Tumor suppressors in Sox2-mediated lung cancers promote distinct cell-intrinsic and immunologic remodeling
Non-small cell lung cancer (NSCLC) largely consists of lung squamous carcinoma (LUSC) and lung adenocarcinoma (LUAD). Alterations in the tumor protein p53 (TP53) and phosphatase and tensin homolog (PTEN) tumor suppressors are common in both subtypes, but their relationship with SOX2 is poorly understood. We deleted Trp53 or Pten in a C57BL/6 Sox2hi Nkx2-1-/- Lkb1-/- (SNL) genetic background and generated a highly metastatic LUSC cell line (LN2A; derived from a Sox2hi mouse model, followed by Trp53, Pten, and cyclin dependent kinase inhibitor 2A [Cdkn2a] deletion). Histologic and single-cell RNA-Seq analyses corroborated that SNL mice developed mixed tumors with both LUAD and LUSC histopathology while SNL-Trp53 and SNL-Pten mice developed LUAD and LN2A tumors that retained LUSC morphology. Compared with SNL mice, additional loss of Trp53 or Pten resulted in significantly reduced survival, increased tumor burden, and altered tumor mucin composition. We identified a subcluster of CD38+ tumor-associated inflammatory monocytes in the LN2A model that was significantly enriched for activation of the classical and alternative complement pathways. Complement factor B (CFB) is associated with poor survival in patients with LUSC, and we observed the LN2A model had significantly improved survival on a Cfb-/- background. Our findings demonstrate a cooperative role of Trp53 and Pten tumor suppressors in Sox2-mediated NSCLC tumor progression, mucin production, and remodeling of the immune tumor microenvironment.
Authors
- George M. Cannon (ORCID: https://orcid.org/0000-0001-9724-8341)
- Virginia Godfrey
- Lincy Edatt (ORCID: https://orcid.org/0000-0001-7594-4012)
- Chad V. Pecot (ORCID: https://orcid.org/0000-0002-5250-2999)
- Rani S. Sellers (ORCID: https://orcid.org/0000-0001-8870-4675)
- Alyaa Dawoud (ORCID: https://orcid.org/0000-0002-8140-1070)
- Katherine I. Zhou (ORCID: https://orcid.org/0000-0001-6442-0475)
- William D. Green (ORCID: https://orcid.org/0000-0001-7472-8756)
- Allison T Woods
- Nisitha Sengottuvel (ORCID: https://orcid.org/0000-0003-3711-1719)
- Jarred M Green
- Hong Yuan (ORCID: https://orcid.org/0000-0002-0535-3214)
- Jennifer L. Modliszewski (ORCID: https://orcid.org/0000-0002-5219-5343)
- Katerina D. Fagan‐Solis
- J. Justin Milner (ORCID: https://orcid.org/0000-0002-0752-2130)
- Kristina M Whately (ORCID: https://orcid.org/0000-0002-5908-8145)
- Aaron C Chack (ORCID: https://orcid.org/0000-0003-3279-7192)
- Yolanda Sánchez (ORCID: https://orcid.org/0000-0002-9428-1872)
- Eric W. Livingston (ORCID: https://orcid.org/0000-0002-2208-989X)
- Weida Gong
- Gaorav P. Gupta (ORCID: https://orcid.org/0000-0001-9177-552X)
Institutions
- University of North Carolina at Chapel Hill (US)
- University of North Carolina Health Care (US)
- BSCS Science Learning (US)
- Systems Analytics (United States) (US)
- Laboratoire d’Imagerie Biomédicale (FR)
- Cancer Genetics (United States) (US)
- Segeberger Kliniken (DE)
- Imaging Center (US)
- UNC Lineberger Comprehensive Cancer Center
Publication Details
- Journal
- JCI Insight
- Published
- 2025-05-06
- DOI
- https://doi.org/10.1172/jci.insight.171364
- Citations
- 3
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- North Carolina Biotechnology Center
- Free To Breathe
- National Institutes of Health
- National Cancer Institute