Biología de sistemas del cáncer: en busca de un código molecular y subcelular de proteínas clave en tumorigénesis

MATÍAS BLAUSTEIN

Seminario; Seminarios del CIBION; 2021

Cancer is a highly heterogeneous disease and even within each tumor, there is significant cell-to-cell variability. This heterogeneity has been traditionally considered as ?noise?. However, understanding the sources of cell-to-cell variability might help to improve existing therapies and design new ones. Akt kinase is an attractive therapeutic target for cancer treatment and it is known to be regulated through numerous post translational modifications as well as to be recruited to different subcellular compartments to fulfill its functions. Little is known about how a cell determines -for a given stimulus or under pathological conditions- which substrates and which functions Akt should regulate. Our hypothesis is that the Akt molecular code, i.e. the profile of post-translational modifications of Akt, can determine Akt subcellular localization and vice versa, thus establishing the subset of Akt substrates and the set of functions that Akt displays after each stimulus and in each cellular context. The general objective of our research is to determine the subcellular compartments to which Akt and its substrates are recruited, the phosphorylation patterns of Akt and Akt substrates in different mammary cell lines, both normal and tumor, and to analyze if a correlation between these variables and the resistance/sensitivity of these cell lines to different antitumor drugs can be established. Our long-term goal is to determine which modification and localization patterns of Akt and its substrates are useful for predicting the evolution of mammary tumors. Here, using a strategy that combines automated imaging and quantitative measurement of Akt localization, we discovered novel Akt modifications and subcellular localizations. Our preliminary results show that phosphorylation and localization patterns of Akt and its substrates differ between different normal and tumor mammary cell lines. Finally, we performed a bioinformatic analysis using the DisGeNET platform to associate subcellular locations of Akt and its substrates with different pathologies, particularly cancer. Our data shed light on the Akt molecular code, improving our understanding of complex cell and tumor behaviors.