Dataset Information

PTEN-restoration abrogates brain colonization and perivascular niche invasion by melanoma cells

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE247232 | GEO | 2023/12/26

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Brain metastases (BrMs) are a devastating complication of solid tumors with challenging clinical management. In this study, immunogenomic and digital spatial analyses were applied to interrogate the peripheral blood and tumor specimens derived from 53 unique patients with metastatic brain tumors originating from different solid tumors including melanoma, breast cancer, lung cancer and renal cell carcinoma. In the peripheral blood, lower levels of neutrophil -lymphocytes ratio (NLR) were detected at time of craniotomy in patients with melanoma-derived brain metastasis (MBM) vs. non-melanoma- derived brain metastasis (non-MBM). Independently from the primary tumor of derivation, patients with BrMs and increased NLR levels were characterized by shorter overall survival (OS) following craniotomy. In the tumor microenvironment (TME), molecular evaluations performed on FFPEs revealed higher expression of genes and mRNA signatures identifying NK cells, CD8 cells and B cells in MBM (n=13) vs. non-MBM brain metastasis (n=41). Focusing on CD8 cells, higher infiltration of CD8+ cells were observed in patients with MBM with longer OS following craniotomy. Spatial proteomic analysis further highlighted the infiltration of CD8+ cells, antigen presenting cells- (HLA-DR+, CD11c+, B2M+), agonists of T cell activity (CD137+, CD40+) and B cells (CD20+) enriched in MBM vs non-MBM. On the contrary, an increased expression of genes associated with neuro-development, cell- cell adhesion, neutrophil enrichment together with the increased infiltrations of cells promoting neuro-differentiation (Neun+, S100+), immune regulatory functions (CD25+, CD127+), and granulocytes aggregation (CD66b+) were observed in non-MBM vs. MBM. These findings highlight that the TME of BrMs plays a pivotal role in the pathogenesis and therapeutic resistance of BrMs derived from different solid tumors. Our results also suggest that distinct neuro-immune interplay may contribute to treatment resistance in BrMs.

Dataset Information

PTEN-restoration abrogates brain colonization and perivascular niche invasion by melanoma cells

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets