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ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer [NCI-H510A]

ABSTRACT: Small cell lung cancer (SCLC) is a highly aggressive malignancy with extremely poor prognosis. SCLC cells exhibit high plasticity and can progress from neuroendocrine (NE) to non-NE phenotypes. This dynamic evolution promotes treatment resistance and relapses, representing a challenge for targeted therapies in this elusive disease. Here we identify the transcription factor ONECUT2 (OC2) as a driver of plasticity in SCLC, leading to non-NE transcriptional states. OC2 is highly expressed in SCLC tumors compared to normal lung tissue and its expression is associated with heightened clinical stage and lymph node metastasis. We show that OC2 is a repressor of ASCL1, the NE master regulator transcription factor. In addition, OC2 upregulates non-NE programs through activation of c-MYC and NOTCH signaling. We also demonstrate that OC2 is required for growth and survival of SCLC cells and that it can be targeted with a small-molecule inhibitor that acts synergically with cisplatin, providing a novel therapeutic strategy for OC2 active SCLC tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280218 | GEO | 2025/05/27

REPOSITORIES: GEO

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ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer [DMS53]

Project description:Small cell lung cancer (SCLC) is a highly aggressive malignancy with extremely poor prognosis. SCLC cells exhibit high plasticity and can progress from neuroendocrine (NE) to non-NE phenotypes. This dynamic evolution promotes treatment resistance and relapses, representing a challenge for targeted therapies in this elusive disease. Here we identify the transcription factor ONECUT2 (OC2) as a driver of plasticity in SCLC, leading to non-NE transcriptional states. OC2 is highly expressed in SCLC tumors compared to normal lung tissue and its expression is associated with heightened clinical stage and lymph node metastasis. We show that OC2 is a repressor of ASCL1, the NE master regulator transcription factor. In addition, OC2 upregulates non-NE programs through activation of c-MYC and NOTCH signaling. We also demonstrate that OC2 is required for growth and survival of SCLC cells and that it can be targeted with a small-molecule inhibitor that acts synergically with cisplatin, providing a novel therapeutic strategy for OC2 active SCLC tumors.

2025-05-27 | GSE280217 | GEO

ONECUT2 acts a lineage plasticity driver

Project description:Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.

2024-08-10 | PXD050634 | Pride

ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer (RNA-seq)

Project description:Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) directly activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC.

2023-11-21 | GSE244024 | GEO

ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer (ATAC-seq)

2023-11-21 | GSE244022 | GEO

ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer (CUT&RUN-seq)

2023-11-21 | GSE244023 | GEO

ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity [OE_MCF7]

Project description:Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer, resulting in tumor progression, therapeutic failure and metastatic spread. Here we identify the transcription factor ONECUT2 (OC2) as a lineage plasticity regulator of breast cancer (BC) that suppresses the estrogen axis and promotes luminal to basal transition. OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors.

2024-05-23 | GSE242540 | GEO

ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity [OE_BT474]

2024-05-23 | GSE242539 | GEO

ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity

Project description:Purpose: Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. Methods: We analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. Results: OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. Conclusions: The transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.

2024-05-23 | GSE242541 | GEO

ONECUT2 Drives Neuroendocrine Prostate Cancer Through Hypoxia Signaling

Project description:To determine the underlying mechanism of ONECUT2 in prostate cancer hypoxia, we conducted a series of RNA-Seq and ChIP-Seq experiments in LNCaP and PC3 cells under normoxia and hypoxia conditions. We did RNA-Seq in LNCaP cells with or without OC2 overexpression and in PC3 cells with or without OC2 knockdown. We used anti-Flag antibody to perform the ChIP-Seq experiment in PC3 cells with Flag and OC2 fusion protein overexpression. We also performed HIF1A ChIP-Seq in AR-negative prostate cancer cell line PC3 under hypoxia condition with or without ONECUT2 or SMAD3 siRNA knockdown. SMAD3 and HIF2A ChIP-Seq were conducted in PC3 cells under hypoxia condition. To confirm the interactions between transcription factors, we also performed ChIP-reChIP-seq. We did the primary ChIP experiment using anti-SMAD3 antibody and then we subjected the ChIPed chromatin by the primary ChIP to reChIP experiments using anti-HIF1A or anti-HIF2A antibody. The reChIPed DNA was submitted to next generation sequencing.

2019-02-27 | GSE106305 | GEO

scRNA-seq of triple knockout SCLC mouse models for subtyping

Project description:Small cell lung cancer (SCLC) tumors comprise heterogeneous mixtures of cell states, categorized into neuroendocrine (NE) and non-neuroendocrine (non-NE) transcriptional subtypes. NE to non-NE state transitions, fueled by plasticity, likely underlie adaptability to treatment and dismal survival rates. Here, we apply an archetypal analysis to model plasticity by recasting SCLC phenotypic heterogeneity through multi-task evolutionary theory. Cell line and tumor transcriptomics data fit well in a five-dimensional convex polytope whose vertices optimize tasks reminiscent of pulmonary NE cells, the SCLC normal counterparts. These tasks, supported by knowledge and experimental data, include proliferation, slithering, metabolism, secretion, and injury repair, reflecting cancer hallmarks. SCLC subtypes, either at the population or single-cell level, can be positioned in archetypal space by bulk or single-cell transcriptomics, respectively, and characterized as task specialists or multi-task generalists by the distance from archetype vertex signatures. In the archetype space, modeling single-cell plasticity as a Markovian process along an underlying state manifold indicates that task trade-offs, in response to microenvironmental perturbations or treatment, may drive cell plasticity. Stifling phenotypic transitions and plasticity may provide new targets for much-needed translational advances in SCLC.

2022-08-22 | GSE211751 | GEO

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