Tumor suppressors in Sox2-mediated lung cancers promote distinct cell intrinsic and immunologic remodeling
Year: 2026
Type: article
Abstract: Non-small cell lung cancer (NSCLC) largely consists of lung squamous (LUSC) and lung adenocarcinoma (LUAD). Alterations in the TRP53 and PTEN tumor suppressors are common in both subtypes, but their relationship with SOX2 is poorly understood. We deleted Trp53 or Pten in a C57BL/6J-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 Cdkn2a deletion). Histologic and single-cell RNAseq 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 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 sub-cluster of CD38+ tumor-associated inflammatory monocytes in the LN2A model that significantly enriched for activation of the classical and alternative complement pathways. Complement Factor B (CFB) is associated with poor survival in LUSC patients, 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.
Source: UNC Libraries
DOI: 10.17615/66g9-qw50
Authors: Zhou, Katherine, Yuan, Hong, Gupta, Gaorav P., Livingston, Eric W., Edatt, Lincy, Milner, J Justin, Gong, Weida, Godfrey, Virginia, Modliszewski, Jennifer L, Chack, Aaron C., Sengottuvel, Nisitha, Fagan-Solis, Katerina D., Pecot, Chad V., Green, Jarred M., Green, William D., Sanchez, Yazmin, Sellers, Rani S., Whately, Kristina M., Dawoud, Alyaa, Cannon, Gabrielle, Woods, Allison T.
Institution: University of North Carolina at Chapel Hill
Language: English
Topic: Lung Cancer Research Studies
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7203857977