Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity

Joel D Pearson; Katherine Huang; Marek Pacal; Sean R McCurdy; Suying Lu; Arthur Aubry; Tao Yu; Kristine M Wadosky; Letian Zhang; Tao Wang; Alex Gregorieff; Mohammad Ahmad; Helen Dimaras; Ellen Langille; Susan P C Cole; Philippe P Monnier; Benjamin H Lok; Ming-Sound Tsao; Nagako Akeno; Daniel Schramek; Kathryn A Wikenheiser-Brokamp; Erik S Knudsen; Agnieszka K Witkiewicz; Jeffrey L Wrana; David W Goodrich; Rod Bremner

doi:10.1016/j.ccell.2021.06.016

Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity

Cancer Cell. 2021 Aug 9;39(8):1115-1134.e12. doi: 10.1016/j.ccell.2021.06.016. Epub 2021 Jul 21.

Authors

Joel D Pearson¹, Katherine Huang², Marek Pacal², Sean R McCurdy², Suying Lu², Arthur Aubry¹, Tao Yu², Kristine M Wadosky³, Letian Zhang³, Tao Wang⁴, Alex Gregorieff⁵, Mohammad Ahmad², Helen Dimaras⁶, Ellen Langille⁷, Susan P C Cole⁸, Philippe P Monnier⁹, Benjamin H Lok¹⁰, Ming-Sound Tsao¹¹, Nagako Akeno¹², Daniel Schramek⁷, Kathryn A Wikenheiser-Brokamp¹³, Erik S Knudsen¹⁴, Agnieszka K Witkiewicz¹⁵, Jeffrey L Wrana⁷, David W Goodrich³, Rod Bremner¹⁶

Affiliations

¹ Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON M5T 3A9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
² Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada.
³ Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
⁴ Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
⁵ Department of Pathology, McGill University and Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, ON H4A 3J1, Canada.
⁶ Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON M5T 3A9, Canada; The Department of Ophthalmology & Vision Sciences, Child Health Evaluative Sciences Program, and Center for Global Child Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Clinical Public Health, Dalla Lana School of Public Health, The University of Toronto, Toronto, ON M5T 3M7, Canada.
⁷ Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁸ Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, ON K7L 3N6, Canada.
⁹ Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON M5T 3A9, Canada; Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, ON M5T 2S8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁰ Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
¹¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
¹² Division of Pathology & Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹³ Division of Pathology & Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; The Perinatal Institute Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pathology & Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
¹⁴ Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
¹⁵ Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
¹⁶ Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON M5T 3A9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].

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 YAP^on or YAP^off cancer classes that express or silence YAP, respectively. YAP^off 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 YAP^off or YAP^on 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Enhancer Elements, Genetic
Gene Expression Regulation, Neoplastic
Humans
Integrins / metabolism
Lung Neoplasms / genetics*
Male
Mice, Transgenic
Prostatic Neoplasms / genetics
Prostatic Neoplasms / pathology
Retinal Neoplasms / genetics
Retinal Neoplasms / pathology
Retinoblastoma / genetics
Retinoblastoma / pathology
Retinoblastoma Binding Proteins / genetics
Small Cell Lung Carcinoma / genetics*
TEA Domain Transcription Factors / genetics*
TEA Domain Transcription Factors / metabolism
Transcriptional Coactivator with PDZ-Binding Motif Proteins / genetics*
Ubiquitin-Protein Ligases / genetics
Xenograft Model Antitumor Assays
YAP-Signaling Proteins / genetics*

Substances

Antineoplastic Agents
Integrins
RB1 protein, human
Retinoblastoma Binding Proteins
TEA Domain Transcription Factors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
WWTR1 protein, human
YAP-Signaling Proteins
YAP1 protein, human
Ubiquitin-Protein Ligases

Abstract

Publication types

MeSH terms

Substances

Grants and funding