CXCL5 neutralization mitigates cancer cachexia by disrupting CAF-cancer cell crosstalk

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BACKGROUND: Advanced metastasis produces cachexia, a complex skeletal muscle wasting syndrome that accounts for one-third of patient deaths. There is currently no approved drug therapy for cancer cachexia. Cancer-associated fibroblasts (CAF) within tumors have been hypothesized to contribute to cachexia, but the detailed mechanism(s) are unknown. METHODS: Myotubes were treated with conditioned media (CM) from CAF or CAF activated by cancer cells. Upregulated chemokines in the cancer-activated CAF CM were identified by cytokine array. The effects of chemokine neutralization were investigated using in vitro myotube cultures and in vivo mouse models. The mechanism of action was characterized by in vivo RNA Seq and validated in human muscle cells. Immunostaining delineated the chemokine expression pattern in a patient tumor type highly associated with cachexia. RESULTS: Cancer-activated CAF induced myotube atrophy. CXCL5 was as the major chemokine highly upregulated in the cancer-activated CAF. CXCL5 treatment alone induced myotube atrophy and inhibited myogenic ERK1/2 signaling, similar to cancer-activated CAF treatment. CXCL5 neutralization inhibited cachexia in mice co-injected with HCT 116 colon cancer cells and CAF. RNA Seq showed that CXCL5 neutralization upregulated hypertrophy-related PI3K-AKT-MyoG signaling and remodeled the muscle ECM. CXCL5 neutralization ameliorated muscle wasting induced by CXCL5 and IL-6 co-treatment, and also prevented atrophy in cancer-activated CAF CM-treated human myotubes. CAF were the major detectable source of CXCL5 in a patient tumor highly associated with cachexia. CONCLUSION: CAF contribute to cachexia via cancer cell crosstalk that upregulates CXCL5 secretion. CXCL5 neutralization offers a novel therapeutic approach to maintain muscle mass in cancer patients.

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