Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA134383 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Amplification of chromosomal region 8p11-12 is a frequent genetic alteration implicated in the etiology of lung squamous cell carcinoma (LUSC). FGFR1 (fibroblast growth factor receptor 1) is the main candidate driver within this region. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful. Here we identify the H3K36 methyltransferase NSD3 (nuclear receptor binding SET domain protein 3), an 8p11-12-localized gene, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11-12 candidate LUSC drivers, increased NSD3 expression strongly correlates with gene amplification. Ablation of NSD3, but not FGFR1, attenuates tumor growth and extends survival in a potent LUSC mouse model. We identify NSD3T1232A as an LUSC-associated variant that increases H3K36 dimethylation (H3K36me2) catalytic activity in vitro and in vivo. Structural dynamic analyses reveal that the T1232A substitution elicits localized mobility changes throughout NSD3’s catalytic domain to relieve auto-inhibition and increase H3 substrate accessibility. NSD3T1232A expression in vivo in LUSC mouse models accelerates tumorigenesis and decreases overall survival. Pathologic generation of H3K36me2 by NSD3T1232A rewires the chromatin landscape to promote oncogenic gene expression programming. Accordingly, depletion of NSD3 and H3K36me2 in patient derived xenografts (PDXs) from primary LUSC harboring NSD3 amplification or the NSD3T1232A variant attenuate neoplastic growth. Finally, NSD3-regulated LUSC PDXs are markedly and selectively sensitive to bromodomain inhibition (BETi). Together, our work identifies NSD3 as a principal 8p11-12 amplicon-associated oncogenic driver in LUSC and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to BETi.
2020-11-24 | GSE149272 | GEO
Project description:Lung cancer is the leading cause of cancer related deaths, worldwide. Fibroblast growth factor receptor 1 (FGFR1) gene amplification is one of the most prominent and potentially targetable genetic alterations in squamous cell lung cancer (SQCLC). Highly selective tyrosine kinase inhibitors have been developed to target FGFR1, however, resistance mechanisms originally existing in patients or acquired throughout treatment have limited treatment efficiency in clinical trials, so far. In this study, we performed a wide-scale phosphoproteomic mass spectrometry analysis to explore signaling pathways that lead to FGFR1 inhibition resistance in lung cancer cells with intrinsic, induced and mutational resistance. We identified a CD44/AKT signaling axis as a new and common mechanism of resistance to FGFR1 inhibition in lung cancer. Co-inhibition of AKT or CD44 synergistically sensitized intrinsic and induced resistant cells to FGFR1 inhibition. Furthermore, strong CD44 expression was significantly correlated to AKT activation in squamous cell lung cancer patients. Collectively, our phosphoproteomic analysis of FGFR1 inhibitor resistant lung cancer cells promotes a large data library of resistance associated phosphorylation patterns and proposes a common resistance pathway consisting of CD44 and AKT activation. Examination of CD44/AKT activation could help to predict response to FGFR1 inhibition and combination with AKT inhibitors might path the way for an effective therapy of FGFR1 dependent lung cancer patients in case of treatment resistance.
