The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer
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ABSTRACT:
PROVIDER: PRJNA673351 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12951500_1.fastq.gz | Fastqsanger.gz | |||
| SRR12951500_2.fastq.gz | Fastqsanger.gz | |||
| SRR12951501_1.fastq.gz | Fastqsanger.gz | |||
| SRR12951501_2.fastq.gz | Fastqsanger.gz | |||
| SRR12951502_1.fastq.gz | Fastqsanger.gz |
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Project description:Oncogenic KRAS mutations and inactivation of the APC tumour suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus upon downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, rendering them ‘addicted’ to glutamine supporting proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino-acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via mTORC1 inhibition, cooperates with Slc7a5 deletion to abrogate growth of established KRAS-mutant tumours. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.
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Project description:The intestine is the critical organ not only for processing and resorbing nutrients from ingested food but also for defending the organism from external stresses such as pathogens. These functions are mainly carried out by the epithelium which is constantly being self-renewed throughout adult life. Intestinal epithelial homeostasis is maintained through well-controlled cell proliferation of the stem cells and transient amplifying cells and the apoptotic degeneration of epithelial cells, mostly at or near the tip of the villi. Many genes and pathways have been found to influence intestinal epithelial cell proliferation. Among them is the mTORC1 signaling pathway, whose activation is known to increase cell proliferation. Here, we report the first intestinal epithelial specific knockout (IEC-KO) of an amino acid transporter capable of activating mTORC1. We show that the transporter, slc7a5, is highly expressed in the intestinal crypt and slc7a5 IEC-KO leads to expected reduction in mTORC1 signal in the crypt or even in intestinal organoids in vitro. Surprisingly, slc7a5 IEC-KO leads to increased proliferation of both transit amplifying cells and crypt base stem cells but a reduction in the secretory cells, particularly mature Paneth cells in the crypt base. Our scRNA-seq and electron microscopic analyses reveals that slc7a5 IEC-KO causes dedifferentiation of the Paneth cells, leading to drastically reduced secretory granules and lysozyme expression without affecting the overall Paneth cell number. We further show that slc7a5 IEC-KO mice are prone to induced colitis due to this loss of Paneth cell differentiation. We propose a model where slc7a5 regulates secretory cell differentiation to affect stem cell niche and/or inflammatory response to regulate cell proliferation in the crypts.
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Project description:Oncogenic KRAS mutations and inactivation of the APC tumour suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus upon downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, rendering them ‘addicted’ to glutamine supporting proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino-acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via mTORC1 inhibition, cooperates with Slc7a5 deletion to abrogate growth of established KRAS-mutant tumours. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.
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