#IDIBELLconnect: The mTOR-LARP1 axis and the anabolic reservoir of tumor cells: A new therapeutic target in colorectal cancer and beyond

Protein synthesis is the final step of the central dogma of biology that converts the genetic information into functional proteins. Ribosomes are in charge of this last step, operating as the cellular factories that generate basically all the cellular biomass. To grow and proliferate cancer cells have a high demand in protein synthesis rate, which in turn requires the hyper activation of the process of ribosome biogenesis.
A central question in cancer biology is how cancer cells hijack the protein synthetic pathway and alter the cellular translational program to meet the high anabolic demand. We have recently discovered that the translatome has an innate hierarchy that places all the ribosome biosynthesis components on the top of the cellular translational program. Thanks to the 40S-LARP1 complex the protein synthesis capacity is preserved in the form of mRNAs upon adverse growth condition characterized by mTOR inhibition. This constitutes an anabolic reservoir that tumor cells can spend when growing conditions return permissive, potentially conferring a metabolic resistance in the process of tumorigenesis and upon chemotherapeutic treatments.

Short bio Antonio Gentilella obtained a Master in Molecular Biology at University of Napoli “Federico II” in 2002, followed by a Residency in Human Genetics at University of Rome “La Sapienza” completed in 2006. Thanks to a join program with the University of Salerno, in 2006 he joined the Department of Neuroscience at Temple University, Philadelphia, PA, to carry out a PhD in Biochemistry studying the role of the “protein quality control” system in Glioblastomas and in tumors of neural origin. After graduating in 2010 he carried out a visiting postdoctoral stay in the laboratory of Chris Lengner at University of Pennsylvania to learn about regulators of protein synthesis in intestinal stem cells. The question of protein synthesis led him to Dr. George Thomas, who was at that time at University of Cincinnati. Thanks to an EMBO Long term Fellowship he joined the group to open the laboratory of Metabolism and Cancer (LMC) in Barcelona. The mission of LMC is understanding the molecular mechanisms that control protein synthesis and cell growth to unravel selective metabolic vulnerabilities of tumors.
During these years his projects led to the discovery of a new biochemical entity formed by the 40S ribosome and the RNA binding protein LARP1 which dictates the hierarchy of the translatome to protect the protein synthetic capacity of cells in adverse growth conditions, mechanism potentially exploited by tumor cells to resume growth when conditions return permissive.
In 2018, he started his own group at IDIBELL and in 2020 he was appointed Assistant Professor at University of Barcelona.