Woldemichael, H. | Search bioRxiv

bioRxiv2025

HIF2-driven PTHrP Causes Cachexia and Hypercalcemia in Kidney Cancer: Treatment with HIF2 Inhibitors

Kidney cancer frequently causes paraneoplastic syndromes, including hypercalcemia and cachexia, but the underlying mechanisms are incompletely understood. The most common form of kidney cancer, clear cell renal cell carcinoma, is frequently caused by loss of the pVHL tumor suppressor protein and the resulting upregulation of the HIF2 transcription factor. We show that PTHLH, which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. Further, we show that the increased PTHLH expression is both necessary and sufficient for the induction of hypercalcemia and cachexia in preclinical orthotopic cell line tumor models. Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in ccRCC patients, including in some patients who did not exhibit objective tumor shrinkage.

cancer biology↗

bioRxiv2025

Cell-death induced immune response and coagulopathy promote cachexia in Drosophila

Tumors can exert a far-reaching influence on the body, triggering systemic responses that contribute to debilitating conditions like cancer cachexia. To characterize the mechanisms underlying tumor-host interactions, we utilized a BioID-based proximity labeling method to identify proteins secreted by Ykiact adult Drosophila gut tumors into the bloodstream/hemolymph. Among the major proteins identified are coagulation and immune-responsive factors that contribute to the systemic wasting phenotypes associated with Ykiact tumors. The effect of innate immunity factors is mediated by NF{kappa}B transcription factors Relish, dorsal, and Dif, which in turn upregulate the expression of the cachectic factors Pvf1, Impl2, and Upd3. In addition, Ykiact tumors secrete Eiger, a TNF-alpha homolog, which activates the JNK signaling pathway in neighboring non-tumor cells, leading to cell death. The release of damage-associated molecular patterns (DAMPs) from these dying cells presumably amplifies the inflammatory response, exacerbating systemic wasting. Targeting the inflammatory response, the JNK pathway, or the production of cachectic factors could potentially alleviate the debilitating effects of cancer cachexia.

genetics↗