Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1032415 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26533308_1.fastq.gz | Fastqsanger.gz | |||
| SRR26533308_2.fastq.gz | Fastqsanger.gz | |||
| SRR26533309_1.fastq.gz | Fastqsanger.gz | |||
| SRR26533309_2.fastq.gz | Fastqsanger.gz | |||
| SRR26533310_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Melanoma brain metastases (MBM) continues to be a significant clinical problem with limited treatment options. Highly invasive melanoma cells migrate along the vasculature and perivascular cells may contribute to residual disease and recurrence. PTEN loss and hyperactivation of AKT occur in MBM; however, a role for PTEN/AKT in perivascular invasion has not been described. Methods: We used in vivo intracranial injections of murine melanoma and bulk RNA sequencing of melanoma cells co-cultured with brain endothelial cells (brECs) to investigate brain colonization and perivascular invasion. Results: We found that PTEN-null melanoma cells were highly efficient at colonizing the perivascular niche relative to PTEN-expressing counterparts. PTEN re-expression (PTEN-RE) in melanoma significantly reduced brain colonization and migration along the vasculature. We hypothesized this phenotype was mediated through vascular-induced TGFβ secretion, which drives AKT phosphorylation. Disabling TGFβ signaling in melanoma cells reduced colonization and perivascular invasion; however, introduction of constitutively-active myristolated-AKT (myrAKT) restored overall tumor size but not perivascular invasion. Conclusions: PTEN loss facilitates perivascular brain colonization and invasion of melanoma. TGFβ-AKT signaling partially contributes to this phenotype, but further studies are needed to determine the complementary mechanisms that enable melanoma cells to both survive and spread along the brain vasculature.
2023-12-26 | GSE247232 | GEO
Project description:To investigate Pten function in neonatal developing brain, we conditionally inactivated Pten in neural stem/progenitor cells at birth using a Nestin-CreER transgenic driver. Pten inactivation created a novel perivascular proliferative niche in the cerebellum that did not progress to malignancy during the lifespan of the mouse. Co-deletion of Pten and Trp53 synergized to cause fully penetrant medulloblastoma originating from a perivascular niche. The Pten and Trp53 double knock-out medulloblastomas showed an extensive and abnormal blood vessel network and advanced neuronal differentiation of tumor cells compared to medulloblastomas arising in Nestin-creER;Trp53fl/fl mice, suggesting that Pten loss promoted angiogenesis and neuronal differentiation in medulloblastoma. EdU pulse-chase experiments demonstrated a lineage hierarchy of the double knock-out medulloblastomas consistent with a perivascular cancer stem cell population. The Pten and Trp53 double knock-out medulloblastomas showed somatic loss of chromosomes 7, 13 and 16, and inactivating mutations in the tumor suppressor gene Ptch1. Gene expression profiles showed that this model recapitulated the subgroup of human medulloblastomas with de-regulated SHH signaling.
2017-03-01 | GSE40106 | GEO
Project description:Development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic, but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating Ptgs2, Tnf, and Ccl/Cxcl 86 cytokines, known to promote brain vascular remodeling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting of exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.
2021-09-08 | PXD015210 | Pride
Project description:Dietary tyrosine regulating melanoma progression has been well-recognized. However, whether tyrosine-based melanin anabolism contributes to pulmonary and cerebral organotropic colonization of melanoma remains elusive. Furthermore, how to inhibit multi-organ metastasis by interfering tyrosinase activity of melanoma cells and function of immunocytes needs to be designed and validated. Patients derived melanoma cells and mouse B16 melanoma cells with different pigment were employed in this investigation. Tyrosine content dynamics in tumors and multiple organs during the melanoma progression were monitored, and tyrosine-based melanin synthesis ability of melanoma cells derived from multi-organ were detected. Additionally, we also adopted the RNA-seq, flowcytometry, real-time PCR and composite metastasis mouse model to analyze organotropic colonization and to design therapeutic strategies. B16 melanoma cells with high activity of tyrosinase and sensitivity of tyrosine utilization for melanin synthesis (Tyr-H cells) easily colonized in the lung, while B16 melanoma cells without above characteristics (Tyr-L cells) exhibited potent proliferation in the brain. Mechanistically, Tyr-H cells recruited and trained neutrophils and macrophages to build up the pulmonary metastatic niche dependent on highly secreted CXCL1 and CXCL2 and an excess melanosome accumulation-induced cell death. Tyr-L cells enhanced PD-L1 expression in tumor-infiltrated macrophages when they are progressing in the brain. Accordingly, intervention of tyrosinase activity (2-Ethoxybenzamide or hydroquinone), together with inhibitors to phagocytosis (GSK343) or chemotaxis (SB225002) suppress organotropic colonization and significantly improve the survival of immune checkpoint blockade (PD1 antibody) treated melanoma bearing mice. The heterogeneity of melanoma cells in utilization of tyrosine is associated with organotropic colonization, providing the basis for developing strategies to combat melanoma and prevent their metastasis.
2022-03-15 | GSE191289 | GEO
Project description:Development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic, but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating Ptgs2, Tnf, and Ccl/Cxcl cytokines, known to promote brain vascular remodeling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting of exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.
