Scavenger Cells Failure to Maintain Systemic RNA Homeostasis Causes Epigenetically Inherited Germline Tumors

In particular, it was recently shown that transient loss of Polycomb silencing in flies irreversibly reprograms cells toward cancer (Parreno et al. 2024). Whether somatic dysfunction in parents can create multi-generational heritable susceptibility to tumorigenesis is unknown.

In eutelic organisms like Caenorhabditis elegans, adult somatic cells no longer divide, precluding somatic cancer, yet tumors can still form in the continuously dividing germline. Here, we show that disruption of coelomocytes, somatic scavenger cells, just in C. elegans mothers, provokes transgenerationally heritable germline tumorigenesis that persists for multiple generations in genetically wild-type descendants. We found that when the coelomocyte’s phagocytic activity dysfunctions, it impairs clear out of RNA from body fluids, and thus disrupts systemic RNA homeostasis, allowing excess somatic RNAs to access the germline, and leading to widespread transcriptional and small RNA dysregulation and transgenerational loss of germline identity.