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<p>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 <i>Drosophila</i> 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 <i>spz5</i> expression. Thus, our study provides insights into the complex regulatory mechanisms by which systemic interorgan communication influences tumor progression.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月23日

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  • Du Kong,
  • Xiaoqin Li,
  • Sihua Zhao,
  • Chenliang Wang,
  • Zixin Cai,
  • Sha Song,
  • Yifan Guo,
  • Xiaoyu Kuang,
  • Xianping Wang,
  • Wenhan Liu,
  • Peng Liu,
  • Xiaowei Guo,
  • Wenyan Xu,
  • Yirong Wang,
  • Bin Zhao,
  • Bin Jin,
  • Li He,
  • Xianjue Ma

摘要

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.