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Multi-organ mapping of cancer risk

ABSTRACT: Cancers are distributed unevenly across the body; but the importance of cell intrinsic factors such as stem cell function in determining organ cancer risk is unknown. Therefore, we used cre-recombination of conditional lineage tracing, oncogene and tumour suppressor alleles to define populations of stem and non-stem cells in mouse organs, and test their life-long susceptibility to tumorigenesis. We show that cancer risk is determined by the life-long generative capacity of mutated cells. This relationship held true in the presence of multiple genotypes and regardless of developmental stage, strongly supporting the notion that stem cells dictate organ cancer risk. Using the liver as a model system, we further show that damage-induced activation of stem cell function markedly increases cancer risk. Therefore, we propose that a combination of stem cell mutagenesis and extrinsic factors that enhance the proliferation of these cell populations, creates a ‘perfect storm’ that ultimately determines organ cancer risk.

ORGANISM(S): Mus musculus

PROVIDER: GSE78076 | GEO | 2016/07/01

SECONDARY ACCESSION(S): PRJNA312535

REPOSITORIES: GEO

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Multi-organ mapping of cancer risk

Project description:Cancers are distributed unevenly across the body; but the importance of cell intrinsic factors such as stem cell function in determining organ cancer risk is unknown. Therefore, we used cre-recombination of conditional lineage tracing, oncogene and tumour suppressor alleles to define populations of stem and non-stem cells in mouse organs, and test their life-long susceptibility to tumorigenesis. We show that cancer risk is determined by the life-long generative capacity of mutated cells. This relationship held true in the presence of multiple genotypes and regardless of developmental stage, strongly supporting the notion that stem cells dictate organ cancer risk. Using the liver as a model system, we further show that damage-induced activation of stem cell function markedly increases cancer risk. Therefore, we propose that a combination of stem cell mutagenesis and extrinsic factors that enhance the proliferation of these cell populations, creates a âperfect stormâ that ultimately determines organ cancer risk. Long-term lineage tracing and conditional oncogenic targeting of Prom1-expressing cells in various mouse organs.

2016-07-01 | E-GEOD-78076 | biostudies-arrayexpress

Mus musculus

Project description:Multi-organ mapping of cancer risk

| PRJNA312535 | ENA

A Basal Stem Cell Signature Identifies Aggressive Prostate Cancer Phenotypes

Project description:Aggressive cancers and normal stem cells often share similar molecular and functional traits. It is unclear if aggressive phenotypes of prostate cancer molecularly resemble normal stem cells residing within the human prostate. We performed high-throughput RNA sequencing on uncultured, highly purified epithelial populations from human prostates obtained after radical prostatectomy. We found the basal population to be defined by genes associated with developmental programs, epigenetic remodeling, and invasiveness. We further generated a 91-gene basal signature and applied it to gene expression datasets from patients with organ-confined or castration-resistant, metastatic prostate cancer. Metastatic prostate cancer was more enriched for the basal stem cell signature than organ-confined prostate cancer. Moreover, histological subtypes within prostate cancer metastases varied in their enrichment of the stem cell signature with small cell neuroendocrine carcinoma being the most stem cell-like. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common to all three signatures. These results suggest that the most aggressive variants of prostate cancer share a core transcriptional program with normal prostate basal stem cells. Transcriptional analysis of 10 uncultured prostatic basal and luminal populations from either the benign or malignant prostate tissue of 8 human prostate cancer patients by high-throughput RNA-seq

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Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities

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Expression profiles of CD24-/CD44+/ESA+ population in MDA-MB-231 and its highly metastatic variants.

Project description:Breast cancer is a curable disease if it is diagnosed at an early stage. However, only little options are left once the tumor is metastasized to distant organs, and more than 90% of breast cancer death is attributed to metastatic disease. The process of metastasis is highly complex and involves many steps for successful colonization of tumor cells at a target organ. According to the cancer stem cell (CSC) theory, which still remains a hypothesis, these metastatic cells must have stem cell-like capability for their self-renewal in addition to their invasive ability. Therefore, it has been predicted that a “metastatic stem cell”, which is distinct from a cancer stem cell, must exist in the primary tumor mass. To identify genes that are involved in metastasis of CSCs, we isolated CSC populations from a well-established model cell line of breast cancer, MDA-MB231, and that of highly metastatic variants, 231BoM-1833 and 231BrM-2a, using CD24, CD44 and EpCAM (ESA), which have been identified as surface markers for CSCs in breast cancers. Overall yield of CSCs from these cells ranged from 2% to 4%. We then performed global expression profile analysis for these CSCs using the Affymetrix Human Gene 1.0ST array. CSC populations (CD24-/CD44+/ESA+) from MDA-MB231, 231BoM-1833 and 231BrM-2a were isolated by magnetic-activated cell sorting (MACS) using specific antibodies to these surface markers. The total RNA was isolated from the CSC populations using the RNeasy RNA isolation kit (Qiagen). The RNA was then converted to cDNA and they were hybridized to the Human Gene 1.0ST chip (Affymetrix). The data was normalized using the RMA algorithm of the Expression Console software (Affymetrix). A comparison of transcriptional profiles was then performed in CSCs of highly metastatic cell lines (231BoM-1833 and 231BrM-2a) compared to the CSCs of MDA-MB-231.

2011-11-30 | E-GEOD-25976 | biostudies-arrayexpress

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Project description:Up to 40% of patients with Estrogen Receptor positive (ER+) breast cancer experience relapse. Breast cancer stem cells (BCSCs) are known to be involved in therapy resistance, relapse, and development of more aggressive and metastatic tumors. Therefore, there is an urgent need to identify genes/pathways that drive stem-like cell properties in ER+ breast tumors. Using single-cell RNA sequencing and bioinformatic approaches, with additional follow-up studies, we identified a unique quiescent stem-like cell population that is driven by ER and NFkB in multiple ER+ breast cancer models. Moreover, a gene signature derived from this stem-like population is expressed in endocrine therapy-resistant and metastatic cell populations and predictive of poor patient outcome. These findings indicate a novel role for ER and NFkB crosstalk in BCSCs biology and understanding the mechanism by which these pathways promote stem properties may be exploited to improve outcomes for ER+ breast cancer patients at risk of relapse.

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A Basal Stem Cell Signature Identifies Aggressive Prostate Cancer Phenotypes

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Expression profiles of CD24-/CD44+/ESA+ population in MDA-MB-231 and its highly metastatic variants.

2011-11-30 | GSE25976 | GEO

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