Asparagine synthetase and G-protein coupled estrogen receptor are critical responders to nutrient supply in KRAS mutant colorectal cancer

Survival differences exist in colorectal cancer (CRC) patients by sex and disease stage. However, the potential molecular mechanism(s) are not well understood. Here we show that asparagine synthetase (ASNS) and G protein-coupled estrogen receptor-1 (GPER1) are critical sensors of nutrient depletion and linked to poorer outcomes for females with CRC. In a 3D spheroid model of isogenic SW48 KRAS wild-type (WT) and G12A mutant (MT) cells grown under a restricted nutrient supply, we found that glutamine depletion inhibited cell growth in both cell types, whereas ASNS and GPER1 expression were upregulated in KRAS MT versus WT. Estradiol decreased growth in KRAS WT but had no effect on MT cells. In a clinical colon cancer cohort of The Cancer Genome Atlas, both high GPER1 and ASNS expression were associated with poorer overall survival for females only in advanced stage tumors. These results suggest KRAS MT cells have mechanisms in place that respond to decreased nutrient supply, typically observed in advanced tumors, by increasing the expression of ASNS and GPER1 to drive cell growth. Furthermore, KRAS MT cells are resistant to the protective effects of estradiol under nutrient deplete conditions. The findings indicate that GPER1 and ASNS expression in the link of nutrient supply and KRAS mutations shed additional light on the mechanisms behind sex differences in metabolism and growth in CRC and have clinical implications in the precision management of KRAS MT CRC.