Isoprenylcysteine carboxyl methyltransferase (ICMT) promotes invadopodia formation and metastasis in cancer cells

CARLA M. BORINI ETICHETTI; CAROLINA DI BENEDETTO; EVELYN AREL ZALAZAR; NABILA COCORDANO; SABRINA VALENTE ; SILVIO BICCIATO ; MAURICIO MENACHO-MÁRQUEZ ; MARÍA CECILIA LAROCCA ; JAVIER GIRARDINI

CELLULAR AND MOLECULAR LIFE SCIENCES

BIRKHAUSER VERLAG AG

Lugar: BASEL; Año: 2021

1420-682X

Modification by the prenylation pathway regulates the action of several proteins involved in oncogenic circuits. Isoprenyl-cysteine Carboxyl Methyltransferase (ICMT) catalyzes the last step of this pathway. We have previously found that ICMT overexpression enhances tumorigenesis in vivo and is correlated with reduced survival in cancer patients. Following evidence suggesting that ICMT regulates the function of proteins that affect invasive traits, we wondered if ICMT may promote metastasis. In this work, we found that ICMT overexpression enhanced lung metastasis from primary tumors in vivo. Accordingly, ICMT overexpression also promoted aggressive phenotypes such as migration and invasion in vitro. Since some ICMT substrates are involved in the regulation of actin cytoskeleton, we hypothesized that actin-rich structures associated to invasion and metastasis may be affected. We found discovered/uncovered/identified that ICMT enhanced the formation of functional invadopodia. Also, ICMT inhibition also reduced the levels of RHO GTPases associated to invadopodia assembly. Through the analysis of cancer patient databases, we found that ICMT is overexpressed in several tumor types. We foundobserved that the combined expression of ICMT and genes related to invadopodia, such as CTTN and ABL2, showed a significant correlation with clinical outcome. In summary, our work identifies ICMT overexpression as a relevant alteration in human cancer that promotes the development of metastatic tumors.