Mighty mouse breakthroughs: a Sox2-driven model for squamous cell lung cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Mukhopadhyay A
PROVIDER: S-EPMC4904963 | biostudies-other | 2015 Apr-Jun
REPOSITORIES: biostudies-other
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Project description:Squamous cell carcinoma (SCC) of the lung is the second most common subtype of lung cancer. With limited treatment options, the 5-year survival rate of SCC is only 15%. Although genomic alterations in SCC have been characterized, identifying the alterations that drive SCC is critical for improving treatment strategies. Mouse models of SCC are currently limited. Using lentiviral delivery of Sox2 specifically to the mouse lung, we tested the ability of Sox2 to promote tumorigenesis in multiple tumor suppressor backgrounds. Expression of Sox2, frequently amplified in human SCC, specifically cooperates with loss of Lkb1 to promote squamous lung tumors. Mouse tumors exhibit characteristic histopathology and biomarker expression similar to human SCC. They also mimic human SCCs by activation of therapeutically relevant pathways including STAT and mTOR. This model may be utilized to test the contribution of additional driver alterations in SCC, as well as for preclinical drug discovery.
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Project description:RationaleImproving the early detection and chemoprevention of lung cancer are key to improving outcomes. The pathobiology of early squamous lung cancer is poorly understood. We have shown that amplification of sex-determining region Y-box 2 (SOX2) is an early and consistent event in the pathogenesis of this disease, but its functional oncogenic potential remains uncertain. We tested the impact of deregulated SOX2 expression in a novel organotypic system that recreates the molecular and microenvironmental context in which squamous carcinogenesis occurs.Objectives(1) To develop an in vitro model of bronchial dysplasia that recapitulates key molecular and phenotypic characteristics of the human disease; (2) to test the hypothesis that SOX2 deregulation is a key early event in the pathogenesis of bronchial dysplasia; and (3) to use the model for studies on pathogenesis and chemoprevention.MethodsWe engineered the inducible activation of oncogenes in immortalized bronchial epithelial cells. We used three-dimensional tissue culture to build an organotypic model of bronchial dysplasia.Measurements and main resultsWe recapitulated human bronchial dysplasia in vitro. SOX2 deregulation drives dysplasia, and loss of tumor promoter 53 is a cooperating genetic event that potentiates the dysplastic phenotype. Deregulated SOX2 alters critical genes implicated in hallmarks of cancer progression. Targeted inhibition of AKT prevents the initiation of the dysplastic phenotype.ConclusionsIn the appropriate genetic and microenvironmental context, acute deregulation of SOX2 drives bronchial dysplasia. This confirms its oncogenic potential in human cells and affords novel insights into the impact of SOX2 deregulation. This model can be used to test therapeutic agents aimed at chemoprevention.
| S-EPMC5470746 | biostudies-literature
Project description:Since the SOX2 amplification was identified in lung squamous cell carcinoma (lung SCC), SOX2 transcriptional downstream targets have been actively investigated; however, such targets are often cell line specific. Here, in order to identify highly consensus SOX2 downstream genes in lung SCC cells, we used RNA-seq data from 178 lung SCC specimens (containing tumor and tumor-associated cells) and analyzed the correlation between SOX2 and previously-reported SOX2-controlled genes in lung SCC. In addition, we used another RNA-seq dataset from 105 non-small cell lung cancer cell lines (NSCLC; including 4 lung SCC cell lines) and again analyzed the correlation between SOX2 and the reported SOX2-controlled genes in the NSCLC cell lines (no tumor-associated cells). We combined the two analyses and identified genes commonly correlated with SOX2 in both datasets. Among the 99 genes reported as SOX2 downstream and/or correlated genes, we found 4 negatively-correlated (e.g., CDKN1A) and 11 positively-correlated genes with SOX2. We used biological studies to demonstrate that CDKN1A was suppressed by SOX2 in lung SCC cells. G1 cell cycle arrest induced by SOX2 siRNA was rescued by CDKN1A siRNA. These results indicate that the tumorigenic effect of SOX2 in lung SCC cells is mediated in part by suppression of CDKN1A.
