Adipose-derived Spz5 remotely promotes tumor progression via endocytosis defects-mediated Hedgehog pathway activation

Inter-organ communication is vital for tissue homeostasis and health in multicellular organisms, and its disruption can lead to diseases such as cancer. Adipose tissue acts as a key endocrine center, secreting cytokines that influence remote organs. Despite clear links between obesity and increased cancer risk, the underlying mechanisms are unclear. Here, utilizing a novel Drosophila melanogaster genetic model combining Gal4-UAS and QF-QUAS systems, we reveal that adipose-secreted Spz5 ligand promotes distal epithelial tumor overgrowth and invasion. Mechanistically, Spz5 binds to tumor cell Toll-6 receptors, triggering the degradation of the endocytic adaptor protein AP-2alpha via Mib1-mediated ubiquitination. Consequently, impaired endocytosis leads to Smoothened (Smo) accumulation on the cell membrane and subsequent activation of the Hedgehog (Hh) pathway. This abnormal Hh activation synergizes with the oncogenic Yorkie (Yki) to drive tumor growth and invasion. Overall, our study provides novel molecular insights into the regulatory mechanisms of inter-organ communication-mediated tumor progression.