Enhancing cancer-associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis.
Enhancing cancer-associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis.
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在具有代谢挑战性的肿瘤微环境中增强癌症相关成纤维细胞脂肪酸分解代谢可驱动结肠癌腹膜转移。
DOI：
10.1002/1878-0261.12917
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发表时间：
2021-05
影响因子：
6.6
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Peng S;Chen D;Cai J;Yuan Z;Huang B;Li Y;Wang H;Luo Q;Kuang Y;Liang W;Liu Z;Wang Q;Cui Y;Wang H;Liu X
大多数与癌症相关的死亡是由于转移的进展性生长。腹膜转移性（PM）结直肠癌患者的总生存率降低。目前，结直肠癌（CRC）细胞为何会在腹膜腔内聚集和增殖尚不清楚，也没有有效的巩固治疗来提高生存率。利用蛋白质组学方法，我们发现PM结直肠癌患者中脂肪酸氧化（FAO）的关键酶降低。此外，通过RT - qPCR、IHC和GEO数据集分析，我们证实了肉碱棕榈酰转移酶IA (CPT1A)，一种FAO的限速酶，在PM结直肠癌患者中表达水平显著较低。然而，脂质组学显示，PM和非PM原发肿瘤之间的FFA水平没有差异。在这里，我们发现癌症相关的成纤维细胞（CAFs）通过上调CPT1A来积极氧化FAs并进行最小的糖酵解，从而促进结肠癌细胞的增殖、迁移和侵袭。此外，共培养诱导的糖酵解在癌细胞中增加，而脂肪酸分解代谢随着脂联素水平的降低而减少。重要的是，糖酵解的抑制显著降低了CAFsCPT1A‐OE体外条件培养基培养后CRC细胞的存活率，并损害了CRC‐PM衍生的类器官的存活和生长。最后，我们发现用依托莫西直接阻断FAO在体外对CAFsCPT1A‐OE的迁移和侵袭有抑制作用，在体内抑制肿瘤生长和腹腔内播散，揭示了CAF CPT1A在促进肿瘤生长和侵袭中的作用。总之，我们的研究结果表明，测试FAO抑制作为一种新的方法和临床策略，可以治疗CAF诱导的伴有腹膜传播/转移的结直肠癌。腹膜转移性（PM）结直肠癌患者的总生存率降低。在代谢具有挑战性的肿瘤微环境中，癌症相关成纤维细胞（CAFs）通过上调CPT1A表达来增强脂肪酸分解代谢，并驱动结肠癌腹膜转移。我们的研究结果表明，测试脂肪酸氧化抑制可能作为一种新的方法和临床策略来治疗CAF诱导的伴有腹膜传播/转移的结直肠癌。
Most cancer‐related deaths result from the progressive growth of metastases. Patients with peritoneal metastatic (PM) colorectal cancer have reduced overall survival. Currently, it is still unclear why colorectal cancer (CRC) cells home to and proliferate inside the peritoneal cavity, and there is no effective consolidation therapy for improved survival. Using a proteomic approach, we found that key enzymes of fatty acid oxidation (FAO) were decreased in patients with PM colorectal cancer. Furthermore, we confirmed that carnitine palmitoyltransferase IA (CPT1A), a rate‐limiting enzyme of FAO, was expressed at significantly low levels in patients with PM colorectal cancer, as determined by RT‐qPCR, IHC, and GEO dataset analysis. However, lipidomics revealed no difference in FFA levels between PM and non‐PM primary tumors. Here, we showed that cancer‐associated fibroblasts (CAFs) promote the proliferation, migration, and invasion of colon cancer cells via upregulating CPT1A to actively oxidize FAs and conduct minimal glycolysis. In addition, coculture‐induced glycolysis increased in cancer cells while fatty acid catabolism decreased with lower adiponectin levels. Importantly, inhibition of glycolysis significantly reduced the survival of CRC cells after incubation with conditioned medium from CAFsCPT1A ‐OE in vitro and impaired the survival and growth of organoids derived from CRC‐PM. Finally, we found that directly blocking FAO in CAFsCPT1A ‐OE with etomoxir inhibits migration and invasion in vitro and decreases tumor growth and intraperitoneal dissemination in vivo, revealing a role for CAF CPT1A in promoting tumor growth and invasion. In conclusion, our results suggest the possibility of testing FAO inhibition as a novel approach and clinical strategy against CAF‐induced colorectal cancer with peritoneal dissemination/metastases. Patients with peritoneal metastatic (PM) colorectal cancer have reduced overall survival. In metabolically challenging tumor microenvironment, cancer‐associated fibroblasts (CAFs) enhance fatty acid catabolism by upregulating CPT1A expression and drive colon cancer peritoneal metastasis. Our results suggest the possibility of testing fatty acid oxidation inhibition as a novel approach and clinical strategy against CAF‐induced colorectal cancer with peritoneal dissemination/metastases.
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