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<p>Fat mass loss is a severe complication in cancer-associated cachexia, but its underlying mechanisms remain unclear. This study identifies the tumor-secreted chaperone clusterin (CLU) as a driver of white adipose tissue (WAT) depletion in triple-negative breast cancer (TNBC). CLU secretion is increased in the serum of cachectic TNBC patients. Mechanistically, extracellular clusterin scavenges 14-3-3 in WAT, inhibiting nucleocytoplasmic translocation of the molecular clock activator BMAL1, and perturbing the transcriptional repression of circadian rhythm genes, including <i>PER3</i>. In tumors, desmosomal protein plakophilin 3 (PKP3) controls CLU stability by competitively binding to its lysosomal receptor LRP2, increasing CLU distribution in plaques and inhibiting its lysosomal degradation. In advanced TNBC patients, increased amounts of secreted CLU, PKP3 and PER3 are associated with cachectic fat loss. Finally, a targeted reduction of PKP3 or CLU in the serum restores PER3 expression rhythmicity and inhibits cachectic adipose wasting in a TNBC mouse model. Taken together, our results identify a targetable a clinically accessible PKP3-clusterin axis that disrupts circadian gene expression in fat tissue in breast cancer.</p>

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Tumor-secreted clusterin promotes cachectic fat wasting via disrupting circadian gene expression and adipogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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  • Yan Liu,
  • Yehui Zhou,
  • Mengmeng Zhang,
  • Jin Zhang,
  • Jiahui Chen,
  • Long Chen,
  • Jia Tian,
  • Xiang Lv,
  • Xinxing Ma,
  • Jing Xu,
  • Jingwei Shi,
  • Liming Chen

摘要

Fat mass loss is a severe complication in cancer-associated cachexia, but its underlying mechanisms remain unclear. This study identifies the tumor-secreted chaperone clusterin (CLU) as a driver of white adipose tissue (WAT) depletion in triple-negative breast cancer (TNBC). CLU secretion is increased in the serum of cachectic TNBC patients. Mechanistically, extracellular clusterin scavenges 14-3-3 in WAT, inhibiting nucleocytoplasmic translocation of the molecular clock activator BMAL1, and perturbing the transcriptional repression of circadian rhythm genes, including PER3. In tumors, desmosomal protein plakophilin 3 (PKP3) controls CLU stability by competitively binding to its lysosomal receptor LRP2, increasing CLU distribution in plaques and inhibiting its lysosomal degradation. In advanced TNBC patients, increased amounts of secreted CLU, PKP3 and PER3 are associated with cachectic fat loss. Finally, a targeted reduction of PKP3 or CLU in the serum restores PER3 expression rhythmicity and inhibits cachectic adipose wasting in a TNBC mouse model. Taken together, our results identify a targetable a clinically accessible PKP3-clusterin axis that disrupts circadian gene expression in fat tissue in breast cancer.