TargMacropin · Targeting macropinocytosis in glioblastoma to achieve precision medicine

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 the Galectin-3 (Gal-3)/KRAS/alphavbeta3 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. My recent work challenged this paradigm of oncogenes, such as oncogenic KRAS, essentiality for macropinocytosis activity in cancer cells. Although the mesenchymal subset is associated with variable expression of 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 this goal, we will combine various functional assays, metabolomic, transcriptomic, and proteomic analyses with a cutting-edge technique of laser capture microdissection together with mass-spectrometry-guided protein identification of the macropinosomes.