Dataset Information

Sox2 Is an Oncogenic Driver of Small-Cell Lung Cancer and Promotes the Classic Neuroendocrine Subtype.

ABSTRACT: Although many cancer prognoses have improved in the past 50 years due to advancements in treatments, there has been little improvement in therapies for small-cell lung cancer (SCLC). One promising avenue to improve treatment for SCLC is to understand its underlying genetic alterations that drive its formation, growth, and cellular heterogeneity. RB1 loss is one key driver of SCLC, and RB1 loss has been associated with an increase in pluripotency factors such as SOX2. SOX2 is highly expressed and amplified in SCLC and has been associated with SCLC growth. Using a genetically engineered mouse model, we have shown that Sox2 is required for efficient SCLC formation. Furthermore, genome-scale binding assays have indicated that SOX2 can regulate key SCLC pathways such as NEUROD1 and MYC. These data suggest that SOX2 can be associated with the switch of SCLC from an ASCL1 subtype to a NEUROD1 subtype. Understanding this genetic switch is key to understanding such processes as SCLC progression, cellular heterogeneity, and treatment resistance. IMPLICATIONS: Understanding the molecular mechanisms of SCLC initiation and development are key to opening new potential therapeutic options for this devastating disease.

SUBMITTER: Voigt E

PROVIDER: S-EPMC8642303 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Sox2 Is an Oncogenic Driver of Small-Cell Lung Cancer and Promotes the Classic Neuroendocrine Subtype.

Voigt Ellen E Wallenburg Madeline M Wollenzien Hannah H Thompson Ethan E Kumar Kirtana K Feiner Joshua J McNally Moira M Friesen Hunter H Mukherjee Malini M Afeworki Yohannes Y Kareta Michael S MS

Molecular cancer research : MCR 20210930 12

Although many cancer prognoses have improved in the past 50 years due to advancements in treatments, there has been little improvement in therapies for small-cell lung cancer (SCLC). One promising avenue to improve treatment for SCLC is to understand its underlying genetic alterations that drive its formation, growth, and cellular heterogeneity. RB1 loss is one key driver of SCLC, and RB1 loss has been associated with an increase in pluripotency factors such as SOX2. SOX2 ...[more]

PMID: 34593608

Similar Datasets

Project description:Background: Radiation therapy plays an important role in the treatment of patients with non-small cell lung cancer (NSCLC). However, the radiocurability is greatly limited because of radioresistance which leads to treatment failure, tumor recurrence, and metastasis. Cancer stem cell (CSC) has been identified as the main factor that contributes to radiation resistance. SOX2, one of the transcription factors specifically expressed in CSC, is involved in tumorigenesis, progression, and maintenance of cell stemness. But the association between SOX2 and NSCLC radioresistance is not clear now. Methods: We constructed the radiotherapy-resistant cell line of NSCLC by multiple radiotherapy treatments. Colony formation assay, western blot, and immunofluorescence were performed to detect the radiosensitivity of cells. Western blot, qRT-PCR, and sphere formation assay were used to detect CSC characteristics of cells. Wound healing assay and Transwell assay were used to determine cell migration motility. The SOX2-upregulated model and SOX2-downregulated model was constructed by lentivirus transduction. Finally, the expression and clinical relevance of SOX2 in NSCLC were investigated by bioinformatics analysis based on TCGA and GEO datasets. Results: The expression of SOX2 was increased in radioresistant cells and a trend of dedifferentiation were observed. The results of wound healing assay and Transwell assay showed that SOX2 overexpression significantly promote the migration and invasion of NSCLC cells. Mechanistically, overexpression of SOX2 enhanced radioresistance and DNA damage repair capability of parental cells, while down-regulation of SOX2 led to decreased radioresistance and DNA repair ability in radioresistant cells, all of which were related to cells dedifferentiation regulated by SOX2. In addition, bioinformatics analysis show that high expression of SOX2 was strongly associated with the progression and poor prognosis of patients with NSCLC. Conclusions: Our study revealed that SOX2 regulates radiotherapy resistance in NSCLC via promoting cell dedifferentiation. Therefore, SOX2 may be a promising therapeutic target for overcoming radioresistance in NSCLC, providing a new perspective to improve the curative effect.

Project description:Background and objectiveFor patients with metastatic non-small cell lung cancer (NSCLC) without an oncogenic driver, systemic therapy with immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy have significantly improved the outcomes. However, the majority of patients do not have a durable response, and there is a need for additional predictive biomarkers. The objective of this narrative review is to describe potential biomarkers for immunotherapy.MethodsNarrative overview of the literature synthesizing the findings of literature reporting retrospective, prospective, and subset analyses of studies investigating potential predictive biomarkers for ICI.Key content and findingsTumor expression of programmed death ligand-1 (PD-L1) is the only clinically available biomarker for patients receiving ICI-based therapy. However, PD-L1 has significant limitations and studies have investigated the predictive value of higher PD-L1 expression levels. There has been interest in tumor mutation burden (TMB) based on the premise that a higher TMB would be associated with a more neoantigens, which would increase the likelihood of an immune response. The studies to date have not revealed a consistent association with TMB level and survival benefit. Kelch-like ECH Associated Protein 1 (KEAP1) and serine/threonine kinase 11 (STK11) mutations have been associated with worse outcomes with ICI but these mutations appear to be associated with a worse prognosis, and not predictive for ICI. Tumor infiltrating lymphocytes (TIL's) are the mechanism of immune response, and there is interest in further investigating the presence, type and distribution of TIL's to predict immune benefit. Circulating tumor deoxyribonucleic acid (ctDNA) levels, at baseline and on treatment samples, are being investigated to assess response to therapy and long-term benefit of ICI.ConclusionsNone of the current biomarkers in development are validated for use in routine clinical care. Given the complexity of NSCLC biology and immune response to ICI most likely a composite biomarker using multiple biomarkers will need to be develop.

Dataset Information

Sox2 Is an Oncogenic Driver of Small-Cell Lung Cancer and Promotes the Classic Neuroendocrine Subtype.

Publications

<i>Sox2</i> Is an Oncogenic Driver of Small-Cell Lung Cancer and Promotes the Classic Neuroendocrine Subtype.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets