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Critical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma

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  • Fernando C. Baltanás

    (CSIC-University of Salamanca and CIBERONC
    Institute of Biomedicine of Seville (IBiS)/“Virgen del Rocío” University Hospital/CSIC/University of Seville and Department of Medical Physiology and Biophysics, University of Seville)

  • Rósula García-Navas

    (CSIC-University of Salamanca and CIBERONC)

  • Pablo Rodríguez-Ramos

    (CSIC-University of Salamanca and CIBERONC)

  • Nuria Calzada

    (CSIC-University of Salamanca and CIBERONC)

  • Cristina Cuesta

    (CSIC-University of Salamanca)

  • Javier Borrajo

    (University of Salamanca)

  • Rocío Fuentes-Mateos

    (CSIC-University of Salamanca and CIBERONC)

  • Andrea Olarte-San Juan

    (CSIC-University of Salamanca and CIBERONC)

  • Nerea Vidaña

    (CSIC-University of Salamanca and CIBERONC)

  • Esther Castellano

    (CSIC-University of Salamanca)

  • Eugenio Santos

    (CSIC-University of Salamanca and CIBERONC)

Abstract

The impact of genetic ablation of SOS1 or SOS2 is evaluated in a murine model of KRASG12D-driven lung adenocarcinoma (LUAD). SOS2 ablation shows some protection during early stages but only SOS1 ablation causes significant, specific long term increase of survival/lifespan of the KRASG12D mice associated to markedly reduced tumor burden and reduced populations of cancer-associated fibroblasts, macrophages and T-lymphocytes in the lung tumor microenvironment (TME). SOS1 ablation also causes specific shrinkage and regression of LUAD tumoral masses and components of the TME in pre-established KRASG12D LUAD tumors. The critical requirement of SOS1 for KRASG12D-driven LUAD is further confirmed by means of intravenous tail injection of KRASG12D tumor cells into SOS1KO/KRASWT mice, or of SOS1-less, KRASG12D tumor cells into wildtype mice. In silico analyses of human lung cancer databases support also the dominant role of SOS1 regarding tumor development and survival in LUAD patients. Our data indicate that SOS1 is critically required for development of KRASG12D-driven LUAD and confirm the validity of this RAS-GEF activator as an actionable therapeutic target in KRAS mutant LUAD.

Suggested Citation

  • Fernando C. Baltanás & Rósula García-Navas & Pablo Rodríguez-Ramos & Nuria Calzada & Cristina Cuesta & Javier Borrajo & Rocío Fuentes-Mateos & Andrea Olarte-San Juan & Nerea Vidaña & Esther Castellano, 2023. "Critical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41583-1
    DOI: 10.1038/s41467-023-41583-1
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    References listed on IDEAS

    as
    1. Leisa Johnson & Kim Mercer & Doron Greenbaum & Roderick T. Bronson & Denise Crowley & David A. Tuveson & Tyler Jacks, 2001. "Somatic activation of the K-ras oncogene causes early onset lung cancer in mice," Nature, Nature, vol. 410(6832), pages 1111-1116, April.
    2. Kian-Huat Lim & Brooke B. Ancrile & David F. Kashatus & Christopher M. Counter, 2008. "Tumour maintenance is mediated by eNOS," Nature, Nature, vol. 452(7187), pages 646-649, April.
    3. Hao-Hsuan Jeng & Laura J Taylor & Dafna Bar-Sagi, 2012. "Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis," Nature Communications, Nature, vol. 3(1), pages 1-8, January.
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