Drosophila midgut tumor-induced insulin resistance systemically remodels lymph gland hematopoiesis during cancer cachexia.

Cancer cachexia involves systemic metabolic deregulation along with classical features of muscle wasting, lipolysis, and chronic inflammation. While tumor nonautonomous effects on peripheral organs are recognized, how the tumor rewires the circulating immune cells and hematopoiesis remains unclear. We utilized a Drosophila larval cancer cachexia model by expressing yki3SA in the adult midgut precursors (AMP), which gives rise to a tumor in the larval midgut and recapitulates key cachectic phenotypes, including insulin resistance. Tumor-induced cachexia results in perturbed blood cell homeostasis with a reduced niche and aberrant blood cell differentiation in the larval hematopoietic organ, the lymph gland (LG). Circulating hemocytes in the tumor background display altered features with increased filopodia, phagocytic ability, and inflammatory gene signatures. Bulk RNA-seq analysis of circulating hemocytes from tumor-bearing larvae revealed upregulation of multiple cachectic ligands, notably ImpL2, an insulin antagonist. We demonstrate that elevated ImpL2 levels reduce LG niche size and promote widespread blood cell differentiation. Elevated ImpL2 levels and systemic insulin resistance in the tumor-induced cachexia scenario both result in abrogation of insulin signaling in the niche-progenitor micro-environment in the LG affecting Wingless signaling. Depletion of tumor-derived ImpL2 is capable of rescuing cachectic phenotypes whereas depletion of hemocyte-derived ImpL2 in the tumor background provides a partial rescue of cachectic phenotypes. Additionally, hemocyte ablation in the tumor background does not affect the tumor load but ameliorates the cachectic phenotypes. Our findings reveal that the tumor remodels hematopoiesis and blood cells which contribute to tissue wasting in cancer-induced cachexia.