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YAP governs intratumoral heterogeneity and chemosensitivity of small cell lung cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE161742 | GEO | 2021/06/01

REPOSITORIES: GEO

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YAP governs intratumoral heterogeneity and chemosensitivity of small cell lung cancer [scRNA-seq]

Project description:Small cell lung cancer is the most aggressive type of lung cancer and has a high degree of plasticity, characterized by a remarkable response to chemotherapy followed by development of resistance. We show that intratumoral heterogeneity of SCLC is progressively established, indicated by the appearance of YAP+ and HES1+ SCLC tumor cells. Notch signaling is required for the generation of Non-NE SCLC cells, but not for the tumorigenesis of SCLC. Furthermore, YAP signals through Notch-dependent and independent pathway to induce REST expression to promote the conversion of NE to Non-NE SCLC tumor cells. In addition, YAP activation enhances the chemoresistance in NE SCLC tumor cells by downregulating GSDME, while inactivation of YAP in Non-NE SCLC tumor cells switches cell death from apoptosis to pyroptosis. Our study will not only provide novel insights into the molecular basis of SCLC tumorigenesis, but also the potential drug targets for SCLC therapy

2021-06-01 | GSE161741 | GEO

YAP governs intratumoral heterogeneity and chemosensitivity of small cell lung cancer [bulk RNA-seq]

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YAP governs intratumoral heterogeneity and chemosensitivity of small cell lung cancer

Project description:YAP governs intratumoral heterogeneity and chemosensitivity of small cell lung cancer

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YAP governs intratumoral heterogeneity and chemosensitivity of small cell lung cancer [scRNA-seq]

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Archetype tasks link intratumoral heterogeneity to plasticity in recalcitrant small cell lung cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

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Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

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Intratumoral heterogeneity of small cell lung cancer

Project description:Small cell lung cancer (SCLC) is a highly malignant tumor with extensive genomic alterations as detected by single-region sequencing. Yet, the intratumoral heterogeneity (ITH) of SCLC remains unknown. We subjected 120 tumor samples from 40 stage I-III SCLC to multi-regional whole-exome sequencing.

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Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer.

Project description:Combining whole exome sequencing, transcriptome profiling, and T cell repertoire analysis, we investigate the spatial features of surgically-removed biopsies from multiple loci in tumor masses of 15 patients with non-small cell lung cancer (NSCLC). This revealed that the immune microenvironment has high spatial heterogeneity such that intratumoral regional variation is as large as inter-personal variation. While the local total mutational burden (TMB) is associated with local T-cell clonal expansion, local anti-tumor cytotoxicity does not directly correlate with neoantigen abundance. Together, these findings caution against that immunological signatures can be predicted solely from TMB or microenvironmental analysis from a single locus biopsy.

| S-EPMC6299138 | biostudies-literature

Archetype tasks link intratumoral heterogeneity to plasticity and cancer hallmarks in small cell lung cancer.

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. A record of this paper's Transparent Peer Review process is included in the supplemental information.

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