCO, International Association for the Study of Lung Cancer (IASLC), Ontario Molecular Pathology Research Network of the Ontario Institute for Cancer Research, Lung Cancer Research Foundation , Canada Foundation for Innovation, Cancer Research Society , CIHR , National Institute of Health/ National Cancer Institute ( U01CA253383 ), Clinical and Translational Science Center at Weill Cornell Medical Center and MSKCC ( UL1TR00457 ). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = aug,
day = "9",
doi = "10.1016/j.ccell.2021.06.016",
language = "English (US)",
volume = "39",
pages = "1115--1134.e12",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "8",
}