2. Academic Validation
  3. Adipose tissue-secreted Spz5 promotes distal tumor progression via Toll-6-mediated Hh pathway activation in Drosophila

Adipose tissue-secreted Spz5 promotes distal tumor progression via Toll-6-mediated Hh pathway activation in Drosophila

  • EMBO J. 2025 Jun 23. doi: 10.1038/s44318-025-00489-y.
Du Kong # 1 2 3,  Xiaoqin Li # 4 5,  Sihua Zhao # 4 5,  Chenliang Wang # 6,  Zixin Cai 7,  Sha Song 4 5,  Yifan Guo 4 5,  Xiaoyu Kuang 4 5,  Xianping Wang 4 5,  Wenhan Liu 4 5,  Peng Liu 4 5,  Xiaowei Guo 8,  Wenyan Xu 4 5,  Yirong Wang 7,  Bin Zhao 6,  Bin Jin 9 10 11,  Li He 12,  Xianjue Ma 13 14
Affiliations

Affiliations

  • 1 School of Life Sciences, Westlake University, 310024, Hangzhou, Zhejiang, China. kongdu@email.sdu.edu.cn.
  • 2 Westlake Laboratory of Life Sciences and Biomedicine, 310024, Hangzhou, Zhejiang, China. kongdu@email.sdu.edu.cn.
  • 3 Department of Hepatobiliary Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, 250033, Jinan, Shandong, China. kongdu@email.sdu.edu.cn.
  • 4 School of Life Sciences, Westlake University, 310024, Hangzhou, Zhejiang, China.
  • 5 Westlake Laboratory of Life Sciences and Biomedicine, 310024, Hangzhou, Zhejiang, China.
  • 6 MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, 310058, Hangzhou, Zhejiang, China.
  • 7 College of Biology, Hunan University, 410082, Changsha, Hunan, China.
  • 8 The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, 410013, Changsha, Hunan, China.
  • 9 Department of Hepatobiliary Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, 250033, Jinan, Shandong, China. jinbin@sdu.edu.cn.
  • 10 Organ Transplant Department, Qilu Hospital of Shandong University, 250033, Jinan, Shandong, China. jinbin@sdu.edu.cn.
  • 11 Shandong Province Engineering Research Center for Multidisciplinary Research on Hepatobiliary and Pancreatic Malignant Tumors, 250033, Jinan, Shandong, China. jinbin@sdu.edu.cn.
  • 12 The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230000, Hefei, Anhui, China. lihe19@ustc.edu.cn.
  • 13 School of Life Sciences, Westlake University, 310024, Hangzhou, Zhejiang, China. maxianjue@westlake.edu.cn.
  • 14 Westlake Laboratory of Life Sciences and Biomedicine, 310024, Hangzhou, Zhejiang, China. maxianjue@westlake.edu.cn.
  • # Contributed equally.
PMID: 40551010 DOI: 10.1038/s44318-025-00489-y
Abstract

Interorgan communication is vital for tissue homeostasis and health in multicellular organisms, and its disruption can lead to diseases such as Cancer. Adipose tissue acts as a key endocrine center, secreting cytokines that influence remote organs. Despite clear links between obesity and increased Cancer risk, the underlying mechanisms are unclear. Here, utilizing a Drosophila genetic model combining Gal4-UAS and QF-QUAS tissue-specific transgene expression systems, we reveal that adipose-secreted Spz5 ligand promotes distal epithelial tumor overgrowth and invasion. Mechanistically, Spz5 binds to tumor cell Toll-6 receptors, triggering the degradation of the endocytic adaptor protein AP-2α via Mib1-mediated ubiquitination. Consequently, impaired endocytosis leads to Smoothened (Smo) accumulation on the cell membrane and subsequent activation of the Hedgehog (Hh) pathway. This abnormal Hh activation synergizes with the oncogenic Yorkie (Yki) to drive tumor growth and invasion. Furthermore, tumor-derived Unpaired ligands (Upds) activate the JAK-STAT pathway in the fat bodies, which leads to Hippo pathway-dependent upregulation of spz5 expression. Thus, our study provides insights into the complex regulatory mechanisms by which systemic interorgan communication influences tumor progression.

Keywords

Drosophila; Fat Body; Hedgehog; Interorgan; Toll-6.

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