Mutant KRAS-associated proteome is mainly controled by exogenous factors

ABSTRACT: KRAS signaling has been extensively studied, yet the clarification between KRAS-autonomous and non-autonomous mechanisms are still less explored. Understanding how KRAS signaling and effects are affected by exogenous stimuli can provide valuable insights not only to understand resistance mechanisms that justify pathway inhibition failure, but also to uncover novel therapeutic targets for mutant KRAS patients. Hence, aiming at understanding KRAS-autonomous versus non autonomous mechanisms, we studied the response of two mutant KRAS colorectal cancer cell lines (HCT116 and LS174T) - control and KRAS silenced- to TGFβ1-activated fibroblasts secretome. By performing a total proteome analysis, we observed that TGFβ1-activated fibroblast-secreted factors triggered cell-line specific proteome alterations and that mutant KRAS governs approximately 1/3 of those alterations. Moreover, the analysis of the impact of exogenous factors on the modulation of KRAS proteome revealed that more than 2/3 of the KRAS-associated proteome is controlled in a KRAS-non-autonomous manner, dependent on the exogeneous factors, in both cell lines. This work highlights the context-dependency of KRAS-associated signaling and reinforces the importance of establishing more integrative models resembling the complexity of the tumor microenvironment to study KRAS-associated signals.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture, Colon, Fibroblast

DISEASE(S): Colon Cancer

SUBMITTER: Hugo Osorio  

LAB HEAD: Sérgia Velho

PROVIDER: PXD030551 | Pride | 2022-04-06

REPOSITORIES: Pride