ABSTRACT
Lysosomes must maintain the integrity of their limiting membrane to ensure efficient fusion with incoming organelles and degradation of substrates within their lumen. Pancreatic cancer cells upregulate lysosomal biogenesis to enhance nutrient recycling and stress resistance, but it is unknown whether dedicated programmes for maintaining the integrity of the lysosome membrane facilitate pancreatic cancer growth. Using proteomic-based organelle profiling, we identify the Ferlin family plasma membrane repair factor Myoferlin as selectively and highly enriched on the membrane of pancreatic cancer lysosomes. Mechanistically, lysosomal localization of Myoferlin is necessary and sufficient for the maintenance of lysosome health and provides an early acting protective system against membrane damage that is independent of the endosomal sorting complex required for transport (ESCRT)-mediated repair network. Myoferlin is upregulated in human pancreatic cancer, predicts poor survival and its ablation severely impairs lysosome function and tumour growth in vivo. Thus, retargeting of plasma membrane repair factors enhances the pro-oncogenic activities of the lysosome.
Subject(s)
Biomarkers, Tumor/metabolism , Calcium-Binding Proteins/metabolism , Cell Proliferation , Intracellular Membranes/metabolism , Lysosomes/metabolism , Membrane Proteins/metabolism , Muscle Proteins/metabolism , Pancreatic Neoplasms/metabolism , Animals , Biomarkers, Tumor/genetics , Calcium-Binding Proteins/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Humans , Intracellular Membranes/pathology , Lysosomes/genetics , Lysosomes/pathology , Membrane Proteins/genetics , Mice, Inbred C57BL , Mice, Transgenic , Muscle Proteins/genetics , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Prognosis , Signal Transduction , Tumor BurdenABSTRACT
Pancreatic ductal adenocarcinoma (PDA) is a heterogeneous disease comprised of a basal-like subtype with mesenchymal gene signatures, undifferentiated histopathology and worse prognosis compared to the classical subtype. Despite their prognostic and therapeutic value, the key drivers that establish and control subtype identity remain unknown. Here, we demonstrate that PDA subtypes are not permanently encoded, and identify the GLI2 transcription factor as a master regulator of subtype inter-conversion. GLI2 is elevated in basal-like PDA lines and patient specimens, and forced GLI2 activation is sufficient to convert classical PDA cells to basal-like. Mechanistically, GLI2 upregulates expression of the pro-tumorigenic secreted protein, Osteopontin (OPN), which is especially critical for metastatic growth in vivo and adaptation to oncogenic KRAS ablation. Accordingly, elevated GLI2 and OPN levels predict shortened overall survival of PDA patients. Thus, the GLI2-OPN circuit is a driver of PDA cell plasticity that establishes and maintains an aggressive variant of this disease.
