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

Wang, Z; Burigotto, M; Ghetti, S; Vaillant, F; Tan, T; Capaldo, BD; Palmieri, M; Hirokawa, Y; Tai, L; Simpson, DS; Chang, C; Huang, AS; Lieschke, E; Diepstraten, ST; Kaloni, D; Riffkin, C; Huang, DCS; Li Wai Suen, CS; Garnham, AL; Gibbs, P; Visvader, JE; Sieber, OM; Herold, MJ; Fava, LL; Kelly, GL; Strasser, A

Author(s): Wang, Z; Burigotto, M; Ghetti, S; Vaillant, F; Tan, T; Capaldo, BD; Palmieri, M; Hirokawa, Y; Tai, L; Simpson, DS; Chang, C; Huang, AS; Lieschke, E; Diepstraten, ST; Kaloni, D; Riffkin, C; Huang, DCS; Li Wai Suen, CS; Garnham, AL; Gibbs, P; Visvader, JE; Sieber, OM; Herold, MJ; Fava, LL; Kelly, GL; Strasser, A;
Details: Publication Year 2024-10-25,Volume 14,Issue #2,Page 362-379
Journal Title: Cancer Discovery
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 wt 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.
Publisher: AACR
Keywords: Humans; Mice; Animals; Cell Line, Tumor; *Tumor Suppressor Protein p53/genetics/metabolism; Mutation; *Colonic Neoplasms/genetics; Cell Proliferation
Research Division(s): Bioinformatics; Cancer Biology And Stem Cells; Inflammation; Personalised Oncology; Blood Cells And Blood Cancer; Cancer Biology and Stem Cells; Personalised Oncology; Inflammation; Bioinformatics
PubMed ID: 37877779
Publisher's Version: https://doi.org/10.1158/2159-8290.Cd-23-0402
Open Access at Publisher's Site: https://doi.org/10.1158/2159-8290.Cd-23-0402
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-11-20 12:03:42

Last Modified: 2024-03-05 09:29:07