Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation

Yaechan Song, Heeju Na, Seung Eon Lee, You Min Kim, Jihyun Moon, Tae Wook Nam, Yul Ji, Young Jin, Jae Hyung Park, Seok Chan Cho, Jaehoon Lee, Daehee Hwang, Sang-Jun Ha, Hyun Woo Park, Jae Bum Kim and Han-Woong Lee ()
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Yaechan Song: Yonsei University
Heeju Na: Yonsei University
Seung Eon Lee: Yonsei University
You Min Kim: Yonsei University
Jihyun Moon: Yonsei University
Tae Wook Nam: Yonsei University
Yul Ji: Seoul National University
Young Jin: Yonsei University
Jae Hyung Park: Yonsei University
Seok Chan Cho: Yonsei University
Jaehoon Lee: Yonsei University
Daehee Hwang: Seoul National University
Sang-Jun Ha: Yonsei University
Hyun Woo Park: Yonsei University
Jae Bum Kim: Seoul National University
Han-Woong Lee: Yonsei University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48179-3

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