2019-08-30 | GSE136628 | GEO
Project description:Brain metastasis is a dismal complication of cancer that hinges on the initial survival and outgrowth of disseminated cancer cells. To better understand these crucial early stages of brain metastatic colonization, we investigated two prevalent sources of cerebral relapse in the clinic, triple-negative breast cancer (TNBC) and HER2+ breast cancer (HER2BC). We elucidated distinctive early tumor architectures, physical and functional stromal interfaces, and autocrine growth programs employed by these two tumor types to colonize the brain. TNBC cells form extensive perivascular sheath colonies with diffusive contact with astrocytes and microglia. In striking contrast, heightened autonomous deposition of several extracellular matrix components prompts HER2BC cells to colonize the brain as compact, spheroidal colonies, segregating stromal cells to the periphery of the colony. Single-cell dissection of the spatially resolved tumor microenvironment (TME) reveals that brain metastases activate – to different degrees – the canonical stages of the disease-associated microglia (DAM) response previously defined in Alzheimer’s disease. Differential engagement of paracrine tumor-DAM signaling through the receptor AXL suggests specific pro-metastatic functions of the tumor architecture in both TNBC perivascular and HER2BC spheroidal colonies. Collectively, our findings illuminate the distinct stereospatial features of two different yet highly efficient modes of brain colonization, and the relevance of these features in future efforts to leverage the TME to treat brain metastasis.
2023-05-02 | GSE223309 | GEO
Project description:Brain metastasis is a dismal complication of cancer that hinges on the initial survival and outgrowth of disseminated cancer cells. To better understand these crucial early stages of brain metastatic colonization, we investigated two prevalent sources of cerebral relapse in the clinic, triple-negative breast cancer (TNBC) and HER2+ breast cancer (HER2BC). We elucidated distinctive early tumor architectures, physical and functional stromal interfaces, and autocrine growth programs employed by these two tumor types to colonize the brain. TNBC cells form extensive perivascular sheath colonies with diffusive contact with astrocytes and microglia. In striking contrast, heightened autonomous deposition of several extracellular matrix components prompts HER2BC cells to colonize the brain as compact, spheroidal colonies, segregating stromal cells to the periphery of the colony. Single-cell dissection of the spatially resolved tumor microenvironment (TME) reveals that brain metastases activate – to different degrees – the canonical stages of the disease-associated microglia (DAM) response previously defined in Alzheimer’s disease. Differential engagement of paracrine tumor-DAM signaling through the receptor AXL suggests specific pro-metastatic functions of the tumor architecture in both TNBC perivascular and HER2BC spheroidal colonies. Collectively, our findings illuminate the distinct stereospatial features of two different yet highly efficient modes of brain colonization, and the relevance of these features in future efforts to leverage the TME to treat brain metastasis.
2023-05-02 | GSE223247 | GEO
Project description:Brain metastasis is a dismal complication of cancer that hinges on the initial survival and outgrowth of disseminated cancer cells. To better understand these crucial early stages of brain metastatic colonization, we investigated two prevalent sources of cerebral relapse in the clinic, triple-negative breast cancer (TNBC) and HER2+ breast cancer (HER2BC). We elucidated distinctive early tumor architectures, physical and functional stromal interfaces, and autocrine growth programs employed by these two tumor types to colonize the brain. TNBC cells form extensive perivascular sheath colonies with diffusive contact with astrocytes and microglia. In striking contrast, heightened autonomous deposition of several extracellular matrix components prompts HER2BC cells to colonize the brain as compact, spheroidal colonies, segregating stromal cells to the periphery of the colony. Single-cell dissection of the spatially resolved tumor microenvironment (TME) reveals that brain metastases activate – to different degrees – the canonical stages of the disease-associated microglia (DAM) response previously defined in Alzheimer’s disease. Differential engagement of paracrine tumor-DAM signaling through the receptor AXL suggests specific pro-metastatic functions of the tumor architecture in both TNBC perivascular and HER2BC spheroidal colonies. Collectively, our findings illuminate the distinct stereospatial features of two different yet highly efficient modes of brain colonization, and the relevance of these features in future efforts to leverage the TME to treat brain metastasis.
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Project description:The interplay of cerebromicrovascular endothelial cells, pericytes and perivascular macrophages is central to the recruitment of neutrophils across the blood-brain barrier into the brain, and therefore to the CNS inflammatory response. This experiment examined the endothelial response to direct stimulation in the presence or absence of pericytes to explore the effect of co-culture on the endothelial inflammatory response. It also assessed the endothelial response to signalling by monocyte-derived macrophages, modelling perivascular macrophages, the only canonical innate immune cell found within the perivascular space.
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Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN in the A375 melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing and functional kinome analysis revealed the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAFand MEK1/2 in PTEN null, BRAFV600E cells dramatically induced expression of ERBB3/HER3 relative to wild type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with inhibitors for mutant BRAF/MEK1/2 identified the pan ERBB/HER inhibitor, neratinib, as reversing the resistance observed in PTEN null, BRAFV600E cells. The findings indicate PTEN null BRAFV600E melanoma becomes dependent on ERBB/HER signaling when treated with clinically approved BRAF and MEK inhibitors. Future studies are warranted to test neratinib reversal of resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.
2024-04-23 | PXD033866 | Pride