Abstract 2880: CD36, a fatty acid translocase, promotes metastasis in CRC
Authors: Drury James Michael , Rychahou Piotr , Weiss Heidi L. , Zaytseva Yekaterina Y. 
Published: July 2021

Altered fatty acid metabolism, a hallmark of cancer, is an attractive target for therapeutic intervention. Fatty acid translocase (CD36), a multifunctional glycoprotein, has an important role in fatty acid metabolism: it serves as a fatty acid transporter. We have previously shown the importance of CD36 in promotion of colorectal cancer (CRC) cell proliferation and tumorigenesis and its role in compensation of de novo fatty acid synthesis inhibition. CD36 also plays important roles in migration, invasion and metastasis in gastric, ovarian and oral carcinomas. Cell lines with higher metastatic potential express higher levels of CD36; however, the role of CD36 in CRC metastasis has not been previously studied. The purpose of our study is (i) to determine the functional effect of CD36 on CRC metastasis, and (ii) to delineate the mechanistic pathways in which CD36 may regulate CRC metastasis.

Methods: In this study we utilized HCT116 and HT29 CRC cell lines. The HT29 LuM3-GFP-Luc cell line was established from HT29 cells and has an increased propensity to metastasize to mouse lungs. The increase in metastatic capacity of HT29 LuM3 is associated with an increase in the expression of CD36. We utilized parental HT29-GFP-Luc and HT29 LuM3-GFP-Luc to overexpress and knockdown CD36, respectively, and we used a CD36 neutralizing antibody to block the activity of CD36 in HCT116 and HT29 LuM3 cells. To measure colonization, migration and invasion in vitro, we used soft agar colony formation assays, a wound healing assay, and spheroid and trans-well invasion assays. In vivo, we utilized the tail-vein injection model to study tumor cell colonization in mouse lungs, and the cecum injection model to study liver metastasis from the primary tumor. We analyzed samples with qRT-PCR, western blot and immunohistochemistry.

Results: Knockdown of CD36 significantly reduced CRC cell invasion and colony formation in HCT116 and HT29 LuM3 in vitro. CRC cell invasion and colony formation increased with overexpression of CD36 in HCT116 cells. Overexpression of CD36 in established CRC cell lines increased markers of survival and invasion, such as phospho-Akt, P-Met, and MMP28. Most importantly, knockdown of CD36 in HT29 LuM3-GFP-Luc cells significantly reduced lung metastasis in vivo.

Conclusions: CRC cells that have a higher propensity to initiate metastasis in vivo express higher levels of CD36. We showed that this upregulation of CD36 represents a unique advantage for CRC cells to initiate tumor colonies, migrate and invade both in vitro and in vivo. Thus, our study highlights the potential of CD36 as a viable target for metastatic disease in CRC patients.

Citation Format: James Michael Drury, Piotr Rychahou, Heidi L. Weiss, Yekaterina Y. Zaytseva. CD36, a fatty acid translocase, promotes metastasis in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2880.