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Les céllules cancéreuses et leur microenvironement: des voies de signalisations géniques à la thérapie

Projet de recherche P7/03 (Action de recherche P7)

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It is now generally accepted that the tumor and its microenvironment (i.e., the stroma) cross-talk to each other at multiple levels to elicit carcinogenesis, invasion and progression to metastasis. In addition to the well-established stepwise accumulation of somatic genetic alterations in tumor cells, it has now become clear that genetic and (epi)genomic alterations that play an important role in the development and/or progression of (solid) tumors also occur in stromal cells and importantly alter their pro-tumorigenic potential.  In this consortium, the first IUAP network focusing on cancer in its totality, a mix of junior and senior top leading cancer, angiogenesis and immunology experts from Belgium together with an European partner are joining forces and using / developing the most advanced state-of-the-art technologies in multi-disciplinary approaches not only to discover new genes and epigenetic factors in murine and human cancers, but also to study their functional role by genetic and pharmacological manipulation in animal models, and to translate these insights into the development of novel possible therapeutic avenues. Importantly, the individual partners have already collaborated with each other and jointly published several high-profile publications in top journals. Furthermore, there is a general consensus amongst all partners that each will greatly benefit from this network, not in the least because of the wealth of available frontline technologies, but also because of the multi-disciplinary approaches that are fertilizing, concept-provocative and bridging groups of scientists who normally interact too little with each other (i.e. tumor cell-focused versus stromal cell-centered). The design of this consortium, combining teams with unique, complementary expertise and high scientific productivity, and a common interest to elucidate epi/genetic mechanisms in cancer, is thus optimally geared to address the specific objectives of the project.

 To discover new bona fide cancer genes/pathways that either promote initiation or drive cancer progression and metastasis we will collect and integrate genomic (DNA copy number and exome sequence), epigenomic (DNA methylation pattern) and transcriptomic (coding and non-coding RNA profiling) data from selected mouse and human tumors of diverse origin. This large-scale comparative onco(epi)genomic endeavor is expected to lead to the identification of a series of recurrent alterations which are either tumor-type-specific or common among different tumor types. Innovative cell-based assays and genetic mouse models will next be used to discriminate the key oncogenic drivers from the bystander’s mutations. The most promising candidate genes will subsequently be enlisted into further in-depth functional, clinico-pathological and mechanistic studies. In addition to the identification of “druggable” anti-cancer targets (i.e. kinases, phosphatases, microRNAs, surface receptors, etc.) this wide integrative tumor survey may lead to the discovery of clinically relevant molecular diagnostic tools.

 Stromal cells, like tumor cells, evolved adaptive pathways to escape from nutrient deprivation, hypoxia and immune surveillance in order to survive in the harsh tumor environment. Recent evidence indeed indicates that stromal cells reprogram their metabolism to survive and to grow within the tumor environment and that this metabolic switch influences blood supply via angiogenesis and anti-tumor immune responses. In this context, we aim at identifying and characterizing the genomic, epigenomic, and functional role of the tumor microenvironment in the control of tumor initiation, progression and metastasis. We will in particular investigate how (oxygen) metabolism of tumor stromal cells, including endothelial cells, CAFs and immune cells, regulate tumor cell behaviour and explore whether targeting metabolic regulators is a valid novel anti-cancer therapeutic avenue.

 Hence, by bringing expert-research groups working on the two essential and inseparable players in tumor biology, the tumor cells themselves and their stroma, we therefore propose to integrate genomic and epigenomic information from both tumor and stroma in order to identify accurate prognostic markers and facilitate the development of combination and targeted therapies with longest durable responses and the lowest likelihood of toxicity than conventional treatments.

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