Similar Datasets
Project description:Non-small cell lung cancer (NSCLC) largely consists of lung squamous (LUSC) and lung adenocarcinoma (LUAD). While driver mutations are common in LUAD, LUSC has few if any actionable targetable drivers. Despite these distinct differences, alterations in the p53 and Pten tumor suppressors are common in both subtypes. While Sox2 is widely considered an LUSC proto-oncogene, the relationship of p53 and Pten with Sox2 is poorly understood. To evaluate the role of these tumor suppressors in Sox2-mediated NSCLC models on disease progression and the tumor microenvironment (TME), we deleted Trp53 or Pten in a C57BL/6J-Sox2hi, Nkx2-1-/-, Lkb1-/- (SNL) genetic background. In parallel, we generated a highly metastatic LUSC cell line (LN2A; derived from a Sox2high mouse model, followed by p53, Pten, and Cdkn2a deletion) that also grows in C57BL/6 mice. 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 implanted LN2A tumors retained LUSC morphology. Compared with SNL mice, additional loss of p53 or Pten resulted in significantly reduced survival, increased tumor burden and altered tumor mucin composition. As the metastatic potential in the tumor models progressed from the least (SNL) to most (LN2A), we observed a progressive increase in cellular infiltrate, most notably high levels of recruited tumor-associated inflammatory monocytes (TIMs). We identified a sub-cluster of CD38+ TIMs in the LN2A model that significantly enriched for activation of the classical and alternative complement pathways. Importantly, 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. Taken together, our findings demonstrate a cooperative role of p53 and Pten tumor suppressors in Sox2-mediated NSCLC tumor progression, mucin production, and remodeling of the immune TME.
2025-05-20 | GSE294471 | GEO
Project description:Non-small cell lung cancer (NSCLC) largely consists of lung squamous (LUSC) and lung adenocarcinoma (LUAD). While driver mutations are common in LUAD, LUSC has few if any actionable targetable drivers. Despite these distinct differences, alterations in the p53 and Pten tumor suppressors are common in both subtypes. While Sox2 is widely considered an LUSC proto-oncogene, the relationship of p53 and Pten with Sox2 is poorly understood. To evaluate the role of these tumor suppressors in Sox2-mediated NSCLC models on disease progression and the tumor microenvironment (TME), we deleted Trp53 or Pten in a C57BL/6J-Sox2hi, Nkx2-1-/-, Lkb1-/- (SNL) genetic background. In parallel, we generated a highly metastatic LUSC cell line (LN2A; derived from a Sox2high mouse model, followed by p53, Pten, and Cdkn2a deletion) that also grows in C57BL/6 mice. 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 implanted LN2A tumors retained LUSC morphology. Compared with SNL mice, additional loss of p53 or Pten resulted in significantly reduced survival, increased tumor burden and altered tumor mucin composition. As the metastatic potential in the tumor models progressed from the least (SNL) to most (LN2A), we observed a progressive increase in cellular infiltrate, most notably high levels of recruited tumor-associated inflammatory monocytes (TIMs). We identified a sub-cluster of CD38+ TIMs in the LN2A model that significantly enriched for activation of the classical and alternative complement pathways. Importantly, 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. Taken together, our findings demonstrate a cooperative role of p53 and Pten tumor suppressors in Sox2-mediated NSCLC tumor progression, mucin production, and remodeling of the immune TME.
2025-05-20 | GSE295824 | GEO
Project description:Tumor suppressors in Sox2-mediated lung cancers promote distinct cell-intrinsic and immunologic remodeling
| PRJNA1256720 | ENA
Project description:Tumor suppressors in Sox2-mediated lung cancers promote distinct cell intrinsic and immunologic remodeling [RNA-seq]
| PRJNA1249506 | ENA
Project description:Tumor suppressors in Sox2-mediated lung cancers promote distinct cell intrinsic and immunologic remodeling [scRNA-seq]
| PRJNA1256447 | ENA
Project description:In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here, we explored the role of exportin 1 in NE transformation. We observed up-regulated exportin 1 in lung and prostate pretransformation adenocarcinomas. Exportin 1 was up-regulated after genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation in different TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the aromatase inhibitor enzalutamide and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs to standard cytotoxics. Together, these data nominate exportin 1 inhibition as a potential therapeutic target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma.
| S-EPMC10777207 | biostudies-literature
Project description:MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately and as a heteromeric complex to restrain p53's functions. MDM2 also has pro-oncogenic roles in cells, tissues, and animals that are independent of p53. There is less information available about p53-independent roles of MDMX or the MDM2-MDMX complex. We found that MDM2 and MDMX facilitate ferroptosis in cells with or without p53. Using small molecules, RNA interference reagents, and mutant forms of MDMX, we found that MDM2 and MDMX, likely working in part as a complex, normally facilitate ferroptotic death. We observed that MDM2 and MDMX alter the lipid profile of cells to favor ferroptosis. Inhibition of MDM2 or MDMX leads to increased levels of FSP1 protein and a consequent increase in the levels of coenzyme Q10, an endogenous lipophilic antioxidant. This suggests that MDM2 and MDMX normally prevent cells from mounting an adequate defense against lipid peroxidation and thereby promote ferroptosis. Moreover, we found that PPARα activity is essential for MDM2 and MDMX to promote ferroptosis, suggesting that the MDM2-MDMX complex regulates lipids through altering PPARα activity. These findings reveal the complexity of cellular responses to MDM2 and MDMX and suggest that MDM2-MDMX inhibition might be useful for preventing degenerative diseases involving ferroptosis. Furthermore, they suggest that MDM2/MDMX amplification may predict sensitivity of some cancers to ferroptosis inducers.
