Ontology highlight
ABSTRACT:
PROVIDER: PRJNA438013 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC following treatment with targeted therapies. Here we designed models to follow the conversion of LUAD to SCLC and found the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells, transcriptionally resembling the pulmonary basal lineage. These findings suggest histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs.
2024-01-01 | GSE248206 | GEO
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.
2024-05-12 | GSE265887 | GEO
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
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 | GSE252567 | GEO
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 | GSE252566 | GEO
Project description:Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC following treatment with targeted therapies. Here we designed models to follow the conversion of LUAD to SCLC and found the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells, transcriptionally resembling the pulmonary basal lineage. These findings suggest histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs.
2024-01-01 | GSE248202 | GEO
Project description:To investigate molecular changes occurring during lung adenocarcinoma to squamous carcinoma transformation.
2023-02-28 | GSE226069 | GEO
Project description:To investigate molecular changes occurring during lung adenocarcinoma to squamous carcinoma transformation.
2023-02-28 | GSE226068 | GEO
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 | GSE237071 | GEO
Project description:Lung cancer is the leading cause of cancer mortality and is classified by the World Health Organization into two broad histological subtypes. Non–small cell lung cancer (NSCLC), including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, accounts for ~85% of all lung cancer cases, with the remaining 15% of cases being due to small cell lung cancer (SCLC), which arises from neuroendocrine cells in the lung. Although most SCLC tumors are initially responsive to chemotherapy and radiation, patients often experience relapse, with the tumor acquiring an aggressiveness and therapeutic resistance that lead to a poor clinical outcome. Improvement of overall survival in individuals with SCLC will require the identification of novel therapeutic targets based on a better understanding of the changes in intracellular signaling of aggressive SCLC cells. The malignant progression of SCLC often occurs concomitantly with the acquisition of chemoresistance, suggesting that phenotypic malignant change is related to adaptation to the stresses induced by chemotherapy. In order to analyze gene expression changes associated with malignant transformation in SCLC, we established a cisplatin-resistant SCLC cell line and performed RNA sequencing.
2021-03-04 | GSE168184 | GEO