Sex-dimorphic tumor growth is regulated by tumor microenvironmental and systemic signals | Science Advances

Tumor growth and progression involve coordinated regulation by internal, microenvironmental, and systemic signals and often display conspicuous sexual dimorphism. The mechanisms governing the integration and coordination of these signals, along with their sex-based differences, remain largely unknown. Using a Drosophila tumor model originating from nonreproductive tissue, we show that female-biased tumor growth involves multifaceted communications among tumor cells, hemocytes, and neuroendocrine insulin-producing cells (IPCs). Notch-active tumor cells recruit hemocytes carrying the tumor necrosis factor–α (TNF-α) homolog Eiger to the tumor microenvironment (TME), activating the c-Jun N-terminal kinase (JNK) pathway in tumor cells, instigating the sexually dimorphic up-regulation of cytokine Unpaired 2 (Upd2). Upd2, in turn, exerts a distal influence by modulating the release of a Drosophila insulin-like peptide (Dilp2) from IPCs. Dilp2 then activates the insulin signaling in the tumor, thereby fostering sexual-dimorphic tumor growth. Together, these findings reveal a relay mechanism involving the TME and systemic signals that collectively control the sexual dimorphism of tumor growth.