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.

肥胖流行与结直肠癌肝转移（colorectal cancer liver metastasis, CRLM）的发病率升高及CRLM切除术后局部复发风险增加密切相关。本研究证实，在高脂饮食诱导的肥胖小鼠体内，M2型肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）在肝转移灶内显著聚集，进而加速CRLM的进展。高脂饮食小鼠来源的TAMs可通过上调SLC27A1促进脂滴扩增，从而促进M2极化。机制层面，SLC27A1与脂滴包被蛋白PLIN2结合，通过分子伴侣介导的自噬（chaperone-mediated autophagy）抑制其降解。此外，合并肥胖的CRLM患者体内SLC27A1阳性TAMs的数量显著升高，提示本研究揭示的机制或参与人类CRLM的疾病进展，可作为潜在的治疗靶点。整体实验设计：将C57BL/6小鼠分为两组，分别喂食对照饮食（control diet, CD，热量来源中脂肪占比10%）与高脂饮食（high-fat diet, HFD，热量来源中脂肪占比60%），持续饲养6周。随后经脾注射5×10⁵个MC38细胞以诱导肝转移。于肿瘤植入后19天，采集4只CD组小鼠与4只HFD组小鼠的肝转移灶，通过流式细胞术分选TAMs。TAMs的鉴定标记为CD45⁺/CD11b⁺/F4/80⁺阳性细胞，分选完成后对其进行RNA测序。