2022-08-12 | PXD025389 | Pride
Project description:Summary: Lung cancer is a leading cause of cancer death, where the amplification of oncogenes contributes to tumorigenesis. Genomic profiling of 128 lung cancer cell lines and tumors revealed frequent focal DNA amplification at cytoband 14q13.3, a locus not amplified in other tumor types. The smallest region of recurrent amplification spanned the homeobox transcription factor TITF1 (also known as NKX2-1), previously linked to normal lung development and function. When amplified, TITF1 exhibited increased expression at both the RNA and protein level. siRNA-mediated knockdown of TITF1 in lung cancer cell lines with amplification led to reduced cell proliferation, manifested by both decreased cell-cycle progression and increased apoptosis. Our findings indicate that TITF1 amplification and overexpression contribute to lung cancer cell proliferation rates and survival, and implicate TITF1 as a lineage-specific oncogene in lung cancer. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Cell Line Keywords: Logical Set cDNA microarrays from the Stanford Functional Genomics Facility were used to perform array based Comparative Genomic Hybridization (aCGH) analysis on 52 non-small cell lung cancer (NSCLC) cell lines and 76 NSCLC tumors (36 adenocarcinomas including 2 metastases, and 40 squamous cell carcinomas including 1 metastasis). In addition, this dataset includes 6 immortalized and 3 non-immortalized lung epithelial cell lines and 1 male vs. female genomic DNA for hybridization control. Map positions for arrayed cDNA clones were assigned using the NCBI genome assembly, accessed through the UCSC genome browser database (NCBI Build 36). The most frequent focal DNA amplification not associated with a previously known oncogene occurred at cytoband 14q13.3 where TITF1 resides. The sample labeled normal is a "Normal male vs.female DNA" comparison; the samples: SAEC, HBEC3-UI, HBEC5-UI, HBEC2-KT, HBEC3-KT, HBEC4-KT, HBEC5-KT, HBEC2-E, BEAS-2B are Normal lung epithelial cell lines; samples starting with L are all Lung tumor samples and all the rest are Lung cancer cell lines. Computed
2008-02-29 | E-GEOD-10025 | biostudies-arrayexpress
Project description:Lung cancer is a leading cause of cancer death, where the amplification of oncogenes contributes to tumorigenesis. Genomic profiling of 128 lung cancer cell lines and tumors revealed frequent focal DNA amplification at cytoband 14q13.3, a locus not amplified in other tumor types. The smallest region of recurrent amplification spanned the homeobox transcription factor TITF1 (also known as NKX2-1), previously linked to normal lung development and function. When amplified, TITF1 exhibited increased expression at both the RNA and protein level. siRNA-mediated knockdown of TITF1 in lung cancer cell lines with amplification led to reduced cell proliferation, manifested by both decreased cell-cycle progression and increased apoptosis. Our findings indicate that TITF1 amplification and overexpression contribute to lung cancer cell proliferation rates and survival, and implicate TITF1 as a lineage-specific oncogene in lung cancer. This SuperSeries is composed of the SubSeries listed below.
2008-03-01 | GSE9995 | GEO
Project description:Lung cancer is a leading cause of cancer death, where the amplification of oncogenes contributes to tumorigenesis. Genomic profiling of 128 lung cancer cell lines and tumors revealed frequent focal DNA amplification at cytoband 14q13.3, a locus not amplified in other tumor types. The smallest region of recurrent amplification spanned the homeobox transcription factor TITF1 (also known as NKX2-1), previously linked to normal lung development and function. When amplified, TITF1 exhibited increased expression at both the RNA and protein level. siRNA-mediated knockdown of TITF1 in lung cancer cell lines with amplification led to reduced cell proliferation, manifested by both decreased cell-cycle progression and increased apoptosis. Our findings indicate that TITF1 amplification and overexpression contribute to lung cancer cell proliferation rates and survival, and implicate TITF1 as a lineage-specific oncogene in lung cancer. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Cell Line Keywords: Logical Set
2008-03-01 | GSE9994 | GEO
Project description:Summary: Lung cancer is a leading cause of cancer death, where the amplification of oncogenes contributes to tumorigenesis. Genomic profiling of 128 lung cancer cell lines and tumors revealed frequent focal DNA amplification at cytoband 14q13.3, a locus not amplified in other tumor types. The smallest region of recurrent amplification spanned the homeobox transcription factor TITF1 (also known as NKX2-1), previously linked to normal lung development and function. When amplified, TITF1 exhibited increased expression at both the RNA and protein level. siRNA-mediated knockdown of TITF1 in lung cancer cell lines with amplification led to reduced cell proliferation, manifested by both decreased cell-cycle progression and increased apoptosis. Our findings indicate that TITF1 amplification and overexpression contribute to lung cancer cell proliferation rates and survival, and implicate TITF1 as a lineage-specific oncogene in lung cancer. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Cell Line Keywords: Logical Set
