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

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

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE193961 | GEO | 2022/07/05

REPOSITORIES: GEO

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Archetype tasks link intratumoral heterogeneity to plasticity in recalcitrant small cell lung cancer [Human tumor]

Project description:Intratumoral heterogeneity underlies cancer treatment resistance, but approaches to neutralize it remain elusive. Here, we recast heterogeneity in a systems perspective that considers cancer cell functional tasks inherited from cells of origin. We apply Archetype Analysis to bulk transcriptomics data from small cell lung cancer (SCLC), which forms tumors composed of neuroendocrine (NE) and non-neuroendocrine (non-NE) transcriptional subtypes. SCLC subtypes fit well in a 5-dimensional polytope whose vertices optimize tasks reminiscent of pulmonary NE cells, the SCLC normal counterpart, and include injury repair, slithering, and chemosensation. SCLC cells near a vertex are specialists for a task, while more distant cells are generalists, bearing gene signatures of multiple archetypes. Evolutionary theory and dynamical systems modeling suggest a division of labor strategy for adaptation to treatment, based on task trade-offs amongst specialists and generalists. Cell Transport Potential, a metric derived from single-cell RNA velocity, uncovers plasticity trends from specialists to generalists, and NE to non-NE subtypes. Transcription factor network simulations indicate that MYC overexpression increases plasticity by de-stabilizing NE subtypes. Framing heterogeneity in archetype space provides insights into transformative cancer treatments aimed at tumor cell plasticity.

2022-07-05 | GSE193960 | GEO

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

2022-07-05 | GSE193959 | GEO

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.

| S-EPMC9615940 | biostudies-literature

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

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

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

Project description:Archetype tasks link intratumoral heterogeneity to plasticity in recalcitrant small cell lung cancer [cell lines]

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Archetype tasks link intratumoral heterogeneity to plasticity in recalcitrant small cell lung cancer [Human tumor]

Project description:Archetype tasks link intratumoral heterogeneity to plasticity in recalcitrant small cell lung cancer [Human tumor]

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YAP governs intratumoral heterogeneity and chemosensitivity of small cell lung cancer

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

2021-06-01 | GSE161742 | GEO

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.

2020-02-12 | GSE138474 | GEO

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.

2021-07-02 | PRJEB45988 | EVA

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.

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