31/01-2022 - Cédric CHAVEROUX : Disrupting the nucleolar homeostasis in colon cancer cells through the inhibition of cell and non-cell autonomous functions of GCN2

26 - Janvier - 2022

LES LUNDIS DE SAINT-ANTOINE

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LUNDI 31 JANVIER 2022

Disrupting the nucleolar homeostasis in colon cancer cells through the inhibition of cell and non-cell autonomous functions of GCN2

Cédric CHAVEROUX

CRCN CNRS (section 24), Centre de Recherche en Cancérologie de Lyon (69) - Responsable du groupe : Nutritional Stress Response (Equipe Dr. T Renno)

Equipe Alex DUVAL, (Equipe Alex Duval) (alex.duval@inserm.fr)

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Tumor cell proliferation and cancer progression is supported by the generation of novel proteins in response to oncogenic cues. Subsequent overactivation of the ribosome biosynthetic machinery, taking place in the nucleolus compartment, operates as a key promoter of malignant cell proliferation. However, notably in solid tumors, variation of nutrient availability determines the proliferation capacities and contributes to tumor heterogeneity. The underlying adaptive mechanisms involve profound reprogramming of the translation processes orchestrated by molecular sensors responsive to the nutritional microenvironment. Nonetheless their contribution to the flexibility of the nucleolus homeostasis remains poorly understood. In this context, taking the colon adenocarcinoma (COAD) as a tumor paradigm combining ribosomal dysfunction and nutritional stress, our group has identified the GCN2 pathway as a determinant of the nucleolus integrity upon nutrient deprivation. Furthermore, using an in-lab developed tool for standardizing assays based on human-derived tumoroid, we also found that this kinase supports the ribosome biosynthetic pathway in proliferative condition in a manner independent of its canonical pathway. Inhibition of GCN2 in this context triggers a massive cell death when combined with RNA PolI inhibitors. Overall, our work demonstrates that GCN2 controls the COAD nucleolus homeostasis through distinct mechanisms according the nutritional microenvironment.

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