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

IF 15.5 1区 医学 Q1 CELL BIOLOGY Journal of Extracellular Vesicles Pub Date : 2024-11-05 DOI:10.1002/jev2.70002
Xiaoyu Wei, Mengmeng Liang, Min Deng, Ji Zheng, Fei Luo, Qinyu Ma
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Abstract

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.

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从溶酶体降解到分泌型自噬的转换启动了前列腺癌的成骨性骨转移。
自噬相关物质降解和非常规分泌的发现,为自噬与大量生理过程和疾病相关的重大突破铺平了道路。然而,协调这两种途径的机制仍然难以捉摸。在这里,我们证明了从溶酶体降解到分泌型自噬途径的转换是由蛋白酪氨酸磷酸酶 1B (PTP1B,由 PTPN1 编码)控制的。PTP1B使syntaxin17(STX17)的两个酪氨酸残基去磷酸化会减少自噬体与溶酶体的融合,同时使细胞转向分泌型自噬途径。PTP1B过表达和肿瘤衍生的细胞外囊泡(EVs)都能激活成骨细胞的分泌性自噬途径。此外,我们还证明了通过分泌性自噬途径产生的成骨细胞 LC3+ EVs 是前列腺癌肿瘤相关骨重塑的主要因素。消耗肿瘤衍生的EVs分泌或基因消减成骨细胞的PTP1B可挽救异常的骨重塑和病变,这突出了LC3+ EVs与骨转移龛形成之间的相关性。我们的研究结果揭示了肿瘤调控的 PTP1B 在自噬体命运决定中的重要作用,并提出了 LC3+ EVs 在形成骨转移龛中的作用。
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来源期刊
Journal of Extracellular Vesicles
Journal of Extracellular Vesicles Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
27.30
自引率
4.40%
发文量
115
审稿时长
12 weeks
期刊介绍: The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies. The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.
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