Resistance to targeted therapies in the brain tumor microenvironment is not drive by genetic mutations
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA731911 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14615163_1.fastq.gz | Fastqsanger.gz | |||
| SRR14615163_2.fastq.gz | Fastqsanger.gz | |||
| SRR14615164_1.fastq.gz | Fastqsanger.gz | |||
| SRR14615164_2.fastq.gz | Fastqsanger.gz | |||
| SRR14615165_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:The brain is a major sanctuary site for metastatic lung cancer cells that evade systemic therapies. We performed pharmacological, biological, and molecular studies to identify the functional link between drug resistance and central nervous system (CNS) relapse in late-stage EGFR mutant non-small cell lung cancer, which frequently progresses in the brain even when treated with the brain penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution in vivo, the brain microvascular tumor microenvironment (TME) is associated with the persistence of malignant cell sub-populations which are poised to further proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are commonly regulated through RhoA signaling, which potentiates the outgrowth of disseminated tumor cells on osimertinib treatment, preferentially in response to extracellular laminin and in the brain. Thus, we identify pre-existing and adaptive features of metastatic and drug resistant cancer cells, which are enhanced by RhoA and the brain TME during the evolution of osimertinib resistant disease.
2022-09-02 | GSE174852 | GEO
Project description:The brain tumor microenvironment primes metastatic cells for resistance to targeted therapies
| PRJNA731909 | ENA
Project description:The brain is a major sanctuary site for metastatic lung cancer cells that evade systemic therapies. We performed pharmacological, biological, and molecular studies to identify the functional link between drug resistance and central nervous system (CNS) relapse in late-stage EGFR mutant non-small cell lung cancer, which frequently progresses in the brain even when treated with the brain penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution in vivo, the brain microvascular tumor microenvironment (TME) is associated with the persistence of malignant cell sub-populations which are poised to further proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are commonly regulated through RhoA signaling, which potentiates the outgrowth of disseminated tumor cells on osimertinib treatment, preferentially in response to extracellular laminin and in the brain. Thus, we identify pre-existing and adaptive features of metastatic and drug resistant cancer cells, which are enhanced by RhoA and the brain TME during the evolution of osimertinib resistant disease.
2022-09-02 | GSE174850 | GEO
Project description:Driver somatic mutations in adult acute myeloid leukemia (AML) are often preceded by a benign or premalignant state termed clonal hematopoiesis (CH) for which the greatest risk factor is aging. To risk-stratify aged individuals and develop therapies to prevent AML, we need to understand the variables that promote transformation from CH to AML. Using our orthogonally inducible Dnmt3aR878H;Npm1cA-mutant model of progression from CH to myeloid malignancy, we find that in young mice, Dnmt3a mutation buffers against myeloid differentiation, proliferation, acquisition of cooperating mutations and transformation induced by stress, inflammation, and the oncogenic Npm1 mutation. However, when Dnmt3a;Npm1-mutant hematopoietic stem cells (HSCs) are transplanted into naturally aged recipient mice, they gain myeloid-biased differentiation capacity and have an accelerated transformation to AML. These results support the hypothesis that alterations in the aged microenvironment drive risk of AML in individuals with CH and help to explain why this Dnmt3a mutation is exceedingly rare in pediatric leukemias.
2021-07-15 | GSE180116 | GEO
Project description:Estrogen receptor positive (ER+) breast cancers that develop resistance to therapies that target the ER are the most common cause of breast cancer death. Beyond mutations in ER, which occur in 25-30% of patients treated with aromatase inhibitors (AIs), our understanding of clinical mechanisms of resistance to ER-directed therapies remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER+ metastatic breast cancer who had developed resistance to ER-directed agents, including AIs, tamoxifen, and fulvestrant. Examination of treatment-naïve primary tumors in five patients revealed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. These mutations were mutually exclusive with ER mutations, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that these mutations conferred estrogen independence. In addition, and in contrast to ER mutations, these mutations resulted in resistance to tamoxifen, fulvestrant, and the CDK4/6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib, highlighting an effective treatment strategy in these patients.
2018-10-19 | GSE121411 | GEO
Project description:The brain is a major sanctuary site for metastatic lung cancer cells that evade systemic therapies. We performed pharmacological, biological, and molecular studies to identify the functional link between drug resistance and central nervous system (CNS) relapse in late-stage EGFR mutant non-small cell lung cancer, which frequently progresses in the brain even when treated with the brain penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution in vivo, the brain microvascular tumor microenvironment (TME) is associated with the persistence of malignant cell sub-populations which are poised to further proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are commonly regulated through RhoA signaling, which potentiates the outgrowth of disseminated tumor cells on osimertinib treatment, preferentially in response to extracellular laminin and in the brain. Thus, we identify pre-existing and adaptive features of metastatic and drug resistant cancer cells, which are enhanced by RhoA and the brain TME during the evolution of osimertinib resistant disease.
2022-09-02 | GSE174851 | GEO
Project description:Oncogenic RAS/MAPK signaling drives metastatic squamous cell carcinomas (SCCs). These cancers are typified by high mutational burden, often featuring activating mutations in phosphatidylinositol-3-kinase (PI3K). Here we show that early in skin HRASG12V-induced oncogenesis, transitions from benign to malignant states are also marked by PI3K, this time super-activated through a temporal cascade of non-genetic events. Coupling clonal skin SCC genetic models with bulk and single-cell transcriptomics, chromatin-landscaping, lentiviral reporters, and lineage-tracing, we trace its roots. We show that following HRASG12V activation, oncogenic stem cells rewire their gene expression program. Initially, they produce an array of angiogenic factors, triggering a striking influx of vasculature and TGFβ into the microenvironment. Sparked by TGFβ-signaling, the stem cells induce leptin receptor (LEPR), which through the angiogenic influx activates LEPR-signaling to launch downstream PI3K-AKT-mTOR signaling. Our findings show how dynamic temporal crosstalk with the microenvironment, orchestrated by the stem cells, can drive the path to malignancy.
2022-10-09 | GSE190414 | GEO
Project description:Oncogenic RAS/MAPK signaling drives metastatic squamous cell carcinomas (SCCs). These cancers are typified by high mutational burden, often featuring activating mutations in phosphatidylinositol-3-kinase (PI3K). Here we show that early in skin HRASG12V-induced oncogenesis, transitions from benign to malignant states are also marked by PI3K, this time super-activated through a temporal cascade of non-genetic events. Coupling clonal skin SCC genetic models with bulk and single-cell transcriptomics, chromatin-landscaping, lentiviral reporters, and lineage-tracing, we trace its roots. We show that following HRASG12V activation, oncogenic stem cells rewire their gene expression program. Initially, they produce an array of angiogenic factors, triggering a striking influx of vasculature and TGFβ into the microenvironment. Sparked by TGFβ-signaling, the stem cells induce leptin receptor (LEPR), which through the angiogenic influx activates LEPR-signaling to launch downstream PI3K-AKT-mTOR signaling. Our findings show how dynamic temporal crosstalk with the microenvironment, orchestrated by the stem cells, can drive the path to malignancy.
2022-10-09 | GSE190411 | GEO
Project description:Oncogenic RAS/MAPK signaling drives metastatic squamous cell carcinomas (SCCs). These cancers are typified by high mutational burden, often featuring activating mutations in phosphatidylinositol-3-kinase (PI3K). Here we show that early in skin HRASG12V-induced oncogenesis, transitions from benign to malignant states are also marked by PI3K, this time super-activated through a temporal cascade of non-genetic events. Coupling clonal skin SCC genetic models with bulk and single-cell transcriptomics, chromatin-landscaping, lentiviral reporters, and lineage-tracing, we trace its roots. We show that following HRASG12V activation, oncogenic stem cells rewire their gene expression program. Initially, they produce an array of angiogenic factors, triggering a striking influx of vasculature and TGFβ into the microenvironment. Sparked by TGFβ-signaling, the stem cells induce leptin receptor (LEPR), which through the angiogenic influx activates LEPR-signaling to launch downstream PI3K-AKT-mTOR signaling. Our findings show how dynamic temporal crosstalk with the microenvironment, orchestrated by the stem cells, can drive the path to malignancy.
2022-10-09 | GSE207975 | GEO
Project description:Resistance to targeted therapies in the brain tumor microenvironment occurs through selection of cells with distinct transcriptomic profiles
| PRJNA731910 | ENA