CD74-NRG1 fusions in lung adenocarcinoma
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ABSTRACT:
PROVIDER: EGAS00001000653 | EGA |
REPOSITORIES: EGA
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Project description:The World Health Organization has subclassified adenocarcinoma based upon predominant cell morphology and growth pattern such as bronchioloalveolar carcinoma (BAC), adenocarcinoma with mixed subtypes (AC-mixed), and homogenously invasive tumors with a variety of histological patterns Pure invasive adenocarcinomas are often devoid of bronchioloalveolar morphology. The clinical importance of lung adenocarcinoma invasion is supported by several recent studies indicating that the risk of death in non-mucinous BAC is significantly lower than that of pure invasive tumors and in tumors with greater than 0.6 cm of fibrosis or linear invasion (J Thorac Oncol 6:244-285) To identify human tumor cell signatures associated with lung adenocarcinoma subtype and invasion, we performed microarray gene expression profiling of microdissected tumor cells noninvasive AC and AC-Mixed invasive tumors. 17 cases of noninvasive AC tumors and 23 cases of AC-mixed subtype invasive lung adenocarcinomas resected from 2002 to 2006 were examined (Columbia Lung Adenocarcinoma dataset)
2011-09-14 | E-GEOD-27716 | biostudies-arrayexpress
Project description:Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial anti-tumor activity followed by recurrence due to cancer cell intrinsic and immune mediated paracrine mechanisms. Here, we explored the potential role of cancer associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2/ERBB3 receptor tyrosine kinases as a mechanism by which KRAS* independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in upregulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a survival factor. Genetic depletion or pharmacological inhibition of ERBB2/ERBB3 or NRG1 abolished KRAS* bypass and synergized with KRASG12D inhibitor in combination treatments in mouse and human PDAC models. Thus, we found that CAFs can contribute to KRAS* inhibitor therapy resistance via paracrine mechanisms, providing an actionable therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients.
2023-09-22 | GSE240232 | GEO
Project description:The World Health Organization has subclassified adenocarcinoma based upon predominant cell morphology and growth pattern such as bronchioloalveolar carcinoma (BAC), adenocarcinoma with mixed subtypes (AC-mixed), and homogenously invasive tumors with a variety of histological patterns Pure invasive adenocarcinomas are often devoid of bronchioloalveolar morphology. The clinical importance of lung adenocarcinoma invasion is supported by several recent studies indicating that the risk of death in non-mucinous BAC is significantly lower than that of pure invasive tumors and in tumors with greater than 0.6 cm of fibrosis or linear invasion (J Thorac Oncol 6:244-285) To identify human tumor cell signatures associated with lung adenocarcinoma subtype and invasion, we performed microarray gene expression profiling of microdissected tumor cells noninvasive AC and AC-Mixed invasive tumors.
2011-09-15 | GSE27716 | GEO
Project description:Neuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here, we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared with nevi or metastatic lesions. Neuregulin 1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma. Gene expression changes are compared between Melan-Ink4a cells stimulated with NRG1-b1 (NRG1) for 21 days and NRG1 untreated Melan-INK4a cells in triplicate using Affymetrix Mouse GeneChip 1.0 ST chip .
2010-05-07 | E-GEOD-21463 | biostudies-arrayexpress
Project description:The four members of the epidermal growth factor receptor (EGFR/ERBB) family form homo- and heterodimers which mediate ligand-specific regulation of many key cellular processes in normal and cancer tissues. While signaling through the EGFR has been extensively studied on the molecular level, signal transduction through ERBB3/ERBB4 heterodimers is less well understood. Here, we generated isogenic mouse Ba/F3 cells that express full-length and functional membrane-integrated ERBB3 and ERBB4 or ERBB4 alone, to serve as a defined cellular model for biological and phosphoproteomics analysis of ERBB3/ERBB4 signaling. ERBB3 co-expression significantly enhanced Ba/F3 cell proliferation upon neuregulin-1 (NRG1) treatment. For comprehensive signaling studies we performed quantitative mass spectrometry (MS) experiments to compare the basal ERBB3/ERBB4 cell phosphoproteome to NRG1 treatment of ERBB3/ERBB4 and ERBB4 cells. We employed a workflow comprising differential isotope labeling with mTRAQ reagents followed by chromatographic peptide separation and final phosphopeptide enrichment prior to MS analysis. Overall, we identified 9686 phosphorylation sites which could be confidently localized to specific residues. Statistical analysis of three replicate experiments revealed 492 phosphorylation sites which were significantly changed in NRG1-treated ERBB3/ERBB4 cells. Bioinformatics data analysis recapitulated regulation of mitogen-activated protein kinase and Akt pathways, but also indicated signaling links to cytoskeletal functions and nuclear biology. Comparative assessment of NRG1-stimulated ERBB4 Ba/F3 cells indicated that ERBB3 did not trigger defined signaling pathways but more broadly enhanced phosphoproteome regulation in cells expressing both receptors. In conclusion, our data provide the first global picture of ERBB3/ERBB4 signaling and provide numerous potential starting points for further mechanistic studies
2016-01-15 | PXD002665 | Pride
Project description:Acinar cells are the principal secretory unit of multiple exocrine organs. A single cell layered, lumenized acinus forms from a large cohort of epithelial progenitors that must initiate and coordinate three cellular programs of acinar specification, namely, lineage progression, secretion, and polarization. Despite this well-known outcome, the mechanism(s) regulating these complex programs are unknown. Here, we demonstrate that neuronal-epithelial cross-talk drives acinar specification through neuregulin (NRG1)-ERBB3-mTORC2 signaling. Using single-cell and global RNA-sequencing of developing salivary glands, we identified NRG1-ERBB3 to precisely overlap with acinar specification during gland development. Genetic deletion of Erbb3 prevented cell lineage progression and the establishment of lumenized, secretory acini. Conversely, NRG1 treatment of isolated epithelia was sufficient to recapitulate the development of secretory acini. Mechanistically, we found NRG1-ERBB3 regulates each developmental program through an mTORC2 signaling pathway. Thus, we reveal a novel neuronal-epithelial (NRG1/ERBB3/mTORC2) mechanism to orchestrate the creation of functional acini.
