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SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing [RNA-seq]

ABSTRACT: Small Cell Lung Cancer (SCLC) can be classified into transcriptional subtypes with distinct degrees of neuroendocrine (NE) differentiation. Recent evidence supports plasticity among subtypes with a bias toward adoption of low-NE states during disease progression or upon acquired chemotherapy resistance. Here, we identify a role for SMARCA4, the catalytic subunit of the SWI/SNF complex, as a regulator of subtype shift in SCLC. SMARCA4 binds to gene loci encoding NE-lineage transcription factors ASCL1 and NEUROD1 and alters chromatin accessibility, suppressing NE programs. In parallel, SMARCA4 also controls REST, a known suppressor of the NE phenotype, by regulating SRRM4-dependent REST splicing. The SMARCA2/4 inhibitor FHD-286 induces loss of NE features and drives ERBB pathway activation in SCLC, rendering SCLC tumors sensitive to afatinib. This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE256347 | GEO | 2024/08/28

REPOSITORIES: GEO

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SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing [ATAC-seq]

Project description:Small Cell Lung Cancer (SCLC) can be classified into transcriptional subtypes with distinct degrees of neuroendocrine (NE) differentiation. Recent evidence supports plasticity among subtypes with a bias toward adoption of low-NE states during disease progression or upon acquired chemotherapy resistance. Here, we identify a role for SMARCA4, the catalytic subunit of the SWI/SNF complex, as a regulator of subtype shift in SCLC. SMARCA4 binds to gene loci encoding NE-lineage transcription factors ASCL1 and NEUROD1 and alters chromatin accessibility, suppressing NE programs. In parallel, SMARCA4 also controls REST, a known suppressor of the NE phenotype, by regulating SRRM4-dependent REST splicing. The SMARCA2/4 inhibitor FHD-286 induces loss of NE features and drives ERBB pathway activation in SCLC, rendering SCLC tumors sensitive to afatinib. This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC.

2024-08-28 | GSE256345 | GEO

SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing [ChIP-seq]

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RNA splicing factors SRRM3 and SRRM4 distinguish molecular phenotypes of castration-resistant neuroendocrine prostate cancer [methylation]

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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.

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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.

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

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SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer

Project description:The neuroendocrine (NE) phenotype is associated with the development of metastatic castration-resistant prostate cancer (CRPC). Our objective was to characterize the molecular features of the NE phenotype in CRPC. Expression of chromogranin A (CHGA), synaptophysin (SYP), androgen receptor (AR), and prostate-specific antigen (PSA) was analyzed by immunohistochemistry (IHC) in 155 CRPC metastases from 50 patients and in 24 LuCaP prostate cancer patient-derived xenografts (PDX). Co-expression of CHGA and SYP in >30% of cells was observed in 22 of 155 metastases (9 patients); 11 of the 22 metastases were AR+/PSA+ (6 patients), 11/22 were AR-/PSA- (4 patients), and 4/24 LuCaP PDXs were AR-/PSA-. Seventy-one of 155 metastases and the 24 LuCaP xenograft lines were analyzed by whole genome microarrays. By IHC, of the 71 metastases analyzed by whole genome microarrays, 5 metastases were CHGA+/SYP+/AR- and 5 were CHGA+/SYP+/AR+. Only CHGA+/SYP+ metastases had a NE transcript signature. The neuronal transcriptional regulator SRRM4 transcript was associated with the NE signature in CHGA+/SYP+ metastases and all CHGA+/SYP+ LuCaP xenografts. Additionally, expression of SRRM4 in the LuCaP NE xenografts correlated with a splice variant of REST that lacks the transcriptional repressor domain. In conclusion, (a) metastatic NE status can be heterogeneous in the same patient, (b) the CRPC NE molecular phenotype can be defined by CHGA+/SYP+ dual positivity, (c) the NE phenotype is not necessarily associated with the loss of AR activity, and (d) the splicing of REST by SRRM4 could promote the NE phenotype in CRPC. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile 24 LuCaP PCa xenograft lines and 71 CRPC metastases from 47 patients. RNA was amplified prior to hybridization against a common reference pool of prostate tumor cell lines.

2015-06-24 | E-GEOD-66187 | biostudies-arrayexpress

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