Patient-derived organoid xenografts model esophageal cancer cachexia and enable assessment of anti-inflammatory drug repositioning

Authors
Bryan Chee-chad Lung, Alvin Ka-kiu Leung, Carissa Wing-Yan Wong, Ian Yu-hong Wong, Cheryl Chee Heng Lung, Anthony Wing-ip Lo, Josephine Mun-Yee Ko, Wei Dai, Dora Lai-wan Kwong, Simon Law, Maria Li Lung, Valen Zhuoyou Yu


Lab

Journal
iScience

Abstract

Summary

Esophageal squamous cell carcinoma (ESCC) is highly associated with cancer cachexia, a wasting syndrome lacking effective treatments. Existing animal models fail to capture key clinical and biological features of this condition. Here, we established a panel of patient-derived organoid xenograft (PDOX) models that authentically replicate the heterogeneity of ESCC-associated cachexia in immunodeficient mice. PDOX lines exhibited slow tumor growth compared with traditional ESCC xenografts. Heterogeneous cachexia phenotypes in PDOX-bearing mice, as compared with non-tumor-bearing mice, including body weight loss, reduction in adipose tissue, reduced grip strength, and elevated pro-inflammatory cytokines, were observed. Using this platform, we tested two macrophage-targeting interventions: 10 mg/kg/day rosiglitazone, a PPAR-γ agonist, and 40 mg/kg/day pexidartinib (PLX3397), a CSF1R inhibitor. Both drugs significantly attenuated cachexia-associated functional decline and systemic inflammation. Transcriptomic analyses confirmed suppression of pro-cachectic cytokine signaling. This study presents a clinically relevant platform for preclinical cachexia research and supports macrophage modulation as a potential anti-cachexia strategy.

Keywords/Topics
health sciences

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://www.cell.com/iscience/fulltext/S2589-0042(26)00013-1

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Grip strength test

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