T-ERC_STG - Tremplin-ERC Starting

Targeting macropinocytosis in glioblastoma to achieve precision medicine – TargMacropin

Submission summary

Tumors must survive microenvironmental stresses, such as nutriment deprivation, low levels of oxygen and anticancer treatments. To do so, tumor cells have developed numerous adaptation mechanisms, and we have recently shown that induction of macropinocytosis is associated with tumor cell survival. In our previous work, we determined that Galectin-3 (Gal-3)/KRAS/avß3 integrin complex acts as a driver of macropinocytosis, an endocytic process by which tumor cells are able to engulf large amounts of nutrients from the local microenvironment. In glioblastoma (GBM) cells, which do not harbor mutations in KRAS, we interestingly uncovered the same phenomenon of macropinocytosis induction, which was associated with the mesenchymal subset of GBM. Indeed, my recent study challenged this paradigm of oncogenes, such as oncogenic KRAS, essentiality for macropinocytosis activity in cancer cells. Although mesenchymal subset is associated with alteration in several genes, a molecular signature rather than a mutation in a single oncogene defines macropinocytosis. In this context, we also found Gal-3 to be involved in macropinocytosis induction in mesenchymal GBM cells, confirming the central role of Gal-3 in this process. Altogether, my results demonstrate that induction of macropinocytosis is not restricted to tumors bearing mutations in specific oncogenes, but can potentially be a universal scavenger process used by tumor cells to survive environmental stress. In this context, the overarching goal of this proposal is to define the molecular mechanisms underlying cancer cell addiction to macropinocytosis, with the ultimate aim to identify targets for the therapeutic exploitation of this mechanism. To achieve these goals, this study will use a straightforward approach combining laser capture microdissection of macropinosomes followed by mass-spectrometry-guided protein identification. In parallel, immunoprecipitation (IP) of Gal-3 with liquid chromatography-mass spectrometry (LC-MS) will allow the identification of Gal-3 partners, for which a contribution to macropinocytosis will be identified. Moreover, by characterizing the tumor cell metabolome, we will also understand how nutrient deprivation along with oxygen deprivation, oxidative stress and/or drug treatments, in vitro, and the local intratumoral nutritional status, in vivo, might regulate macropinocytosis. Finally, this project aims at defining a molecular profiling to predict whether a given tumor might be sensitive to macropinocytosis inhibitors or to any other inhibitors found to disrupt this process and/or its signalling pathways. Therefore, we will determine whether targeting the identified genes/proteins/pathways has an impact on tumor growth and tumor microenvironment in vivo. Altogether, in addition to its relevance to fundamental aspects of the macropinocytosis pathway, the proposed work has a strong translational potential, as it will provide targets that can be further explored for new therapeutic strategies.
This application will highlight on the fundamental requirements for macropinocytosis activity / regulation, and identify the potential candidates can be used for therapeutic approaches. To do so, we will use not only different in vitro 2D/3D patient-derived stem cell lines, but also human pluripotent stem cells to generate 3D self-organized engineered brain-like tissues. The cross-domain nature of this proposal resides in the different analyses and technics that will be used to decipher the mechanisms underlying macropinocytosis activity. In collaboration with different academic groups and University Core Facilities, we will evaluate 1) macropinocytosis activity of several cells, 2) the the impact of various forms of stress on macropinocytosis, 3) the metabolite profiles of addicted vs non-addicted cancer cells, 4) the best candidates and key drivers of macropinocytosis and 5) the transcriptomic and proteomic profile of cancer cells.

Project coordination

Erika Cosset (Centre de Recherche en Cancérologie de Lyon)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CRCL Centre de Recherche en Cancérologie de Lyon

Help of the ANR 28,250 euros
Beginning and duration of the scientific project: March 2022 - 24 Months

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