2. Academic Validation
  3. The thermogenic activity of adjacent adipocytes fuels the progression of ccRCC and compromises anti-tumor therapeutic efficacy

The thermogenic activity of adjacent adipocytes fuels the progression of ccRCC and compromises anti-tumor therapeutic efficacy

  • Cell Metab. 2021 Oct 5;33(10):2021-2039.e8. doi: 10.1016/j.cmet.2021.08.012.
Gang Wei 1,  Honglin Sun 1,  Kai Dong 2,  Libing Hu 3,  Qi Wang 4,  Qian Zhuang 5,  Yan Zhu 2,  Xianjing Zhang 1,  Yaodi Shao 1,  Huiru Tang 4,  Zhenfei Li 5,  Suzhen Chen 1,  Junxi Lu 1,  Yibing Wang 6,  Xinxin Gan 2,  Tao P Zhong 7,  Dingkun Gui 1,  Xiaoyong Hu 1,  Linhui Wang 8,  Junli Liu 9
Affiliations

Affiliations

  • 1 Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
  • 2 Department of Urology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
  • 3 Department of Urology, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650051, China.
  • 4 State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Metabonomics and Systems Biology Laboratory at Shanghai International Centre for Molecular Phenomics, Zhongshan Hospital, Fudan University, Shanghai 200438, China.
  • 5 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
  • 6 School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China.
  • 7 Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 8 Department of Urology, Changhai Hospital, Naval Medical University, Shanghai 200433, China. Electronic address: [email protected].
  • 9 Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China. Electronic address: [email protected].
PMID: 34508696 DOI: 10.1016/j.cmet.2021.08.012
Abstract

Clear cell renal cell carcinoma (ccRCC) preferentially invades into perinephric adipose tissue (PAT), a process associated with poor prognosis. However, the detailed mechanisms underlying this interaction remain elusive. Here, we describe a bi-directional communication between ccRCC cells and the PAT. We found that ccRCC cells secrete parathyroid-hormone-related protein (PTHrP) to promote the browning of PAT by PKA activation, while PAT-mediated thermogenesis results in the release of excess lactate to enhance ccRCC growth, invasion, and metastasis. Further, tyrosine kinase inhibitors (TKIs) extensively used in the treatment of ccRCC enhanced this vicious cycle of ccRCC-PAT communication by promoting the browning of PAT. However, if this cross-communication was short circuited by the pharmacological suppression of adipocyte browning via H89 or KT5720, the anti-tumor efficacy of the TKI, sunitinib, was enhanced. These results suggest that ccRCC-PAT cross-communication has important clinical relevance, and use of combined therapy holds great promise in enhancing the efficacy of TKIs.

Keywords

PKA; PTHrP; adipocytes browning; cell-to-cell communication; clear cell renal cell carcinoma; lactate; lung metastasis; tyrosine kinase inhibitors.

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