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Non-cell-autonomous cancer progression from chromosomal instability.
Li, Jun; Hubisz, Melissa J; Earlie, Ethan M; Duran, Mercedes A; Hong, Christy; Varela, Austin A; Lettera, Emanuele; Deyell, Matthew; Tavora, Bernardo; Havel, Jonathan J; Phyu, Su M; Amin, Amit Dipak; Budre, Karolina; Kamiya, Erina; Cavallo, Julie-Ann; Garris, Christopher; Powell, Simon; Reis-Filho, Jorge S; Wen, Hannah; Bettigole, Sarah; Khan, Atif J; Izar, Benjamin; Parkes, Eileen E; Laughney, Ashley M; Bakhoum, Samuel F.
Afiliación
  • Li J; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Hubisz MJ; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Earlie EM; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
  • Duran MA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • Hong C; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
  • Varela AA; Bioinformatics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA.
  • Lettera E; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
  • Deyell M; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • Tavora B; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
  • Havel JJ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Phyu SM; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Amin AD; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Budre K; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Kamiya E; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
  • Cavallo JA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • Garris C; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
  • Powell S; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Reis-Filho JS; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Wen H; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
  • Bettigole S; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • Khan AJ; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
  • Izar B; Volastra Therapeutics Inc., New York, NY, USA.
  • Parkes EE; Volastra Therapeutics Inc., New York, NY, USA.
  • Laughney AM; Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, UK.
  • Bakhoum SF; Columbia Center for Translational Immunology, New York, NY, USA.
Nature ; 620(7976): 1080-1088, 2023 Aug.
Article en En | MEDLINE | ID: mdl-37612508
Chromosomal instability (CIN) is a driver of cancer metastasis1-4, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing-a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell-cell interactions from single-cell transcriptomic data-we show that CIN-induced chronic activation of the cGAS-STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Progresión de la Enfermedad / Inestabilidad Cromosómica / Neoplasias Límite: Humans Idioma: En Revista: Nature Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Progresión de la Enfermedad / Inestabilidad Cromosómica / Neoplasias Límite: Humans Idioma: En Revista: Nature Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido