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MRNA-seq data HNSCC cell line PLX51107 treatment for HNSCC subtypes

ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant morbidity and mortality and frequent recurrence. Pre-NGS efforts to transcriptionally classify HNSCC into groups of varying prognosis have identified four accepted molecular subtypes of disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigated the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identified samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes. Cell lines belonging to atypical subtype were more resistant to bromodomain inhibitors (BETi). PRO-Seq experiments that both TCGA tumors and AT cell lines showed higher eRNA transcripts for enhancers controlling BETi resistance pathways, such as lipid metabolism and MAPK signaling. Additionally, HiChIP experiments suggested higher enhancer-promoter (E-P) contacts in the AT subtype, including on genes identified in the eRNA analysis. Consistently, known BETi resistance pathways were upregulated upon exposure to these inhibitors. Together, our results identify that the AT subtype of HNSCC is associated with high enhancer activity, resistance to BET inhibition, and signaling pathways that could serve as future targets for sensitizing HNSCC to BET inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185534 | GEO | 2022/07/20

REPOSITORIES: GEO

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HiChIP data for HNSCC subtypes

Project description:Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant morbidity and mortality and frequent recurrence. Pre-NGS efforts to transcriptionally classify HNSCC into groups of varying prognosis have identified four accepted molecular subtypes of disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigated the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identified samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes. Cell lines belonging to atypical subtype were more resistant to bromodomain inhibitors (BETi). PRO-Seq experiments that both TCGA tumors and AT cell lines showed higher eRNA transcripts for enhancers controlling BETi resistance pathways, such as lipid metabolism and MAPK signaling. Additionally, HiChIP experiments suggested higher enhancer-promoter (E-P) contacts in the AT subtype, including on genes identified in the eRNA analysis. Consistently, known BETi resistance pathways were upregulated upon exposure to these inhibitors. Together, our results identify that the AT subtype of HNSCC is associated with high enhancer activity, resistance to BET inhibition, and signaling pathways that could serve as future targets for sensitizing HNSCC to BET inhibition.

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PRO-seq data for HNSCC subtypes

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The apoptotic network and expression of BH3-containing proteins predict phenotypic response to BET bromodomain inhibitors

Project description:Small molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are in clinical trials for a variety of cancers, but patient selection strategies are limited. This is due in part to the heterogeneity of response following BET inhibition (BETi), which includes differentiation, senescence, and cell death in subsets of cancer cell lines. To elucidate the dominant features defining response to BETi, we carried out phenotypic and gene expression analysis of both treatment naÃ¯ve cell lines and engineered tolerant lines. We found that both de novo and acquired tolerance to BET inhibition are driven by the robustness of the apoptotic response and that genetic or pharmacological manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further identify that ordered expression of the apoptotic genes BCL2, BCL2L1, and BAD significantly predicts response to BETi. Our findings highlight the role of the apoptotic network in response to BETi, providing a molecular basis for patient stratification and combination therapies. Gene expression profiling of A375 melanoma cells or NOMO-1 AML cells treated with DMSO or the BET inhibitor, CPI203. Also, gene expression profiling of the respective derived BETi-tolerant cells treated with DMSO or CPI203.

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Integrative genomic analysis identifies clinically relevant subtypes of head and neck cancer characterized by hypoxia, T-cell infiltration, and EMT

Project description:Current classification of head and neck squamous cell carcinomas (HNSCC) based on anatomic site and clinical stage fails to capture biologic heterogeneity or adequately inform treatment. Here we use consensus clustering on 371 HNSCC in three cohorts, including a new cohort of 134 patients with locoregionally advanced HNSCC and 43% HPV(+) tumors to identify five HNSCC subtypes. Subtypes closely correlate with biologic processes (hypoxia, cytotoxic T-cell infiltration, copy number changes, EGFR/HER-ligand phenotype), survival, and HPV-status. Two biologically distinct HPV-associated subtypes are identified. Gene modules of candidate drivers characterize each subtype using the CONEXIC algorithm. The proposed 5-subtype classification provides a biologic basis for future clinical and preclinical studies and lays the groundwork for improved prognostication and therapy development in HNSCC. We use consensus clustering on 371 HNSCC in three cohorts, including a new cohort of 134 patients with locoregionally advanced HNSCC and 43% HPV(+) tumors to identify five HNSCC subtypes.

