Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 downregulation in lung and prostate cancers [ATAC-seq]

ABSTRACT: In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here we explored the role of exportin 1 in NE transformation. We observed upregulated exportin 1 in lung and prostate pre-transformation adenocarcinomas. Exportin 1 was induced upregulated following genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation and extended response to targeted therapies in both lung anddifferent TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the AR inhibitor enzalutamide, and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE transformationNE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs tumors after NE transformation to standard cytotoxics. Together these data nominate exportin 1 inhibition as a novel potential therapeutic approach target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237071 | GEO | 2023/07/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 downregulation in lung and prostate cancers [RNA-seq]

Project description:In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here we explored the role of exportin 1 in NE transformation. We observed upregulated exportin 1 in lung and prostate pre-transformation adenocarcinomas. Exportin 1 was induced upregulated following genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation and extended response to targeted therapies in both lung anddifferent TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the AR inhibitor enzalutamide, and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE transformationNE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs tumors after NE transformation to standard cytotoxics. Together these data nominate exportin 1 inhibition as a novel potential therapeutic approach target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma.

2023-07-12 | GSE237072 | GEO

microarray in SCLC transformation

Project description:The histological transformation of lung adenocarcinoma (LUAD) to an aggressive neuroendocrine (NE) derivative resembling SCLC is a signature example of lineage plasticity in cancer.But the changes of gene expression need to be studied. We used microarrays to detail the global programme of gene expression under transformation and reversed transformation cells and identified distinct classes of up-regulated genes during this process.

2024-06-12 | GSE242843 | GEO

The contribution of FGFR1 to the development of SCLC is dictated by the cell-of-origin

Project description:Enhanced RAF/MEK/ERK signaling plays an obligatory role in many different types of cancer. Although genetic lesions promoting its aberrant activation are found in lung adenocarcinoma (LADC), the biological role of this pathway is not well documented in small cell lung cancer (SCLC). Here we explored the role of this pathway in SCLC and the broader class of tumors with neuroendocrine (NE) differentiation by introducing a constitutively active form of Fibroblast growth factor receptor 1 (Fgfr1) together with biallelic inactivation of Rb1 and Trp53 in mouse lung. Our data show that FGFR1 expression primarily results in LADC but also in NE tumors depending on the cell-of-origin. FGFR1 activation selectively promoted NE bronchial lesions in a novel lung cell subpopulation, whereas it impaired progression of typical central SCLC initiated from CGRP-expressing NE cells, which is believed to be the most prominent cell-of-origin of SCLC. Strikingly, FGFR1 activation was well tolerated by K14-expressing cells that were efficiently transformed into SCLC and other NE lesions. Taken together, our results indicate that FGFR1 can serve either as driver or suppressor of distinct lung cancer subtypes depending on the cell-of-origin, which should be taken into account when considering FGFR1 as a therapeutic target.

2020-03-27 | GSE132759 | GEO

CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation III

Project description:Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Upregulation of the cell cycle kinase CDC7 occurred in tumors undergoing NE transformation, after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of MYC, implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a strategy to constrain lineage plasticity and to effectively treat NE tumors. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk.

2024-05-01 | GSE252568 | GEO

CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation II

2024-05-01 | GSE252567 | GEO

CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation I

2024-05-01 | GSE252566 | GEO

CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

2024-05-12 | GSE265887 | GEO

RNAseq of combined LUAD and SCLC tumors to look at gene expression changes

Project description:For in-depth characterization of neuroendocrine transformation, we analyzed clinical specimens consisting of combined lung adenocarcinoma (LUAD)/small cell lung carcinoma (SCLC) histology exhibiting clear spatial separation. Microdissection was performed for RNA sequencing.

2021-06-03 | E-MTAB-10399 | biostudies-arrayexpress

Unraveling the Global Proteome and Phosphoproteome of Prostate Cancer Patient-Derived Xenografts

Project description:Resistance to androgen deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform to emergent aggressive variant prostate cancer (AVPC) which has neuroendocrine (NE)-like features. To this end, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflects and retains key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. When we compared 15 NE versus 33 AdCa PDX samples, we identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of protein and RNA concordance from these tumors revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa. Keywords: Proteomics, phosphoproteomics, Neuroendocrine, Adenocarcinoma, biomarkers, surfaceome, secretome, blood proteins, prostate cancer, patient-derived xenograft

2023-06-09 | MSV000092139 | MassIVE

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

Project description:Small cell lung cancer is the most aggressive type of lung cancer and has a high degree of plasticity, characterized by a remarkable response to chemotherapy followed by development of resistance. We show that intratumoral heterogeneity of SCLC is progressively established, indicated by the appearance of YAP+ and HES1+ SCLC tumor cells. Notch signaling is required for the generation of Non-NE SCLC cells, but not for the tumorigenesis of SCLC. Furthermore, YAP signals through Notch-dependent and independent pathway to induce REST expression to promote the conversion of NE to Non-NE SCLC tumor cells. In addition, YAP activation enhances the chemoresistance in NE SCLC tumor cells by downregulating GSDME, while inactivation of YAP in Non-NE SCLC tumor cells switches cell death from apoptosis to pyroptosis. Our study will not only provide novel insights into the molecular basis of SCLC tumorigenesis, but also the potential drug targets for SCLC therapy

2021-06-01 | GSE161740 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data