A switch from lysosomal degradation to secretory autophagy initiates osteogenic bone metastasis in prostate cancer

The identification of both autophagy-related material degradation and unconventional secretion has paved the way for significant breakthroughs linking Autophagy to a plethora of physiological processes and disease conditions. However, the mechanisms that coordinate these two pathways remain elusive. Here, we demonstrate that a switch from the lysosomal degradation to a secretory Autophagy pathway is governed by protein tyrosine Phosphatase 1B (PTP1B, encoded by PTPN1). Dephosphorylation at two tyrosine residues of syntaxin17 (STX17) by PTP1B reduces autophagosome-lysosome fusion while switching the cells to a secretory Autophagy pathway. Both PTP1B overexpression and tumour-derived extracellular vesicles (EVs) can activate the secretory Autophagy pathway in osteoblasts. Moreover, we demonstrate that osteoblastic LC3+ EVs, generated via the secretory Autophagy pathway, are the primary contributor to tumour-associated bone remodelling in prostate Cancer. Depletion of tumour-derived EVs secretion or genetic ablation of osteoblastic PTP1B rescues aberrant bone remodelling and lesions, highlighting the relevance between LC3+ EVs and the formation of bone metastatic niche. Our results reveal the significance of tumour-regulated PTP1B in the fate decision of autophagosomes, and propose a role ofLC3+ EVs in shaping the bone metastatic niche.

autophagosome‐lysosome fusion; bone metastatic niche; extracellular vesicles; secretory autophagy; tumour‐associated bone remodelling.