Amino acid transporter SLC7A5 is required for growth of Kras-mutant colorectal cancer in vivo


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Arafath Najumudeen1,Fatih Ceteci1,Owen Sansom1
1Beatson Institute for Cancer Research



Colorectal Cancer (CRC) is the third most common cancer worldwide and Ras/MAPK pathway deregulation is strongly associated with the development of CRC, often through activating KRAS mutations (40%) and inactivation of APC (80%). Recent studies from our laboratory and others showed that expression of oncogenic Kras dramatically increases intestinal tumorigenesis initiated by the inactivation of APC in mice. However, the role of Kras mutation in metabolic rewiring of intestinal tumours is not yet fully understood.


We use extensive combinations of genetically engineered mouse (GEM) models of intestinal cancer, targeted liquid chromatography/Mass spectrometry (LC/MS) metabolomics and transcriptomic analysis on intestinal organoids.


Here we demonstrate in GEM models of intestinal cancer that Wnt activation (by Apc loss) and Kras mutation co-ordinately rewire intestinal metabolism in vivo and in vitro by increasing both glucose and glutamine consumption to support anabolic processes that fuel cell proliferation. From this analysis, we identified Solute carrier member 7a5 (Slc7a5) to be significantly upregulated in both mouse and human CRC to meet the increased nutrient demand of the cancer cells. This work aims to determine the mechanism by which Slc7a5 contributes to CRC. Using genetic deletion of Slc7a5 in murine models of CRC we show that Slc7a5 is functionally required for Kras driven (not wildtype) epithelial cell proliferation and tumorigenesis. Mechanistically, Slc7a5 is needed for Kras mediated nutrient sensing and subsequent mTOR1 signaling downstream. Importantly, Slc7a5 deletion sensitises Kras tumours to rapamycin (further suppressing mTORC1 signalling) causing tumour cells to undergo growth arrest. 


In conclusion, our results reveal a Kras mediated metabolic rewiring mechanism that couples amino acid transport by Slc7a5 and mTOR1 activation with control of intestinal tumorigenesis and further suggest that altering Slc7a5 activity may provide a therapeutic opportunity for colorectal cancer.