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Abstract：
Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.
摘要：
肥胖已成为恶性肿瘤发展的主要危险因素。然而,关于脂肪细胞在肿瘤微环境(TME)中的作用阐明肥胖与癌症之间的相关性的现有文献仍然不足.这里,我们的目的是使用含有功能失调的小鼠模型研究癌症相关脂肪细胞(CAAs)的形成及其对肿瘤生长的影响.具体来说,我们采用脂肪细胞特异性BECN1KO（BaKO）小鼠，由于脂肪细胞功能失调而表现出脂肪营养不良。我们的结果揭示了CAAs和BECN1缺陷的脂肪细胞中YAP/TAZ信号的激活，诱导脂肪细胞去分化和恶性TME的形成。从BaKO小鼠中额外删除YAP/TAZ可显着恢复脂肪营养不良和炎症表型，导致肿瘤消退。此外，高脂饮食(HFD)的小鼠在其脂肪组织中表现出BECN1减少和YAP/TAZ表达增加。用YAP/TAZ抑制剂治疗，维替泊芬,抑制BaKO和HFD喂养小鼠的肿瘤进展，强调其对代谢失调小鼠的功效。总的来说,我们的发现提供了对CAA的关键介体及其在开发TME中的意义的见解，从而提出了一种靶向脂肪细胞稳态以抑制癌症生长的可行方法。
