Abstract
Oncogenic stress responses are crucial modulators of tumour cell adaptation to hostile microenvironments and clonal dynamics. The evolutionarily conserved Hsp70 chaperone promotes tumour cell survival by suppressing apoptosis and facilitating metastatic progression. However, the temporal order and regulation of its expression in neoplastic tumours remains ill defined. Here, we show a non-canonical regulation of stress-inducible Hsp70 expression during neoplastic transformation in the Drosophila wing epithelium. Mosaic analysis with a repressible cell marker (MARCM) clones carrying the malignant lgl4 ykiOE mutations exhibited a delayed and progressive induction of Hsp70, which was tightly correlated with clonal expansion and tissue invasion. Loss of Hsp70 function in developing lgl4 ykiOE clones suppressed tumour growth in both larval wing discs and allograft assays, underscoring its significant role in tumour fitness and growth. We identify a non-canonical pathway where ROS-activated JNK signalling drives FOXO-dependent induction of Hsp70, bypassing HSF and Hif1α, to promote tumour growth and invasion. Genetic disruption of Nox or JNK abrogated Hsp70 induction and curtailed tumour expansion. Stress adaptation and malignancy of developing lgl4 ykiOE epithelial tumour thus require Hsp70 as a redox-responsive and temporally regulated effector of the JNK-FOXO axis.