| S-EPMC7111265 | biostudies-literature
Project description:PurposeAround 10% to 15% of prostate cancers harbor recurrent aberrations in the Forkhead Box A1 gene, FOXA1, whereby the alteration type and the effect on the forkhead (FKH) domain affect protein function. We developed a FOXA1 classification system to inform clinical management.Experimental designA total of 5,014 prostate cancer samples were examined using whole-exome and -transcriptome sequencing from the Caris Life Sciences database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain. These were in the first part of the FKH domain [class 1A: amino acids (AA) 168-246], within the Wing2 region of FKH (class 1B: AA 247-269), or outside FKH (class 1C: AA 1-167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1-269 and class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims.ResultsFOXA1 alterations did not influence survival when considered in aggregate but had distinct prognostic effects when stratified by class. In primary prostate samples, class 1A alterations were associated with overall improved survival (HR, 0.57; P = 0.03); a similar trend was seen in metastatic biopsies with class 1B (HR, 0.84; P = 0.09). Conversely, in primary specimens, class 1C exhibited worse survival upon second-generation androgen receptor signaling inhibitor treatment (HR, 1.93; P < 0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR, 2.05; P < 0.001) and worse outcomes to first-line androgen-deprivation therapies (HR, 2.5; P < 0.001). Class 3A alterations indicated improved survival (HR, 0.70; P = 0.01), whereas class 3B alterations portended poor outcomes (HR, 1.50; P < 0.001). Amplifications (class 4) indicated poor outcomes in metastatic samples (HR, 1.48; P = 0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European Americans, African Americans had increased class 1C alterations, whereas Asian/Pacific Islander patients had increased class 1B alterations.ConclusionsFOXA1 alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision-making for patients with prostate cancer and uncovers important racial differences.
| S-EPMC11873805 | biostudies-literature
Project description:The local immune infiltrate's influence on tumor progression may be closely linked to tumor-intrinsic factors. The study aimed to investigate whether integrating immunologic and tumor-intrinsic factors can identify patients from a low-risk cohort who may be candidates for radiotherapy (RT) de-escalation. The SweBCG91RT trial included 1,178 patients with stage I to IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median of 15.2 years. We trained two models designed to capture immunologic activity and immunomodulatory tumor-intrinsic qualities, respectively. We then analyzed if combining these two variables could further stratify tumors, allowing for identifying a subgroup where RT de-escalation is feasible, despite clinical indicators of a high risk of ipsilateral breast tumor recurrence (IBTR). The prognostic effect of the immunologic model could be predicted by the tumor-intrinsic model (Pinteraction = 0.01). By integrating measurements of the immunologic- and tumor-intrinsic models, patients who benefited from an active immune infiltrate could be identified. These patients benefited from standard RT (HR, 0.28; 95% CI, 0.09-0.85; P = 0.025) and had a 5.4% 10-year incidence of IBTR after irradiation despite high-risk genomic indicators and a low frequency of systemic therapy. In contrast, high-risk tumors without an immune infiltrate had a high 10-year incidence of IBTR despite RT treatment (19.5%; 95% CI, 12.2-30.3). Integrating tumor-intrinsic and immunologic factors may identify immunogenic tumors in early-stage breast cancer populations dominated by ER-positive tumors. Patients who benefit from an activated immune infiltrate may be candidates for RT de-escalation.
| S-EPMC10150244 | biostudies-literature
Project description:Previous work has identified divergent mechanisms by which cervical remodeling is achieved in preterm birth (PTB) induced by hormone withdrawal (mifepristone) or lipopolysaccharide (LPS). Our current study aims to document how collagen architecture is modified to achieve premature cervical remodeling in mice treated with LPS as a model of infection-induced inflammation. Cervices were collected on gestation day (d) 15 from mice with premature cervical ripening induced by LPS and compared to d15 and d18 controls as well as a hormone withdrawal PTB model. Second harmonic generation (SHG) and electron microscopy were utilized for visualization of collagen morphology and ultrastructure. LPS-mediated premature cervical ripening is characterized by unique structural changes in collagen fiber morphology. LPS treatment increased the interfibrillar spacing of collagen fibrils. A preferential disruption of collagen fiber architecture in the subepithelial region compared to midstroma region was evidenced by increased pores lacking collagen signal in SHG images in the LPS-treated mice. Coinciding with this alteration, the infiltration of neutrophils was concentrated in the subepithelial stromal region as compared to midstromal region implicating the potential role of immune cells to extracellular matrix reorganization in inflammation-induced preterm cervical ripening. The current study demonstrates a preferential disorganization of collagen interfibrillar spacing and collagen fiber structure in LPS-mediated ripening.
| S-EPMC5803761 | biostudies-literature