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DSS1 inhibits autophagy to activate epithelial-mesenchymal transition in a pro-metastatic niche of renal cell carcinoma

Author

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  • Xiaoyu Chen

    (Yuzhong District)

  • Qingyuan Liu

    (Yuzhong District
    Henan Provincial People’s Hospital)

  • Jingxian Wu

    (Yuzhong District)

  • Pengfei Zhou

    (Yuzhong District)

  • Mingming Zhao

    (Yuzhong District)

  • Jing Song

    (Yuzhong District)

Abstract

The mechanisms underlying clear cell renal cell carcinoma (ccRCC) metastasis remain largely unexplored. We demonstrate that Deleted in Split hand/Split foot protein 1 (DSS1), a critical cofactor of BRCA2 in DNA repair, is upregulated in metastatic ccRCC and promotes both tumor growth and distant metastasis. Mechanistically, DSS1 interacts with LC3 and promotes its degradation via TRIM25-mediated Lys63 (K63)-linked polyubiquitination at LC3B-K51. This impairs (macro) autophagic flux and leads to p62 accumulation, thereby stabilizing TWIST1 and facilitating its nuclear translocation, ultimately activating epithelial-mesenchymal transition (EMT). DSS1 highly expressed (DSS1hi) tumor cells are enriched in late-stage tumors and are associated with microvascular invasion within a vascularized invasive niche at the tumor-stromal interface, mediated by SPP1-ITGB1 interactions. Clinically, DSS1hi tumor cells correlate with therapeutic resistance and poorer patient outcomes. Collectively, these findings provide new insights into the mechanisms of ccRCC metastasis and suggest potential avenues for therapeutic intervention.

Suggested Citation

  • Xiaoyu Chen & Qingyuan Liu & Jingxian Wu & Pengfei Zhou & Mingming Zhao & Jing Song, 2025. "DSS1 inhibits autophagy to activate epithelial-mesenchymal transition in a pro-metastatic niche of renal cell carcinoma," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62135-9
    DOI: 10.1038/s41467-025-62135-9
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    1. Ayuko Hoshino & Bruno Costa-Silva & Tang-Long Shen & Goncalo Rodrigues & Ayako Hashimoto & Milica Tesic Mark & Henrik Molina & Shinji Kohsaka & Angela Di Giannatale & Sophia Ceder & Swarnima Singh & C, 2015. "Tumour exosome integrins determine organotropic metastasis," Nature, Nature, vol. 527(7578), pages 329-335, November.
    2. Divya Bezwada & Luigi Perelli & Nicholas P. Lesner & Ling Cai & Bailey Brooks & Zheng Wu & Hieu S. Vu & Varun Sondhi & Daniel L. Cassidy & Stacy Kasitinon & Sherwin Kelekar & Feng Cai & Arin B. Aurora, 2024. "Mitochondrial complex I promotes kidney cancer metastasis," Nature, Nature, vol. 633(8031), pages 923-931, September.
    3. David A. Barbie & Pablo Tamayo & Jesse S. Boehm & So Young Kim & Susan E. Moody & Ian F. Dunn & Anna C. Schinzel & Peter Sandy & Etienne Meylan & Claudia Scholl & Stefan Fröhling & Edmond M. Chan & Ma, 2009. "Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1," Nature, Nature, vol. 462(7269), pages 108-112, November.
    4. Suoqin Jin & Christian F. Guerrero-Juarez & Lihua Zhang & Ivan Chang & Raul Ramos & Chen-Hsiang Kuan & Peggy Myung & Maksim V. Plikus & Qing Nie, 2021. "Inference and analysis of cell-cell communication using CellChat," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    5. Justine Lengrand & Ievgenia Pastushenko & Sebastiaan Vanuytven & Yura Song & David Venet & Rahul M. Sarate & Melanie Bellina & Virginie Moers & Alice Boinet & Alejandro Sifrim & Nicolas Rama & Benjami, 2023. "Pharmacological targeting of netrin-1 inhibits EMT in cancer," Nature, Nature, vol. 620(7973), pages 402-408, August.
    6. Qing Ji & Lihong Zhou & Hua Sui & Liu Yang & Xinnan Wu & Qing Song & Ru Jia & Ruixiao Li & Jian Sun & Ziyuan Wang & Ningning Liu & Yuanyuan Feng & Xiaoting Sun & Gang Cai & Yu Feng & Jianfeng Cai & Yi, 2020. "Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    7. Aleksandr Ianevski & Kristen Nader & Kyriaki Driva & Wojciech Senkowski & Daria Bulanova & Lidia Moyano-Galceran & Tanja Ruokoranta & Heikki Kuusanmäki & Nemo Ikonen & Philipp Sergeev & Markus Vähä-Ko, 2024. "Single-cell transcriptomes identify patient-tailored therapies for selective co-inhibition of cancer clones," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Arun Prakash Mishra & Suzanne A. Hartford & Sounak Sahu & Kimberly Klarmann & Rajani Kant Chittela & Kajal Biswas & Albert B. Jeon & Betty K. Martin & Sandra Burkett & Eileen Southon & Susan Reid & Ma, 2022. "BRCA2-DSS1 interaction is dispensable for RAD51 recruitment at replication-induced and meiotic DNA double strand breaks," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    9. Adele M. Alchahin & Shenglin Mei & Ioanna Tsea & Taghreed Hirz & Youmna Kfoury & Douglas Dahl & Chin-Lee Wu & Alexander O. Subtelny & Shulin Wu & David T. Scadden & John H. Shin & Philip J. Saylor & D, 2022. "A transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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