Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells
Zilu Wang, Matteo Burigotto, Sabrina Ghetti, François Vaillant, Tao Tan, Bianca D. Capaldo, Michelle Palmieri, Yumiko Hirokawa, Lin Tai, Daniel S. Simpson, Catherine Chang, Allan Shuai Huang, Elizabeth Lieschke, Sarah T. Diepstraten, Deeksha Kaloni, Chris Riffkin, David C.S. Huang, Connie S.N. Li Wai Suen, Alexandra L. Garnham, Peter Gibbs, Jane E. Visvader, Oliver M. Sieber, Marco J. Herold, Luca L. Fava, Gemma L. Kelly, Andreas Strasser
Abstract
Mutations in the tumor suppressor TP53 cause cancer and impart poor chemotherapeutic responses, reportedly through loss-of-function, dominant-negative effects and gain-of-function (GOF) activities. The relative contributions of these attributes is unknown. We found that removal of 12 different TP53 mutants with reported GOFs by CRISPR/Cas9 did not impact proliferation and response to chemotherapeutics of 15 human cancer cell lines and colon cancer-derived organoids in culture. Moreover, removal of mutant TP53/TRP53 did not impair growth or metastasis of human cancers in immune-deficient mice or growth of murine cancers in immune-competent mice. DepMap mining revealed that removal of 158 different TP53 mutants had no impact on the growth of 391 human cancer cell lines. In contrast, CRISPR-mediated restoration of wild-type TP53 extinguished the growth of human cancer cells in vitro. These findings demonstrate that LOF but not GOF effects of mutant TP53/TRP53 are critical to sustain expansion of many tumor types. SIGNIFICANCE: This study provides evidence that removal of mutant TP53, thereby deleting its reported GOF activities, does not impact the survival, proliferation, metastasis, or chemotherapy responses of cancer cells. Thus, approaches that abrogate expression of mutant TP53 or target its reported GOF activities are unlikely to exert therapeutic impact in cancer. See related commentary by Lane, p. 211 . This article is featured in Selected Articles from This Issue, p. 201.