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

## TL;DR

This study shows that tumor-secreted clusterin disrupts fat tissue rhythms and causes cachexia in breast cancer by interfering with circadian genes.

## Contribution

The study identifies a novel tumor-secreted pathway involving clusterin and PKP3 that drives cachectic fat loss in breast cancer.

## Key findings

- Tumor-secreted clusterin (CLU) disrupts circadian gene expression in fat tissue, leading to cachexia.
- PKP3 stabilizes CLU in tumor cells by inhibiting its lysosomal degradation.
- Reducing CLU or PKP3 restores circadian rhythms and prevents fat wasting in a mouse model of breast cancer.

## Abstract

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.

The molecular mechanisms underlying fat mass loss in cancer-associated cachexia remain unclear. This study shows that the secreted chaperone clusterin (CLU) is first secreted from triple-negative breast cancer (TNBC) tumors and then taken up by fat cells where it disrupts circadian gene expression and adipogenesis.

Secrected CLU is more abundant in the serum of cachectic TNBC patients.Tumor-derived CLU sequesters the circadian regulator 14-3-3, perturbing BMAL1/CLOCK-dependent expression of PER3 and white adipose tissue maintenance.The desomosmal protein plakophilin 3 (PKP3) stabilizes CLU expression in tumor cells by inhibiting its lysosomal degradation.Targeting CLU or PKP3 restores adipose tissue circadian rhythms and alleviates cachectic fat wasting in a TNBC mouse model.

Secrected CLU is more abundant in the serum of cachectic TNBC patients.

Tumor-derived CLU sequesters the circadian regulator 14-3-3, perturbing BMAL1/CLOCK-dependent expression of PER3 and white adipose tissue maintenance.

The desomosmal protein plakophilin 3 (PKP3) stabilizes CLU expression in tumor cells by inhibiting its lysosomal degradation.

Targeting CLU or PKP3 restores adipose tissue circadian rhythms and alleviates cachectic fat wasting in a TNBC mouse model.

The extracellular chaperone clusterin perturbs circadian rhythms and adipocyte differentiation in breast cancer cachexia.