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Transcriptional profiling of breast cancer stem cell xenografts and their metastatic derivatives

ABSTRACT: Breast cancer stem cell (BCSC) line #1 and #4 were grown in either stem cell medium or medium favoring the differentiation. Cells were genetically labeled with fluorescent protein expression cassettes and xenotransplanted into immunocompromised mice, giving rise to tumors. Tumors were explanted, dissociated and kept in culture so as to isolate growing cells. Cells were then sorted for fluorescent protein expression and RNA was extracted. Breast cancer stem (BCSC) and differentiated (dBCCs) cells, grown in opportune conditions, were transfected with lentiviral vector encoding luciferase/enhanced green fluorescent protein (Luc/EGFP-BCSCs) or luciferase/red fluorescent protein (Luc/RFP-dBCCs) reporter genes and orthotopically injected in defined ratios (1:1) into immunocompromised mice. Primary tumor growth and the onset of distant metastases was then observed in time. Following primary and metastatic lesions resection, labeled dBCCs, BCSCs and metastatic derivatives, thereafter referred to as fat pad differentiated cells (FPD), fat pad stem cells (FPS) and metastases (Ms) respectively, were consequently isolated from through fluorescent-activated cell sorting and RNA extracted. 14 samples, with at least 2 biological replicates for each category

ORGANISM(S): Homo sapiens

SUBMITTER: pagliuca alfredo

PROVIDER: S-ECPF-GEOD-48371 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, representing the most common form of liver cancer. As HCC incidence and mortality continue to increase, there is a growing need for improved translational animal models to bridge the gap between basic HCC research and clinical practice to improve early detection and treatment strategies for this deadly disease. Recently the Oncopig cancer model-a novel transgenic swine model that recapitulates human cancer through Cre recombinase induced expression of KRAS G12D and TP53 R167H driver mutations-has been validated as a large animal translational model for human HCC. Due to the similar size, anatomy, physiology, immunology, genetics, and epigenetics between pigs and humans, the Oncopig has the potential to improve translation of novel diagnostic and therapeutic modalities into clinical practice. Recent studies have demonstrated the importance of tumor cells in shaping its surrounding microenvironment into one that is more proliferative, invasive, and metastatic; however, little is known about the impact of microenvironment signaling on HCC tumor biology and differential gene expression between HCC tumors and its tumor microenvironment (TME). In this study, transcriptional profiling was performed on Oncopig HCC xenograft tumors (n = 3) produced via subcutaneous injection of Oncopig HCC cells into severe combined immunodeficiency (SCID) mice. To differentiate between gene expression in the tumor and surrounding tumor microenvironment, RNA-seq reads originating from porcine (HCC tumor) and murine (microenvironment) cells were bioinformatically separated using Xenome. Principle component analysis (PCA) demonstrated clustering by group based on the expression of orthologous genes. Genes contributing to each principal component were extracted and subjected to functional analysis to identify alterations in pathway signaling between HCC cells and the microenvironment. Altered expression of genes associated with hepatic fibrosis deposition, immune response, and neo angiogenesis were observed. The results of this study provide insights into the interplay between HCC and microenvironment signaling in vivo, improving our understanding of the interplay between HCC tumor cells, the surrounding tumor microenvironment, and the impact on HCC development and progression.

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Transcriptional profiling of breast cancer stem cell xenografts and their metastatic derivatives

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