Transcriptional profile of tumor-associated macrophages from control-diet- and high-fat-diet-fed C57BL/6 mice with colorectal liver metastasis.
The obesity epidemic is associated with increased incidence of colorectal cancer liver metastasis (CRLM) and the local recurrence following CRLM resection. Here, we demonstrate that M2 type tumor-associated macrophages (TAMs) significantly accumulate within liver metastases in high-fat-diet-induced obese mice, and thus accelerating the development of CRLM. The TAMs from mice with high-fat diet facilitate the expansion of lipid droplets by upregulating SLC27A1, and as a result, M2 polarization is promoted. Mechanistically, SLC27A1 binds with PLIN2, a lipid droplet coat protein, to inhibit its degradation via chaperone-mediated autophagy. Moreover, the number of SLC27A1+ TAMs is significantly increased in obese patients with CRLM, suggesting that the mechanism revealed here likely plays a role in the progression of human CRLM and represents a potential target for treatment. Overall design: C57BL/6 mice were fed a control diet (CD, 10% kcal from fat)) and a high-fat diet (HFD, 60% kcal from fat)) for 6 weeks. We then performed an intrasplenic injection of 5 × 105 MC38 cells to induce liver metastasis. The liver metastases from 4 CD-fed and 4 HFD-fed mice were utilized for flow cytometry sorting 19 days post tumor implantation. The TAMs were characterized as CD45/CD11b/F4/80-positive cells through sorting, and then were subjected to RNA sequencing.