Page 34 - The Hormel Institute 2024 Annual Report

34 | THE HORMEL INSTITUTE
// UNIVERSITY OF MINNESOTA
The liver is the most common distant site affected by colorectal cancer (CRC), and the process of CRC entering the liver is
called liver metastasis, which can be detected
in more than 50% of patients, mostly within two years of diagnosis of colorectal cancer. CRC liver metastasis is a significant contributor to patient deaths due to the lack of effective disease man- agement and targeted therapy against it.
Positron emission tomography is a widely used clinical diagnostic tool and its highly sensitive for the detection of CRC liver metastases, it has approximately 97% sensitivity, indicating that colorectal cancer cells in the liver exhibit enhanced glucose uptake and that interfering with glucose uptake may prevent these cancer cells from getting energy and thus suppress their growth in the liver.
Glucose transporter 1 (Glut1) is a protein on
the plasma membrane and it is responsible for moving glucose across the cell membrane and into the cell; our year’s work focused on under- standing Glut1 biology and explored how Glut1 is transported onto the plasma membrane of colorectal cancer cells from the site where it is synthesized. One of our studies was recently published in the high-impact journal Experimental & Molecular Medicine.
In the study, we identified CMTM6, a member of the CKLF-like MARVEL transmembrane domain
(CMTM)-containing protein family, as a new player regulating Glut1 trafficking of colorectal cancer cells. Mechanistically, CMTM6 forms a protein complex with Glut1 and Rab11, and this complex is required for transport of Glut1 onto the plasma membrane and for the protection of Glut1 from lysosomal degradation (breakdown of cellular materials).
We showed that knocking down CMTM6 induced Glut1 degradation, decreased glucose uptake and glycolysis in colorectal cancer cells, and suppressed subcutaneous colorectal cancer growth in murine models and liver metastasis
in C57BL/6 strains. Multiomics revealed global alterations in the messenger RNA molecules in CMTM6-deficient colorectal cancer cells that affected the transcriptomes of adjacent fibro- blasts of CRC liver metastases as the conse- quences of targeting Glut1 and glycolysis of col- orectal cancer cells. Consistently, patient data
in The Cancer Genome Atlas confirmed that CMTM6 expression was increased in colorectal cancer with its elevation associated with worse survival of colorectal cancer patients. Taken together, our data support CMTM6 as a critical player and therapeutic target for its controlling glucose metabolism, transcriptome, and liver metastasis of colorectal cancer.