ALTERATION OF THE PRENYLATION PATHWAY IN CANCER CELLS: ROLE OF ICMT ON THE TUMOR MICROENVIRONMENT

BORINI ETICHETTI, CARLA M; GIRARDINI, JAVIER

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2021; 2021

Posttranslational modification by the prenylation pathway is a regulatory mechanism that affects the C-terminus of key proteins in cell behavior. Mounting evidence points at a critical role for ICMT in cancer. Our previous work showed that ICMT overexpression enhanced tumorigenesis in vivo using xenografts in immunocompromised mice. In this work, we wondered if ICMT may enhance tumorigenesis in inmmunocompetent mice. To answer this question, we used an orthotopic model of breast cancer in BALB/c mice. Our results showed that ICMT enhanced tumor aggressiveness. We took advantage of bioinformatic tools to analyze the interplay between cancer cells and the tumor microenvironment (TME). We first analyzed the expression of ICMT in normal and tumor tissues in public databases using GEPIA 2. We found that ICMT expression is increased in tumors. Interestingly, the analysis of GEO datasets showed that ICMT mRNA levels were significatively increased in tumor cell lines co-cultured with fibroblasts, suggesting that the TME contributes to ICMT overexpression in cancer cells. By using algorithms available in TIMER 2.0, that allow to identify different cell types in tumor samples through deconvolution of cell-specific transcriptional programs from microarray databases, we found that ICMT overexpression in tumors enhanced infiltration of cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs). We also studied if the combination of ICMT overexpression with CAFs or TAMs infiltration affects clinical outcome in breast cancer by correlation analysis. We found that cases with low ICMT expression and low infiltration of these cell types displayed a significant increase in survival. Moreover, we found that cases with high ICMT expression and augmented presence of M2-like macrophages showed reduced survival. Collectively, our results showed that ICMT overexpression enhances tumor progression and suggest that it contributes to reshape the TME.