Protein Tyrosine Phosphatase 4A1 (PTP4A1) Regulates Early Events in Colorectal Cancer Intraperitoneal Dissemination in the Aged Male Host.

[BACKGROUND] Cancer predominantly affects older individuals, with age being a significant risk factor for cancer incidence and metastasis. Biological sex also plays a crucial role in influencing metastasis and survival outcomes. In colorectal cancer (CRC), both the incidence and mortality from metastatic disease are higher in males relative to females.

[AIM] The aim of this study was to use a syngeneic murine intraperitoneal (i.p.) metastasis model of CRC (MC-38 cells) to compare disease burden between young and aged female and male mice.

[METHODS] MC-38 cells tagged with red fluorescent protein were injected i.p. and tumor burden quantified longitudinally and at endpoint. As the peritoneal mesothelial cell is the initial site of tumor:host interaction in i.p. metastasis, primary murine peritoneal mesothelial cells were subjected to bottom up proteomic analysis to identify proteins differentially expressed among the cohorts.

[RESULTS] Recapitulating human epidemiological data, aged male mice exhibited the highest i.p. metastatic burden. Proteomic results identified multiple differentially expressed proteins. Protein tyrosine phosphatase 4A1 (PTP4A1), highly overexpressed in the male aged cohort relative to male young, female aged or female young, was chosen for further study. Functional analyses indicated that PTP4A1 promotes cancer:mesothelial adhesion and a small molecule inhibitor of PTP4A1, designated CMPD-43, reduced RhoA activity and inhibited heterotypic cell adhesion.

[CONCLUSION] These results provide a resource for comparative proteomics of the peritoneal mesothelial cell in sex- and age-based cohorts. Functional data support further consideration of PTP4A1 as a potential therapeutic target for impeding CRC metastasis particularly in an aged male cohort.