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PROJET HoLOGRAM

Deciphering cellular and molecular HeterOgeneity in LOw-GRAde serous ovarian cancer for new treatMents

Ce projet est porté par l’Institut Curie.

CONTEXT

Epithelial ovarian cancer is a silent disease with poor prognosis. Low-grade serous carcinoma of the ovary or peritoneum (LGSC) has been separated 20 years ago from high-grade serous carcinomas (HGSC). Low-grade serous carcinoma is a rare disease that is genetically and clinically distinct from the high-grade serous carcinoma, but much less explored until now. Nowadays, the therapeutic strategy resides first in the surgical resection of the tumor followed by a systemic treatment (chemotherapy or hormonotherapy). As low-grade serous carcinoma carries mutations in RAS or RAF, targeted therapies have been tested in clinical trials with variable results, depending on the drug used and on the trial design. In this project, we will precisely define cellular composition and molecular features of LGSC tumors in order to define new therapeutic opportunities.

OBJECTIVES

Our consortium plans to establish a comprehensive and integrated map based on a set of biological and spatial data from an available LGSC patient collection, and to combine them with representative -already collected- clinical data. The current project aims to study LGSC by combining clinical and biological analyses. This project will benefit from the association between clinicians and biologists joining their skills to analyze this rare subgroup of ovarian cancer. The project will be based on an already constituted retrospective cohort of low-grade serous ovarian cancer, including 270 patients. The project will be subdivided into 3 main axes, which aim to:

RESULTS

In brief, we will define inter-tumor heterogeneity in LGSC by performing transcriptomic and genomic profiling. In addition, we will determine the cellular composition and molecular signatures of the different tumor microenvironment (TME) components in LGSC through deconvolution of bulk RNA sequencing and spatial transcriptomics. By comparing them with already generated data from high-grade serous ovarian cancer, we will highlight the common features between LGSC and HGSOC but also uncover the specific characteristics of LGSC (considering the content in different TME cell types and states, their spatial distribution, and molecular signatures). We will test the impact of LGSC molecular features and cellular composition on clinical outcome, in order to predict patient resistance to chemotherapy. Finally, we will identify novel therapeutic options for LGSC according to newly identified biological properties.

This tumor has received little attention since its definition 20 years ago. Hopefully several teams are now developing research programs on it and a strong competition has started. We dispose of several assets with a national database and high-level techniques to explore this disease and find new therapeutic options. Importantly, all these acquired knowledge and expertise (single cell analyses, deconvolution methods, spatial omics) will be transposable to other cancer types.

RECENT PUBLICATIONS

1. Kieffer, Y., Hocine, H.R., Gentric, G., Pelon, F., Bernard, C., Bourachot, B., Lameiras, S., Albergante, L., Bonneau, C., Guyard, A., et al. (2020). Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer. Cancer Discovery 10, 1330-1351. 10.1158/2159-8290.CD-19-1384.

2. H. Croizer, R. Mhaidly, Y. Kieffer, G. Gentric, L. Djerroudi, R. Leclere, F. Pelon, M. Bohec, A. Meng, D. Meseure, E. Romano, S. Baulande, A. Peltier, A. Vincent-Salomon and F. Mechta-Grigoriou. Comprehensive landscape of stromal heterogeneity and plasticity in breast cancer. Under Revision

3. M. Licaj, R. Mhaidly, Y. Kieffer, H. Croizer, C. Bonneau, A. Meng, L. Djerroudi, K. Mujangi-Ebeka, H. R. Hocine, B. Bourachot, I. Magagna, R. Leclere, M. Bohec, S. Baulande, M. Kamal, C. Le Tourneau, F. Lecuru, V. Becette, R. Rouzier, A. Vincent-Salomon, G. Gentric and F. Mechta-Grigoriou. Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway. Under Revision

4. Brouillard-Saby F, Saint-Martin C, Ray-Coquard I, Gladieff L, Pomel C, Colombo PE, Classe JM, Chevrier M, Joly F, De la Motte Rouge T, Floquet A, Sabatier R, Barranger E, Costaz H, Leblanc E, Marchal F, Pautier P, Bosquet L, Rodrigues M. Efficacy of chemotherapy according to BRCA status in patients with high-grade serous ovarian carcinoma at first platinum-sensitive relapse. Int J Gynecol Cancer. 2023 Jan 11:ijgc-2022- 003993.

5. Hanvic B, Lecuru F, Vanacker H, Pautier P, Narducci F, Cherifi F, Floquet A, Angeles MA, Berton D, Pomel C, Kalbacher E, Provansal M, Fernandez Y, Rouge TM, Roméo C, Laas E, Morice P, Hudry D, Meriaux E, Guyon F, Illac-Vauquelin C, Selle F, Meeus P, Genestie C, Salleron J, Ray-Coquard I. Impact of surgery and chemotherapy in ovarian sex cord-stromal tumors from the multicentric Salomé study including 469 patients. A TMRG and GINECO group study. Gynecol Oncol. 2023 May 19;174:190-199.

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