Convergent roles of GDF-15 in mechanotransduction, vascular disorganization, and immune suppression in melanoma.

Authors

Yu-Chi Chen, Vishnu Sravan Bollu, Sina Kheirabadi, Kyle LaPenna, Arthur Berg, Pingnian He, Todd D Schell, Amir Sheikhi, Erdem D Tabdanov, Gavin P Robertson

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 35. Pages e2602594123. Epub Aug 24, 2026.

Abstract

Melanoma, particularly in its advanced forms, remains one of the most lethal skin cancers, with limited effective treatments for both common cutaneous subtypes and rarer variants such as acral melanoma. The effects of the extracellular matrix (ECM) and other cancer-cell extrinsic processes on melanoma development remain underexplored. This study identifies growth differentiation factor-15 (GDF-15) as a mechanosensing-regulated driver of melanoma pathogenesis across melanoma types. GDF-15 is shown here to be mechanically induced by ECM rigidity and compressive forces occurring during metastatic progression, leading to significantly elevated levels in both cutaneous and acral melanoma cells. In this study, ECM rigidity was recapitulated using cell-adhesive gelatin methacryloyl (GelMA) hydrogel microparticles (microgels) with tunable stiffness, providing a biomimetic platform to investigate how mechanical cues in the tumor microenvironment regulate GDF-15 expression in melanoma. A previously unrecognized synergy between GDF-15 and inflammatory factors commonly present in tumors was identified and found to promote a disorganized, hyperpermeable vasculature, thereby facilitating tumor nutrient access and impeding effective immune cell infiltration. GDF-15 knockdown reduced the intratumoral hemorrhage phenotype, indicating a causal role. GDF-15 also functions by directly suppressing natural killer (NK) cell-mediated cytotoxicity, revealing a second cooperating mechanism of immune evasion. These effects position GDF-15 as a key node linking mechanical stress, co-operation with inflammatory factors, abnormal vascular development, and immune dysfunction, thereby converging on pathways and processes relevant to melanoma progression and treatment.

PMID:
42636371
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.