Principal investigator: PIERRE HAINAUT
Peritoneal carcinomatosis heterogeneity
Peritoneal carcinomatosis (PC) can be considered as a system of cancer ecosystem. Indeed, multiple and disseminated metastases of primary ovarian or gastrointestinal cancers develop in the peritoneal cavity and may invade abdominal organs or distant organs via lymphatic/systemic dissemination. The partners of Pitcher are creating an open network to investigate the phenotypic and functional diversity of PC as a model of different ecosystems derived of the same cancer
With the networks RENAPE & BIG-RENAPE, Pitcher have access to 350 samples from 46 patients and could recruit 10-15 patients a month for a prospective study. With such biological resources (normal tissue, primary and derived from PCs tumors), a large-scale genome, epigenome and transcriptome analysis could be performed with the help of EPIMED network, a bioinformatics pipeline for analyzing transcriptomic and sequencing data and algorithms/resources for interconnecting “omics” data of different sources with clinical and pathological annotations.
The role of extracellular matrix, cytoskeleton and nucleoskeleton in the mechanical plasticity of PC cells and its response to mechanical constraints is of interest for Pitcher network. The partners work to the identification of structural and biochemical characteristics of tumor cell skeletal elements by cell image analysis, mass spectrometry of detergent-resistant fractions. They develop 3-D cultures and animal xenograft models of PC cells to analyze their experimental responses to mechanic constraints.
The role of axonogenesis in the development of PC is studied by the network. Tumor cells secrete axon guidance molecules and neurotrophic factors that induces axon growth and sprouting inside the tumor. On the other hand, axonal fibers secrete factors that regulate cancer cell survival, proliferation and migration. Pitcher teams are investigating how different types of axonal projections may contribute to the development and spread of PC by identification of axonal subtypes and patterns of infiltration in normal tissue, primary tumor and PC lesions (immunodetection, transcriptome and selective ablation of peripherical nerves in vivo).
By Integrating clinical, genetic, epigenetic and functional data with phenotypic diversity Pitcher aim to identify patterns of adaptive reprogramming towards robustness. Moreover, they want to link it to phenotypic diversity and mathematically model its impact on early clinical responses to chemotherapy and hyperthermic intraperitoneal chemotherapy.
Pitcher constitute a strong scientific collaborative consortium exploiting the unique potential of Renape/Big-Renape networks. The expected outcomes are to better understand how cancer cells reprogram themselves towards increased robustness, how epigenetic reprogramming generates new selectable phenotypic traits leading to heterogeneity. They aim to identify predictive markers of PC, new targets for potential therapies in order to develop epidrugs or target the environment of the peritoneal cavity.
This French program is organized by ITMO Cancer, in collaboration with ITMO BCDE (Cell Biology, Development and Evolution) and ITMO Technologies for Health of the National Alliance for Life Sciences and Health (AVIESAN) with the National Cancer Institute (INCA) and Inserm within the framework of the Cancer Plan. Operational management is entrusted to Inserm.
It was launch in order to develop a critical mass of resources and skills in order to conduct interdisciplinary research projects in the field of functional heterogeneity of cellular tumor relations in their ecosystem: the "HTE Program".