ERV-derived dsRNAs induce stress granules that drive neural crest fate to initiate melanoma

Drake, K. D.; Formato, E.; Hakobyan, S.; Hongo, R. A.; Yang, S.; Porat, J.; Sanborn, O.; Robertson, A. L.; Kretov, D. A.; Zhou, Y.; Cifuentes, D.; Kunz, M.; Binder, H.; Flynn, R. A.; Zon, L. I.

doi:10.64898/2026.11.06.764901

bioRxiv · 10.64898/2026.11.06.764901

ERV-derived dsRNAs induce stress granules that drive neural crest fate to initiate melanoma

Drake, K. D.·Formato, E.·Hakobyan, S.·Hongo, R. A.·Yang, S.·Porat, J.·Sanborn, O.·Robertson, A. L.·Kretov, D. A.·Zhou, Y.·Cifuentes, D.·Kunz, M.·Binder, H.·Flynn, R. A.·Zon, L. I.

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Abstract

Melanoma arises when melanocytes are oncogenically reprogrammed into neural crest-like cells, but what initiates this switch is unknown. Here we show that endogenous retrovirus (ERV)-derived double stranded RNAs (dsRNAs) induce stress granules (SGs) that drive this fate change. In zebrafish, melanoma progresses through a stage-specific ERV switch: zferv marks precursor cells before crestin activates in tumor cells. Both elements generate dsRNA that triggers eif2ak2-dependent SGs within precursor lesions and through transformation. SGs are tumorigenic as G3BP1 overexpression accelerates melanoma onset, whereas mosaic, melanocyte-specific g3bp1/2 knockout delays it. Small molecule-mediated inhibition of G3BP1/2 eliminates precursor lesions and reduces tumor burden. Similarly, blocking dsRNA sensing prevents SG formation and lowers melanoma incidence. Human nevi and melanomas show analogous, stage-specific ERV programs and SG assembly. In human melanoma cells, SGs sequester and translationally repress SOX10-regulating mRNAs, including the tumor suppressor KMT2D. Mosaic knockout of kmt2d in vivo enhances SOX10-driven neural crest reactivation. Thus, an ERV-SG axis establishes an oncogenic translatome that enables melanoma fate, with diagnostic and therapeutic potential.

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Drake, K. D., Formato, E., Hakobyan, S., Hongo, R. A., Yang, S., Porat, J., Sanborn, O., Robertson, A. L., Kretov, D. A., Zhou, Y., Cifuentes, D., Kunz, M., Binder, H., Flynn, R. A., Zon, L. I.. 2026-11-09. ERV-derived dsRNAs induce stress granules that drive neural crest fate to initiate melanoma. https://doi.org/10.64898/2026.11.06.764901

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