Post-transcriptional plasticity in cellular adaptation to tumorigenesis and chemoresistance: new models and tools
- Funding: INCA
- Partnership : IRCAN & IBV
- Duration : 3 years
ABSTRACT
Small Cell Lung Cancers (SCLC) are fast evolving tumors, characterized by rapid growth, quick metastasis, and despite sensitivity to initial systemic cytotoxic chemotherapy, SCLCs quickly develop chemotherapy resistance. Although mRNA translation control is critical to the rapid adaptation of gene expression to stress, its contribution to cellular survival and chemoresistance in the tumor microenvironment remains to be established.
Translationally repressed mRNAs are stored in P-bodies and are of particular relevance to study tumorigenesis because they control cell proliferation, differentiation, and resistance to stress, and they can be quickly mobilized to adapt gene expression to cellular needs. In addition, deregulation of the expression of P-body components is a signature of SCLC as revealed by our recent analysis. In the model organism C. elegans, disruption of P-body regulatory components induces tumorigenesis. Here, using these two complementary models, SCLC spheroids and induced C. elegans tumors, we will assess how alterations in P-body post-transcriptional pathways participate to tumorigenesis and stress resistance.
We aim to: (1) identify post-transcriptional signatures of SCLC tumors and oxidative stress resistance, (2) dissect how these post-transcriptional regulations participate to resistance in a tumor context, and (3) develop candidate and screen approaches to target P-body remodeling in tumors. By developing cutting edge sequencing methods and adapting two complementary models, we will provide a comprehensive and mechanistic view of the plasticity of RNA translation control during tumorogenesis and in response to oxidative stress using an approach distinct from the classical methods used to identify transcriptional signatures.