GDF15 Drives Cachexia Through Multisystem Feed-Forward Loop

Many patients suffer from cancer cachexia, a muscle and fat wasting syndrome that negatively impacts both quality of life and prognosis. Ongoing efforts aim to better understand the intercellular signaling pathways driving cachexia and how these pathways may be leveraged therapeutically. One of the most promising targets thus far is growth and differentiation factor 15 (GDF15), with inhibitory antibodies under investigation in advanced clinical trials. In addition to new treatment modalities, the mechanisms by which GDF15 contributes to cachexia are also being actively explored. To this end, Shi, Arreola, Zhou, Yang, Liu, Cai and colleagues analyzed single-cell RNA sequencing data from a cachectic mouse model of pancreatic adenocarcinoma (PDAC) to find that Gdf15 expression was enriched in tumor macrophages. Macrophage depletion studies in tumor-bearing mice supported this finding, as GDF15 levels were markedly reduced in the serum of clodronate-treated animals. Given that the expression of the GDF15 receptor complex, comprised of GFRAL and RET, is restricted to the central nervous system, the authors also sought to characterize the effects of GDF15 on neurotransmitter signaling. Interestingly, relative to those in wild-type controls, PDAC tumors from Gdf15–/– mice exhibited reduced levels of norepinephrine (NE), a neurotransmitter produced by the sympathetic nervous system. In vitro studies in PDAC cell lines revealed that NE treatment exacerbates secretion of the macrophage colony stimulating factor CSF1 via activation of the zinc transporter ZIP4, suggesting that macrophages may not only produce GDF15 but may also be affected by GDF15 production in a multisystem signaling circuit. In PDAC tumors, Zip4 knockdown reduced macrophage polarization and infiltration, anorexia, tissue wasting, and serum levels of GDF15, all of which were reversible upon CSF1 overexpression in these tumors. Administration of an anti-CSF1R antibody or RET inhibitor suppressed cancer cachexia and tumor growth in vivo, underscoring the translational potential of these mechanistic findings. Taken together, this study identifies the cell types and signaling mechanisms by which GDF15 promotes cachexia in cancer, providing promising new approaches to disrupt this detrimental circuit.Shi X, Arreola AX, Zhou Z, Yang J, Liu M, Cai Y, et al. Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia. Cancer Cell 2026 Feb 12 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.