Sengottuvel Nisitha, Whately Kristina M, Modliszewski Jennifer L, Sellers Rani S, Green William D, Gong Weida, Woods Allison T, Livingston Eric W, Fagan-Solis Katerina D, Cannon Gabrielle, Edatt Lincy, Yuan Hong, Chack Aaron C, Sanchez Yazmin, Zhou Katherine, Dawoud Alyaa, Green Jarred M, Godfrey Virginia, Milner J Justin, Gupta Gaorav P, Pecot Chad V
Lineberger Comprehensive Cancer Center.
Curriculum in Genetics and Molecular Biology.
JCI Insight. 2025 May 6;10(12). doi: 10.1172/jci.insight.171364. eCollection 2025 Jun 23.
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.
非小细胞肺癌（NSCLC）主要由肺鳞状细胞癌（LUSC）和肺腺癌（LUAD）组成。肿瘤蛋白p53（TP53）和磷酸酶及张力蛋白同源物（PTEN）肿瘤抑制因子的改变在这两种亚型中都很常见，但它们与SOX2的关系却知之甚少。我们在C57BL/6 Sox2hi Nkx2-1-/- Lkb1-/-（SNL）基因背景下敲除Trp53或Pten，并生成了一种高转移性LUSC细胞系（LN2A；源自Sox2hi小鼠模型，随后敲除Trp53、Pten和细胞周期蛋白依赖性激酶抑制剂2A [Cdkn2a]）。组织学和单细胞RNA测序分析证实，SNL小鼠发生了具有LUAD和LUSC组织病理学特征的混合肿瘤，而SNL-Trp53和SNL-Pten小鼠发生了保留LUSC形态的LUAD和LN2A肿瘤。与SNL小鼠相比，Trp53或Pten的额外缺失导致生存率显著降低、肿瘤负担增加以及肿瘤粘蛋白组成改变。我们在LN2A模型中鉴定出一个CD38+肿瘤相关炎性单核细胞亚群，该亚群在经典和替代补体途径的激活方面显著富集。补体因子B（CFB）与LUSC患者的不良生存相关，并且我们观察到LN2A模型在Cfb-/-背景下生存率显著提高。我们的研究结果表明，Trp53和Pten肿瘤抑制因子在Sox2介导的NSCLC肿瘤进展、粘蛋白产生以及免疫肿瘤微环境重塑中发挥协同作用。
