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

UID: 11014

Author(s): 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.* * MSK affiliated

Description
Summary from GEO:

"High-grade serous ovarian carcinoma (HGSOC) is associated with a dismal prognosis. While most patients initially respond to platinum-based chemotherapy, they almost always acquire resistance, and only a small subset of HGSOC patients benefit from immune checkpoint blockade (ICB). To elucidate the disease mechanisms and factors underlying sensitivity and resistance to conventional and immune-based therapies, we developed a fast and flexible pre-clinical mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immune competent mice using tissue electroporation. Tumors in these mice recapitulate both the proclivity of HGSOC to metastasize to the peritoneum and omentum and display histological, molecular, and treatment response features reminiscent of the human disease. Using this model, we show that the clinically observed increase in sensitivity of homologous recombination (HR) deficient ovarian tumors to platinum-based chemotherapy is driven by the preferential induction of senescence in the tumor cells. Intriguingly, HR-deficient (but not HR-proficient) tumors are uniquely sensitive to the combination of cisplatin and ICB owing to senescence-mediated activation of the cytosolic DNA sensing. This output becomes deactivated in a therapy-resistant model. Thus, genetically defined electroporation-based mouse models can be leveraged to elucidate the biology and therapy responses of HGSOG with the goal of improving treatment options for this deadly disease."

Overall design from GEO:

"For RNA-seq analysis of the transcriptional profiles of MP EPO-GEMM ovarian tumors, as well as normal ovaries of wild-type (WT) C57BL/6, total RNA was extracted from bulk tissue using the RNeasy Mini Kit (Qiagen). Purified polyA mRNA was subsequently fragmented, and first and second strand cDNA synthesis performed using standard Illumina mRNA TruSeq library preparation protocols. Double stranded cDNA was subsequently processed for TruSeq dual-index Illumina library generation."
Subject of Study
Mus musculus
Subject(s)
Carcinoma, Ovarian Epithelial
Cellular Senescence
Homologous Recombination
Immune Checkpoint Inhibitors
Ovarian Neoplasms
OncoTree Cancer Type(s)
High-Grade Serous Ovarian Cancer
Access via GEO


Accession #: GSE181651

Access via BioProject


Accession #: PRJNA752878

Access via SRA


Accession #: SRP331529

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus. BioProject., and SRA databases provide open access to these files.
Associated Publications
Paffenholz S, Salvagno C, Ho Y, Limjoco M, Baslan T, Tian S, Kulick A, de Stanchina E, Wilkinson J, Barriga F, Zamarin D, Cubillos-Ruiz J, Leibold J, Lowe S. Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer. Proceedings of the National Academy of Sciences of the United States of America. 2022; 119(5):e2117754119.
Equipment Used
Illumina HiSeq 2500

High throughput sequencing system

Dataset Format(s)
CSV
Dataset Size
7 MB
Data Catalog Record Updated
2023-11-07