PDF(Pubmed)
Abstract：
With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.
摘要：
治疗选择有限，恶病质仍然是癌症患者的主要挑战。表征肿瘤细胞和免疫微环境之间的相互作用可能有助于确定癌症恶病质的潜在治疗靶标。在这里，我们研究了巨噬细胞通过促进肿瘤分泌TWEAK（TNF样弱凋亡诱导剂）在增强胰腺癌诱导的肌肉萎缩中的关键作用。具体来说,巨噬细胞的消耗逆转了肿瘤细胞诱导的肌肉降解。巨噬细胞通过CCL5/TRAF6/NF-κB途径诱导TWEAK的非自主分泌。TWEAK通过激活MuRF1启动的肌肉重塑促进肌肉萎缩。值得注意的是,肿瘤细胞通过CCL2/CCR2轴募集和重新编程巨噬细胞,并破坏巨噬细胞和肿瘤细胞之间的相互作用减轻肌肉消耗。总的来说，这项研究确定了胰腺癌细胞和巨噬细胞之间的前馈环，肿瘤细胞分泌TWEAK的非自主激活，从而为胰腺癌恶病质提供有希望的治疗靶点。
