Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer

Paffenholz, Stella V, Salvagno, Camilla, Ho, Yu-Jui, Limjoco, Matthew, Baslan, Timour, Tian, Sha, Kulick, Amanda, de Stanchina, Elisa, Wilkinson, John E, Barriga, Francisco M, Zamarin, Dmitriy, Cubillos-Ruiz, Juan R, Leibold, Josef, Lowe, Scott W (February 2022) Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer. Proceedings of the National Academy of Sciences of USA, 119 (5). e2117754119-e2117754119. ISSN 0027-8424

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Abstract

High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease. By leveraging these models, we show that the ability to undergo senescence underlies the clinically observed increase in sensitivity of homologous recombination (HR)-deficient HGSOC tumors to platinum-based chemotherapy. Further, cGas/STING-mediated activation of a restricted senescence-associated secretory phenotype (SASP) was sufficient to induce immune infiltration and sensitize HR-deficient tumors to immune checkpoint blockade. In sum, our study identifies senescence propensity as a predictor of therapy response and defines a limited SASP profile that appears sufficient to confer added vulnerability to concurrent immunotherapy and, more broadly, provides a blueprint for the implementation of electroporation-based mouse models to reveal mechanisms of oncogenesis and therapy response in HGSOC.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > neoplasms organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > drugs and therapies organism description > animal > gender > female organism description > animal > gender diseases & disorders > cancer > drugs and therapies > Immunotherapy organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > ovarian cancer diseases & disorders > cancer > prognosis organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence diseases & disorders > cancer > cancer types
CSHL Authors:	Baslan, Timour Lowe, Scott W.
Communities:	CSHL labs > Krasnitz lab CSHL labs > Lowe lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	1 February 2022
Date Deposited:	03 Feb 2022 19:24
Last Modified:	16 Jan 2024 20:59
PMCID:	PMC8812522
URI:	https://repository.cshl.edu/id/eprint/40512

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