2008-03-01 | GSE10025 | GEO
Project description:Lung cancer is a leading cause of cancer death, where the amplification of oncogenes contributes to tumorigenesis. Genomic profiling of 128 lung cancer cell lines and tumors revealed frequent focal DNA amplification at cytoband 14q13.3, a locus not amplified in other tumor types. The smallest region of recurrent amplification spanned the homeobox transcription factor TITF1 (also known as NKX2-1), previously linked to normal lung development and function. When amplified, TITF1 exhibited increased expression at both the RNA and protein level. siRNA-mediated knockdown of TITF1 in lung cancer cell lines with amplification led to reduced cell proliferation, manifested by both decreased cell-cycle progression and increased apoptosis. Our findings indicate that TITF1 amplification and overexpression contribute to lung cancer cell proliferation rates and survival, and implicate TITF1 as a lineage-specific oncogene in lung cancer. This SuperSeries is composed of the following subset Series: GSE9994: Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer: Expression Arrays GSE10025: Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer: aCGH Arrays Keywords: SuperSeries Refer to individual Series
2008-02-29 | E-GEOD-9995 | biostudies-arrayexpress
Project description:Amplification-mediated oncogene overexpression is a critical and widespread driver event in cancer, yet our understanding of how amplification and dosage mediate oncogene regulation is limited. Here, we find that the most significant focal amplification event in lung adenocarcinoma (LUAD) targets a lineage “super-enhancer” near the NKX2-1 lineage transcription factor. The NKX2-1 super-enhancer is targeted by focal and co-amplification with NKX2-1 and controls NKX2-1 expression and regulation. We find that NKX2-1 directly controls enhancer accessibility to drive a lineage-addicted state in LUAD. We precisely map the effects of NKX2-1 dosage modulation upon both overexpression and knockdown and identify both linear and non-linear regulation by NKX2-1 dosage. We find that NKX2-1 is a widespread dependency in LUAD cell lines and that NKX2-1 confers persistence to EGFR inhibitors. Our data suggest a defining role for dosage in the oncogenic regulation of amplified NKX2-1 and that amplified NKX2-1 lineage addiction defines LUAD tumors.
2025-03-25 | GSE229541 | GEO
Project description:Amplification-mediated oncogene overexpression is a critical and widespread driver event in cancer, yet our understanding of how amplification and dosage mediate oncogene regulation is limited. Here, we find that the most significant focal amplification event in lung adenocarcinoma (LUAD) targets a lineage “super-enhancer” near the NKX2-1 lineage transcription factor. The NKX2-1 super-enhancer is targeted by focal and co-amplification with NKX2-1 and controls NKX2-1 expression and regulation. We find that NKX2-1 directly controls enhancer accessibility to drive a lineage-addicted state in LUAD. We precisely map the effects of NKX2-1 dosage modulation upon both overexpression and knockdown and identify both linear and non-linear regulation by NKX2-1 dosage. We find that NKX2-1 is a widespread dependency in LUAD cell lines and that NKX2-1 confers persistence to EGFR inhibitors. Our data suggest a defining role for dosage in the oncogenic regulation of amplified NKX2-1 and that amplified NKX2-1 lineage addiction defines LUAD tumors.
2025-03-25 | GSE229540 | GEO
Project description:Amplification-mediated oncogene overexpression is a critical and widespread driver event in cancer, yet our understanding of how amplification and dosage mediate oncogene regulation is limited. Here, we find that the most significant focal amplification event in lung adenocarcinoma (LUAD) targets a lineage “super-enhancer” near the NKX2-1 lineage transcription factor. The NKX2-1 super-enhancer is targeted by focal and co-amplification with NKX2-1 and controls NKX2-1 expression and regulation. We find that NKX2-1 directly controls enhancer accessibility to drive a lineage-addicted state in LUAD. We precisely map the effects of NKX2-1 dosage modulation upon both overexpression and knockdown and identify both linear and non-linear regulation by NKX2-1 dosage. We find that NKX2-1 is a widespread dependency in LUAD cell lines and that NKX2-1 confers persistence to EGFR inhibitors. Our data suggest a defining role for dosage in the oncogenic regulation of amplified NKX2-1 and that amplified NKX2-1 lineage addiction defines LUAD tumors.
2025-03-25 | GSE292519 | GEO