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SOX9 drives KRAS-induced lung adenocarcinoma progression and suppresses anti-tumor immunity

Oncogene volume 42, pages 2183–2194 (2023)Cite this article

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Abstract

The SOX9 transcription factor ensures proper tissue development and homeostasis and has been implicated in promoting tumor progression. However, the role of SOX9 as a driver of lung adenocarcinoma (LUAD), or any cancer, remains unclear. Using CRISPR/Cas9 and Cre-LoxP gene knockout approaches in the KrasG12D-driven mouse LUAD model, we found that loss of Sox9 significantly reduces lung tumor development, burden and progression, contributing to significantly longer overall survival. SOX9 consistently drove organoid growth in vitro, but SOX9-promoted tumor growth was significantly attenuated in immunocompromised mice compared to syngeneic mice. We demonstrate that SOX9 suppresses immune cell infiltration and functionally suppresses tumor associated CD8+ T, natural killer and dendritic cells. These data were validated by flow cytometry, gene expression, RT-qPCR, and immunohistochemistry analyses in KrasG12D-driven murine LUAD, then confirmed by interrogating bulk and single-cell gene expression repertoires and immunohistochemistry in human LUAD. Notably, SOX9 significantly elevates collagen-related gene expression and substantially increases collagen fibers. We propose that SOX9 increases tumor stiffness and inhibits tumor-infiltrating dendritic cells, thereby suppressing CD8+ T cell and NK cell infiltration and activity. Thus, SOX9 drives KrasG12D-driven lung tumor progression and inhibits anti-tumor immunity at least partly by modulating the tumor microenvironment.

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Fig. 1: SOX9 promotes lung tumor progression and loss of Sox9 prevents high-grade tumor formation and increases survival.
Fig. 2: SOX9 promotes growth of KrasG12D mouse lung tumor cells in 3D organoid culture and subcutaneous transplantation systems.
Fig. 3: Cell proliferation and immune suppression are significantly associated with Sox9 overexpression.
Fig. 4: Suppression of CD8+ T cells, NK cells and dendritic cells in Sox9-upregulated mouse lung tumors.
Fig. 5: Suppression of CD8+ T cells, NK cells and dendritic cells in SOX9-upregulated human LUAD tumors.

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Data availability

The datasets generated during this study can be accessed here: https://doi.org/10.6084/m9.figshare.20810164.

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Acknowledgements

We thank Jia Peng for suggestions and discussions. We thank the Wenwei Hu laboratory for help with tissue sectioning and imaging. We thank Gina Castellano and Samantha Grabler for maintaining NSG mice for subcutaneous transplantation. We thank Lucyann Franciosa and Shafiq Bhat from CINJ histology laboratory for IHC staining. We thank Joshua Vieth and Shashi Sharma from the CINJ Immune Monitoring & Advanced Genomics core facility for the flow cytometry assay. Services and results in support of this research project were generated by the Rutgers Cancer Institute of New Jersey Histopathology and Immune Monitoring Shared Resources, supported, in part, with funding from NCI P30CA072720-5919. This work was supported by NCI R01CA190578 (SRP), R01CA237347-01A1 (JYG) and ACS 134036-RSG-19-165-01-TBG (JYG).

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Authors and Affiliations

  1. Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901, USA

    Hua Zhong, Jian Cao, Gregory Riedlinger, Jessie Yanxiang Guo, Shridar Ganesan, Hatim E. Sabaawy & Sharon R. Pine

  2. Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901, USA

    Hua Zhong, Jian Cao, Jessie Yanxiang Guo, Shridar Ganesan, Hatim E. Sabaawy & Sharon R. Pine

  3. Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901, USA

    Hua Zhong & Sharon R. Pine

  4. Howard Hughes Medical Institute, Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Department of Medicine, Department of Microbiology and Immunology, University of California, San Francisco, CA, 94143-0795, USA

    Wen Lu

  5. Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA

    Yong Tang, Yong Wei & Yibin Kang

  6. Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA

    Yong Tang, Yong Wei & Yibin Kang

  7. Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, 405 30, Gothenburg, Sweden

    Clotilde Wiel

  8. Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 405 30, Gothenburg, Sweden

    Clotilde Wiel & Martin O. Bergo

  9. Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901, USA

    Gregory Riedlinger & Hatim E. Sabaawy

  10. Perlmutter NYU Cancer Center, Department of Pathology, New York University School of Medicine, New York, NY, 10016, USA

    Thales Papagiannakopoulos

  11. Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, NJ, 08854, USA

    Jessie Yanxiang Guo

  12. Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA

    Hatim E. Sabaawy & Sharon R. Pine

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  1. Hua Zhong
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Contributions

HZ, HES and SRP conceptualized and directed the overall project; HZ, WL, YT, YW, JC, YK and SRP conceptualized and explained the suppression of anti-tumor immunity; HZ, designed and performed experiments, and analyzed RNA sequencing data; CW and MB generated KrasG12D mouse lung tumor cell lines; HZ, GR and SRP read tumor grades; TP performed pSECC guide RNA screening and provided pSECC plasmids; JYG proposed the mouse model; HZ, WL and SRP prepared figures; HZ and SRP wrote the manuscript; SRP and SG provided funding and research space; HZ, WL, JYG, YK, HES and SRP edited the manuscript.

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Correspondence to Sharon R. Pine.

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Zhong, H., Lu, W., Tang, Y. et al. SOX9 drives KRAS-induced lung adenocarcinoma progression and suppresses anti-tumor immunity. Oncogene 42, 2183–2194 (2023). https://doi.org/10.1038/s41388-023-02715-5

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