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

TL;DR

This study introduces a new mouse model of esophageal cancer cachexia using patient-derived organoids and shows that drugs targeting macrophages can reduce cachexia symptoms.

Contribution

The novel contribution is the development of a patient-derived organoid xenograft model that authentically replicates ESCC-associated cachexia and demonstrates macrophage-targeting drugs as potential treatments.

Findings

PDOX models exhibit heterogeneous cachexia phenotypes including weight loss and elevated pro-inflammatory cytokines.

Rosiglitazone and PLX3397 significantly reduced cachexia symptoms by targeting macrophages.

Transcriptomic analysis confirmed suppression of pro-cachectic cytokine signaling by the drugs.

Abstract

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.

•Patient-derived organoid xenografts in mice mimic esophageal cancer cachexia•Rosiglitazone prevents tumor-induced cancer cachexia via depleting inflammatory macrophages•PLX3397 depletes macrophages to curb systemic inflammation and blunt key inflammatory pathways•Both rosiglitazone and PLX3997 attenuated cancer cachexia by targeting macrophages

Patient-derived organoid xenografts in mice mimic esophageal cancer cachexia

Rosiglitazone prevents tumor-induced cancer cachexia via depleting inflammatory macrophages

PLX3397 depletes macrophages to curb systemic inflammation and blunt key inflammatory pathways

Both rosiglitazone and PLX3997 attenuated cancer cachexia by targeting macrophages

Health sciences

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