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RNA-seq expression profiling of metastasis-associated endothelial cells from murine bone marrow

ABSTRACT: Breast tumour cells were found to remodel the murine bone marrow vascular microenvironment to support metastatic expansion. To gain insight into the host vasculature in response to tumor colonization, cells from the isogenic murine mammary tumour cell line 4T1.2 were intracardially injected into immunocompetent BALB/c mice. We analysed the transcriptional profiles of endothelial cells extracted from heavily infiltrated (Metastatic) bone marrow stroma and the adjacent tumor-free bone marrow stroma (Non-metastatic), as well as from healthy bones (Control). Methods: Immunocompetent BALB/c mice were intracardically injected with 4T1.2 tumor cells. The bones of these tumor-burdened mice were examined under fluorescence stereomicroscope to microdissect heavily-infiltrated (Metastatic) and the adjacent tumour-free (Non-metastatic) areas. Bones from healthy mice were used as controls. The dissected bone material from both burdened and control mice was processed to isolate EMCNhi/CD31hi endothelial cells using flow cytometry. RNA was extracted for 75bp paired-end RNA-seq profiling using an Illumina NextSeq 500 sequencer.

ORGANISM(S): Mus musculus

PROVIDER: GSE160100 | GEO | 2021/09/16

REPOSITORIES: GEO

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Project description:The reciprocal interaction between cancer cells and the tissue-specific stroma is critical for primary and metastatic tumor growth progression. Prostate cancer cells colonize preferentially bone (osteotropism), where they alter the physiological balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and elicit prevalently an osteoblastic response (osteoinduction). The molecular cues provided by osteoblasts for the survival and growth of bone metastatic prostate cancer cells are largely unknown. We exploited the sufficient divergence between human and mouse RNA sequences together with redefinition of highly species-specific gene arrays by computer-aided and experimental exclusion of cross-hybridizing oligonucleotide probes. This strategy allowed the dissection of the stroma (mouse) from the cancer cell (human) transcriptome in bone metastasis xenograft models of human osteoinductive prostate cancer cells (VCaP and C4-2B). As a result, we generated the osteoblastic bone metastasis-associated stroma transcriptome (OB-BMST). Subtraction of genes shared by inflammation, wound healing and desmoplastic responses, and by the tissue type-independent stroma responses to a variety of non-osteotropic and osteotropic primary cancers generated a curated gene signature (“Core” OB-BMST) putatively representing the bone marrow/bone-specific stroma response to prostate cancer-induced, osteoblastic bone metastasis. The expression pattern of three representative Core OB-BMST genes (PTN, EPHA3 and FSCN1) seems to confirm the bone specificity of this response. A robust induction of genes involved in osteogenesis and angiogenesis dominates both the OB-BMST and Core OB-BMST. This translates in an amplification of hematopoietic and, remarkably, prostate epithelial stem cell niche components that may function as a self-reinforcing bone metastatic niche providing a growth support specific for osteoinductive prostate cancer cells. The induction of this combinatorial stem cell niche is a novel mechanism that may also explain cancer cell osteotropism and local interference with hematopoiesis (myelophthisis). Accordingly, these stem cell niche components may represent innovative therapeutic targets and/or serum biomarkers in osteoblastic bone metastasis. Keywords: cancer, transcription-profile, bone, metastasis, stroma 3 samples of VCaP xenografted mouse bones (VCaP xenografts 1/2/3), 3 samples of C4-2B xenografted mouse bones (C4-2B xenografts 1/2/3), 2 samples of Ep156T xenografted mouse bones (Ep156T xenografts 1/2), 2 samples of sham-operated mouse bones (sham-operated bones 1/2) and 3 samples of intact mouse bones (intact bones 1/2/3) were profiled on Affymetrix Mouse Genome 430A 2.0 Arrays. Sample code: MVX stands for VCaP xenografts, MBM for Intact bone samples, MCX for C4-2B xenografts and MNX for Sham-operated bones samples

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RNA-seq expression profiling of metastasis-associated endothelial cells from murine bone marrow

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