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Project description:RationaleAmplification of distal 3q is the most common genomic aberration in squamous lung cancer (SQC). SQC develops in a multistage progression from normal bronchial epithelium through dysplasia to invasive disease. Identifying the key driver events in the early pathogenesis of SQC will facilitate the search for predictive molecular biomarkers and the identification of novel molecular targets for chemoprevention and therapeutic strategies. For technical reasons, previous attempts to analyze 3q amplification in preinvasive lesions have focused on small numbers of predetermined candidate loci rather than an unbiased survey of copy-number variation.ObjectivesTo perform a detailed analysis of the 3q amplicon in bronchial dysplasia of different histological grades.MethodsWe use molecular copy-number counting (MCC) to analyze the structure of chromosome 3 in 19 preinvasive bronchial biopsy specimens from 15 patients and sequential biopsy specimens from 3 individuals.Measurements and main resultsWe demonstrate that no low-grade lesions, but all high-grade lesions, have 3q amplification. None of seven low-grade lesions progressed clinically, whereas 8 of 10 patients with high-grade disease progressed to cancer. We identify a minimum commonly amplified region on chromosome 3 consisting of 17 genes, including 2 known oncogenes, SOX2 and PIK3CA. We confirm that both genes are amplified in all high-grade dysplastic lesions tested. We further demonstrate, in three individuals, that the clinical progression of high-grade preinvasive disease is associated with incremental amplification of SOX2, suggesting this promotes malignant progression.ConclusionsThese findings demonstrate progressive 3q amplification in the evolution of preinvasive SQC and implicate SOX2 as a key target of this dynamic process.
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Project description:BackgroundFor metachronous second pulmonary squamous cell carcinoma (msPSC) in patients with resected PSC, the method to distinguish tumour clonality has not yet been well established, which makes it difficult to determine accurate staging and predict prognosis.MethodsPatients who underwent surgery for first PSC and encountered msPSC were recruited from the Surveillance, Epidemiology, and End Results (SEER) database. We extracted overall survival 1 (OS1) for the first PSC, overall survival 2 (OS2) for msPSC, and interval survival for the time interval between the first and second PSC. The nomogram was calibrated for OS2, and recursive partitioning analysis (RPA) was performed for risk stratification.ResultsA total of 617 patients were identified. Several independent prognostic factors were identified and integrated into the nomogram for OS2, including gender, age (2nd), nodal status (1st), node metastasis (2nd), and extrapulmonary metastasis (2nd). The calibration curves showed optimal agreement between the predictions and actual observations, and the c-index was 0.678. Surgery was associated with longer survival for msPSC patients. The prognosis of sublobectomy was comparable and inferior to that of lobectomy in the low- and moderate-risk groups, respectively. Radiotherapy was associated with better outcomes in patients who did not undergo surgery.ConclusionsThe RPA-based clinical nomogram appears to be suitable for the prognostic prediction and risk stratification of OS2 in msPSC. This practical system may help clinicians make decisions and design clinical studies.
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Project description:Tumorigenesis depends on intricate interactions between genetically altered tumor cells and their surrounding microenvironment. While oncogenic drivers in lung squamous carcinoma (LUSC) have been described, the role of stroma in modulating tissue architecture, particularly cell polarity, remains unclear. Here, we report the establishment of a 3D coculture system of LUSC epithelial cells with cancer-associated fibroblasts (CAFs) and extracellular matrix that together capture key components of the tumor microenvironment (TME). Single LUSC epithelial cells develop into acinar-like structures with 0.02% efficiency, and addition of CAFs provides proper tumor-stromal interactions within an appropriate 3D architectural context. Using this model, we recapitulate key pathological changes during tumorigenesis, from hyperplasia to dysplasia and eventually invasion, in malignant LUSC spheroids that undergo phenotypic switching in response to cell intrinsic and extrinsic changes. Overexpression of SOX2 is sufficient to mediate the transition from hyperplasia to dysplasia in LUSC spheroids, while the presence of CAFs makes them invasive. Unexpectedly, CAFs suppress the activity of high SOX2 levels, restore hyperplasia, and enhance the formation of acinar-like structures. Taken together, these observations suggest that stromal factors can override cell intrinsic oncogenic changes in determining the disease phenotype, thus providing fundamental evidence for the existence of dynamic reciprocity between the nucleus and the TME of LUSC.