2022-10-11 | GSE214976 | GEO
Project description:Neuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here, we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared with nevi or metastatic lesions. Neuregulin 1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma.
2010-04-26 | GSE21463 | GEO
Project description:Clinical FFPE tissue proteomic analyses were performed for early lung adenocarcinomas including adenocarcinoma in-situ (AIS), minimally invasive adenocarcinoma (MIA) and lepidic predominant invasive adenocarcinoma (LPA).
2020-01-30 | PXD017334 | JPOST Repository
Project description:During cancer evolution, cellular differentiation programs become dysregulated. The transcription factor Nkx2-1 is a master regulator of pulmonary differentiation that is downregulated in poorly differentiated lung adenocarcinoma. Here we use conditional murine genetics to study the fate of lung epithelial cells upon loss of their master cell fate regulator. Nkx2-1 deletion in normal and neoplastic lung causes not only loss of pulmonary identity but also gastric transdifferentiation. Nkx2-1 maintains pulmonary identity by sequestering the Foxa1 transcription factor at lung-specific loci and inhibiting Foxa1 binding to gastrointestinal targets. Murine Nkx2-1-negative lung tumors mimic the mucinous subtype of human lung adenocarcinoma, which also exhibits gastric transdifferentiation. Nkx2-1-negative lung adenocarcinomas are dependent on the gastrointestinal gene Hnf4a for efficient initiation. Thus, loss of Nkx2-1 results in transdifferentiation rather than stable dedifferentiation in vivo, suggesting that inactivation of both active and latent differentiation programs may be required for tumors to reach a primitive, dedifferentiated state. The study was designed to compare the expression profiles of Nkx2-1-positive lung adenocarcinomas with tumors in which Nkx2-1 was deleted at the time of initiation or 6-7 months after initiation.
2013-04-10 | E-GEOD-36473 | biostudies-arrayexpress
Project description:The mucin MUC4 and its membrane partner the ErbB2 oncogenic receptor are potential actors and partners in pancreatic tumourigenesis. However, the way they function is still largely unknown. We thus undertook in this work to identify the cellular mechanisms and the intracellular signalling pathways under the control of both ErbB2 and MUC4. Using co-immunoprecipitation, we show that MUC4 and ErbB2 interact in the human pancreatic adenocarcinomatous cell line CAPAN-2. Stable Knocked-Down (KD) cellular clones for both MUC4 and ErbB2 were raised by a shRNA approach. Biological properties of these cells were then studied in vitro and in vivo. Our results show that ErbB2-KD cells are more apoptotic and less proliferative (decreased cyclin D1 and increased p27kip1 expression) while migration and invasive properties were not altered. MUC4-KD clones were less proliferative with decreased cyclin D1 expression, G1 cell cycle arrest and altered ErbB2/ErbB3 expression. Their migration properties were reduced whereas invasive properties were increased. Importantly, inhibition of ErbB2 and MUC4 expression did not impair the same signalling pathways (inhibition of MUC4 expression affected the JNK pathway whereas that of ErbB2 altered the MAPK pathway). Finally, ErbB2-KD and MUC4-KD cells showed impaired tumour growth in vivo. This indicates that ErbB2 and MUC4, that physically interact, activate different intracellular signalling pathways to regulate biological properties of pancreatic cancer cells. Altogether, these data bring new information regarding molecular mechanisms under the control of both MUC4 and ErbB2 that will have to be taken into account for developing efficient targeting of both proteins in order to slow down/stop pancreatic tumourigenesis. profiling of pancreatic cells depleted for ErbB2 and MUC4
2012-03-20 | E-GEOD-31322 | biostudies-arrayexpress