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Stem-cell states converge in multi-stage cutaneous squamous cell carcinoma development [RNA-seq]

ABSTRACT: Stem cells play a critical role in cancer development by contributing to cell heterogeneity, lineage plasticity, and drug resistance. We created gene expression networks from hundreds of mouse normal and tumor samples, and integrated these with lineage tracing and single-cell RNA-seq, to identify convergence of cell states in pre-malignant tumor cells expressing markers of lineage plasticity and drug resistance. Two of these cell states representing multilineage plasticity or proliferation were inversely correlated, suggesting a mutually exclusive relationship. Treatment of carcinomas in vivo with chemotherapy repressed the proliferative state and activated multilineage plasticity, while inhibition of differentiation repressed plasticity and potentiated responses to cell-cycle inhibitors. Manipulation of this cell state transition point may provide a rich source of potential combinatorial targets for cancer therapy. These RNAseq data encompass bulk data used to treat cancer cell lines with a Pp2a inhibitor.

ORGANISM(S): Mus musculus

PROVIDER: GSE261743 | GEO | 2024/03/22

REPOSITORIES: GEO

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Stem-cell states converge in multi-stage cutaneous squamous cell carcinoma development [scRNA-seq]

Project description:Stem cells play a critical role in cancer development by contributing to cell heterogeneity, lineage plasticity, and drug resistance. We created gene expression networks from hundreds of mouse normal and tumor samples, and integrated these with lineage tracing and single-cell RNA-seq, to identify convergence of cell states in pre-malignant tumor cells expressing markers of lineage plasticity and drug resistance. Two of these cell states representing multilineage plasticity or proliferation were inversely correlated, suggesting a mutually exclusive relationship. Treatment of carcinomas in vivo with chemotherapy repressed the proliferative state and activated multilineage plasticity, while inhibition of differentiation repressed plasticity and potentiated responses to cell-cycle inhibitors. Manipulation of this cell state transition point may provide a rich source of potential combinatorial targets for cancer therapy. These scRNAseq data encompass normal skin, papilloma, and squamous cell cacinoma samples.

2024-03-22 | GSE261766 | GEO

Dynamic transcriptional reprogramming leads to novel immunotherapeutic vulnerabilities in myeloma

Project description:While there is extensive evidence for genetic variation as a basis for treatment resistance, other sources of variation result from cellular plasticity. Using multiple myeloma as an example of an incurable lymphoid malignancy, we show how cancer cells modulate lineage restriction, adapt their enhancer usage and employ cell-intrinsic diversity for survival and treatment escape. By using single cell transcriptome and chromatin accessibility profiling, we show that distinct transcriptional states co-exist in individual cancer cells and that differential transcriptional regulon usage and enhancer rewiring underlie these alternate transcriptional states. We demonstrate that exposure to standard treatment further promotes transcriptional reprogramming and differential enhancer recruitment, while simultaneously reducing developmental potential. Importantly, treatment generates a novel complement of actionable immunotherapy targets, such as CXCR4, which can be exploited to overcome treatment resistance. Our studies therefore delineate how to transform the cellular plasticity that underlies drug resistance into novel immuno-oncologic therapeutic opportunities.

2021-08-25 | GSE162337 | GEO

Analysis of gene expression (RNAseq) from shTP53:RB1 LNCaP/AR cell lines

Project description:Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. Here we show, using in vitro and in vivo prostate cancer models, that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR) dependent luminal epithelial cells to AR independent basal-like cells. This lineage plasticity is enabled by loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2 and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.

2017-01-06 | GSE89226 | GEO

ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer [ATAC-seq]

Project description:Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offers promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity.

2024-04-05 | GSE260467 | GEO

ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer [5hmC-seq]

2024-04-05 | GSE260466 | GEO

ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer [RNA-seq]

2024-04-05 | GSE230601 | GEO

ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer [ChIP-seq]

2024-04-05 | GSE230600 | GEO

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Project description:Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance seen in 10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify SWI/SNF subunits that are deregulated in NEPC, demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease and that SMARCA4 depletion impairs prostate cancer cell growth. We also show that SWI/SNF complexes interact with different lineage-specific factors in prostate adenocarcinoma and in NEPC cells, and that induction of lineage plasticity through depletion of REST is accompanied by changes in SWI/SNF genome occupancy. These data suggest a specific role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.

2020-11-04 | PXD016861 | Pride

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

Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling

Project description:In many cancers, treatment failure is linked to changes in tumor cell state or lineage, and often involves the reactivation of stem-like or developmental transcriptional programs. How this plasticity unfolds at a molecular level and whether it plays a causal role in drug resistance remains unclear. Here, we model the origin and dynamics of lineage plasticity in prostate cancer and its relationship to antiandrogen-based therapeutic resistance. In time course experiments utilizing genetically engineered mouse models and murine organoid cultures of prostate cancer, we find that plasticity initiates in an epithelial population defined by mixed luminal and basal lineage gene expression, and that it depends on elevated JAK and FGFR kinase activity. Organoid cultures from patients with late-stage castration-resistant disease harboring mixed-lineage cells reproduce the dependency we observe in mice, by upregulating luminal gene expression upon JAK and FGFR kinase inhibitor treatment. Single-cell analysis of human tumor samples confirms the presence of mixed lineage cells with elevated JAK/STAT and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.

2022-09-01 | GSE210358 | GEO

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