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Project description:We have identified SOX2 as a new oncogene and a likely driver of recurrent 3q26.3 amplifications in lung Squamous Cell Carcinoma. SOX2 is a crucial transcription factor implicated in Embryonic and Neural Stem Cells, that we found widely activatd in human lung SCC. This part of the study aimed at analyzing the transcriptomic consequences of SOX2 overexpression in a simple in vitro model (human lung squamous immortalized cells). Human lung squamous BEAS-2B cells were transduced for Control or SOX2 expression, and their transcriptomes compared using Affymetrix arrays.
| S-ECPF-GEOD-14883 | biostudies-other
Project description:Squamous cell lung cancer (SCC) is the second leading cause of lung cancer death in the US and has a 5-year survival rate of only 16%. Histological changes in the bronchial epithelium termed dysplasia are precursors to invasive SCC. However, the cellular mechanisms that cause dysplasia are unknown. To fill this knowledge gap, we used topical application of N-nitroso-tris chloroethylurea (NTCU) for 32 weeks to induce squamous dysplasia and SCC in mice. At 32 weeks the predominant cell type in the dysplastic airways was Keratin (K) 5 and K14 expressing basal cells. Notably, basal cells are extremely rare in the normal mouse bronchial epithelium but are abundant in the trachea. We therefore evaluated time-dependent changes in tracheal and bronchial histopathology after NTCU exposure (4, 8, 12, 16, 25 and 32 weeks). We show that tracheal dysplasia occurs significantly earlier than that of the bronchial epithelium (12 weeks vs. 25 weeks). This was associated with increased numbers of K5+/K14+ tracheal basal cells and a complete loss of secretory (Club cell secretory protein expressing CCSP+) and ciliated cells. TUNEL staining of NTCU treated tissues confirmed that the loss of CCSP+ and ciliated cells was not due to apoptosis. However, mitotic index (measured by bromodeoxyuridine incorporation) showed that NTCU treatment increased proliferation of K5+ basal cells in the trachea, and altered bronchial mitotic population from CCSP+ to K5+ basal cells. Thus, we demonstrate that NTCU-induced lung epithelial dysplasia starts in the tracheal epithelium, and is followed by basal cell metaplasia of the bronchial epithelium. This analysis extends our knowledge of the NTCU-SCC model by defining the early changes in epithelial cell phenotypes in distinct airway locations, and this may assist in identifying new targets for future chemoprevention studies.
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Project description:Lung cancer is the leading cause of cancer mortality worldwide, with squamous cell carcinoma (SQCC) being the second most common form. SQCCs are thought to originate in bronchial basal cells through an injury response to smoking, which results in this stem cell population committing to hyperplastic squamous rather than mucinous and ciliated fates. Copy number gains in SOX2 in the region of 3q26-28 occur in 94% of SQCCs, and appear to act both early and late in disease progression by stabilizing the initial squamous injury response in stem cells and promoting growth of invasive carcinoma. Thus, anti-SOX2 targeting strategies could help treat early and/or advanced disease. Because SOX2 itself is not readily druggable, we sought to characterize SOX2 binding partners, with the hope of identifying new strategies to indirectly interfere with SOX2 activity. We now report the first use of proximity-dependent biotin labeling (BioID) to characterize the SOX2 interactome in vivo We identified 82 high confidence SOX2-interacting partners. An interaction with the coactivator EP300 was subsequently validated in both basal cells and SQCCs, and we demonstrate that EP300 is necessary for SOX2 activity in basal cells, including for induction of the squamous fate. We also report that EP300 copy number gains are common in SQCCs and that growth of lung cancer cell lines with 3q gains, including SQCC cells, is dependent on EP300. Finally, we show that EP300 inhibitors can be combined with other targeted therapeutics to achieve more effective growth suppression. Our work supports the use of BioID to identify interacting protein partners of nondruggable oncoproteins such as SOX2, as an effective strategy to discover biologically relevant, druggable targets.
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Project description:SOX2 is a transcription factor essential for self-renewal and pluripotency of embryonic stem cells. Recently SOX2 was found overexpressed in the majority of the lung squamous cell carcinoma (SQC), in which it acts as a lineage-survival oncogene. However, downstream targets/pathways of SOX2 in lung SQC cells remain to be identified. In order to identify genes/pathways likely to be downstream of SOX2, we conducted SOX2 silencing experiments in LK2 and NCI-H520 (H520 thereafter), two SOX2-abundant lung SQC cell lines and analyzed global gene transcription changes by gene expression microarray assay. Each of H520 and LK2 cell lines was treated with either pooled siRNAs of SOX2 or non-silencing (control) siRNAs. After 48 h, cells were harvested and totoal RNA extracted for gene expression microarray analysis using Illumina HumanHT12 v3 BeadChip.
| S-ECPF-GEOD-48871 | biostudies-other