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2016-07-21 | E-GEOD-82329 | biostudies-arrayexpress

RNA-seq analysis of HNSCC cells after JQ1 treatment

Project description:We performed RNA sequencing (RNA-seq) of HNSCC cells to examine genome-wide gene expression pattern following JQ1 treatment. BET inhibition by JQ1 significantly inhibits a cohort of key oncogenes associate with tumorigenesis and metastasis. Suggesting BET inhibition is effective strategy to suppress the tumorigenesis and metastasis of head and neck squamous cell carcinoma.

2021-05-05 | GSE131967 | GEO

Single-cell transcriptomic characterization primary HNSCC tumors

Project description:Despite aggressive multi-modal treatment, advanced head and neck squamous cell carcinoma (HNSCC) patients are at high risk of recurrence. Matched pairs (n=38) of primary/recurrent tumors were subjected to whole exome and RNA sequencing. Mutational landscapes and genomic copy number alterations indicated diverging clonal origins in a subset of cases. Transcriptional subtyping (classical/CL, basal/BA, inflamed-mesenchymal/IMS) in primary and recurrent HNSCC (n=112) revealed more frequent CL and IMS in primary tumors with low recurrence rates and a prevalence of BA in recurrent tumors associated with p-EMT and early recurrence. 44% of matched cases underwent a subtype change from primary to recurrent tumors, preferably from IMS to BA or CL. In recurrences, HYPOXIA, P-EMT and RADIATION RESISTANCE signatures were up- and TUMOR INFLAMMATION down-regulated compared to index tumors. A therapy-induced selection of transcriptional subtypes demonstrates the importance of molecular characterization of recurrences for second-line therapy decisions to enable optimally tailored treatments.

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Integrative genomic analysis identifies clinically relevant subtypes of head and neck cancer characterized by hypoxia, T-cell infiltration, and EMT

2015-03-04 | GSE40774 | GEO

Global transcriptome profiling of triple-negative breast cancer cell lines treated with small-molecules targeting Bromodomain and Extra Terminal (BET) proteins

Project description:Triple negative breast cancer (TNBC) represents the most clinically challenging subtypes of breast cancer for which targeted therapeutics are still lacking. Bromodomain and Extra Terminal (BET) proteins, including ubiquitously expressed BRD2, BRD3, BRD4 and testis-specific BRDT, are epigenetic “readers” and play a major role in epigenetic regulation of gene transcription. BET proteins have emerged as new therapeutic targets for human cancer and other diseases. Based upon a new class of BET bromodomain (BRD) inhibitor, BETi-211, we have developed a highly selective and potent BET protein degrader, BETd-246. In comparison, BETd-246 is much more potent and effective than the corresponding BET inhibitor BETi-211 in growth inhibition and apoptosis induction in TNBC cell lines, indicating critical differences between these two different BET targeting approaches in their regulation of gene transcription. To understand the mechanisms of actions of BETi-211 and BETd-246 in TNBC, we performed RNA-seq analysis on MDA-MB-157, MDA-MB-231 and MDA-MB-468. These cell lines were treated for 3 h to capture the early transcriptional responses to BETi-211 or BETd-246. RNA-seq analysis reveals that BETd-246 predominantly down-regulates the expression of a large number of genes whereas BETi-211 up- and down-regulates an approximately equal number of genes in TNBC cells. Critically, transcriptomic analysis uncovers that a set of proliferation and survival-related genes, including MCL1 and BRD2, were oppositely regulated by BETd-246 and BETi-211 in these TNBC cell lines.

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