When exposed to adverse environmental conditions, cells degrade their own content to recycle cellular building blocks through a process called autophagy. A large body of literature has connected autophagy to cancer, but most studies up until now focused on its function in transformed cells. In her thesis, Nadja Katheder dissected the role of autophagy in a well-characterized neoplastic in vivo tumor model in Drosophila and demonstrates a novel non-cell-autonomous requirement of this process for tumor growth. Neighboring epithelial cells and distal tissues increase autophagy in the presence of a malignant tumor. Pharmacological autophagy inhibition reduces tumor growth and genetic ablation of autophagy in the microenvironment reveals a tumor-supportive role of this process in this specific cell population. Tumor cells are metabolically stressed and induce autophagy in their neighbors through a TNFα-JNK-IL-6 signaling cascade. Moreover, they are dependent on amino acid import to sustain their proliferation, which indicates a coupling of metabolism between these two cell populations. Finally, allografted growth-impaired tumors from autophagy-deficient donor animals resume growth in an autophagy-competent host. Together, the results described in this thesis highlight the tumor-promoting role of autophagy the microenvironment and show that cancer cells engage their epithelial neighbors as essential contributors aiding their own growth.
Keywords: Drosophila; JNK; amino acid transporter; autophagy; hippo; interleukin-6; microenvironment; ras; scribble.