Identification of gene signature in human colorectal CD44+ cancer stem cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE100433 | GEO | 2018/11/09
REPOSITORIES: GEO
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Project description:To investigate the significance of CD44+ hepatocellular carcinoma (HCC) HuH7 cells, microRNA (miRNA) expression profiles of CD44-positive HuH7, CD44-negative HuH7, and human nomal hepatocyes were analyzed. Results provide the insight into the significance of CD44-positive HCC cells as the liver CSCs.
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Project description:We analyzed gene expression of 3 lines LGR5-GFP, 2 lines KRT20-GFP knock-in colorectal tumor organdies. The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5+ colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen inducible Cre knock-in allele of LGR5 reveal the self-renewal and differentiation capacity of LGR5+ tumour cells. Selective ablation of LGR5+ CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5+ CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5+ CSCs and contributing to tumour regrowth after LGR5+ CSC ablation. We also show that combined chemotherapy potentiates LGR5+ CSCs targeting. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer.
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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.
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Project description:Osteosarcoma is the most common type of pediatric bone tumor. Despite great advances in chem-otherapy during the past decades the survival rates of osteosarcoma patients remains usatisfacto-ry. Drug resistance is one of the main reasons leading to treatment failure and poor progno-sis. Previous reports correlated expression of cluster of differentiation 44 (CD44) with drug re-sistance and poor survival of osteosarcoma patients, however the underlying mechanisms are poorly defined. Here, we investigated the role of CD44 in the regulation of drug chemoresistance using osteosarcoma cells isolated from mice carrying a mutation of the tumor suppressor neurofi-bromatosis type 2 (Nf2) gene. CD44 expression was knocked-down in the cells using CRISPR/Cas9 approach. Subsequently, CD44 isoforms and mutants were re-introduced to investigate CD44-dependent processes. Sensitivity to doxorubicin was analyzed in the osteosarcoma cells with modified CD44 expression by immunoblot, colony formation- and WST-1 assay. To dissect the molecular alterations induced by deletion of Cd44, RNA sequencing was performed on Cd44-positive and Cd44-negative primary osteosarcoma tissues isolated from Nf2-mutant mice. Subsequently, expression of candidate genes was evaluated by quantitative reverse transcription PCR (qRT-PCR). Our results indicate that CD44 increases the resistance of osteosarcoma cells to doxorubicin by up-regulating the levels of multidrug resistance (MDR) 1 protein expression, and suggest the role of proteolytically released CD44 intracellular domain, and hyaluronan interac-tions in this process. Moreover, high throughput sequencing analysis identified differential regula-tion of several apoptosis-related genes in Cd44-positive and -negative primary osteosarcomas, in-cluding p53 apoptosis effector related to PMP-22 (Perp). Deletion of CD44 in osteosarcoma cells led to doxorubicin-dependent p53 activation and a profound increase in Perp mRNA expression. Overall, our results suggest that CD44 might be an important regulator of drug resistance and suggest that targeting CD44 can sensitize osteosarcoma to standard chemotherapy.
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Project description:Brain metastasis of lung cancer causes high mortality, but the exact mechanisms underlying the metastasis remain unclear. Here we report that vascular pericytes derived from CD44+ lung cancer stem cells (CSCs) in lung adenocarcinoma (ADC) potently cause brain metastases through GPR124-mediated trans-endothelial migration (TEM). CD44+ CSCs in the perivascular niche generate the majority of vascular pericytes in lung ADC. CSC-derived pericyte-like cells (Cd-pericytes) exhibit remarkable TEM capacity to effectively intravasate into vessel lumina, survive in the circulation, extravasate into the brain parenchyma, and then de-differentiate into tumorigenic CSCs to form metastases. Moreover, Cd-pericytes uniquely express GPR124, a G-protein-coupled receptor. GPR124 mediates through Wnt7-β-Catenin activation to enhance TEM capacity of Cd-pericytes for intravasation and extravasation, two critical steps during tumor metastasis. Furthermore, selective disruption of Cd-pericytes, GPR124 or Wnt7-β-Catenin signaling markedly reduced brain and liver metastases of lung ADC. Our findings uncover an unappreciated cellular and molecular paradigm driving tumor metastasis.
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Project description:Brain metastasis of lung cancer causes high mortality, but the exact mechanisms underlying the metastasis remain unclear. Here we report that vascular pericytes derived from CD44+ lung cancer stem cells (CSCs) in lung adenocarcinoma (ADC) potently cause brain metastases through GPR124-mediated trans-endothelial migration (TEM). CD44+ CSCs in the perivascular niche generate the majority of vascular pericytes in lung ADC. CSC-derived pericyte-like cells (Cd-pericytes) exhibit remarkable TEM capacity to effectively intravasate into vessel lumina, survive in the circulation, extravasate into the brain parenchyma, and then de-differentiate into tumorigenic CSCs to form metastases. Moreover, Cd-pericytes uniquely express GPR124, a G-protein-coupled receptor. GPR124 mediates through Wnt7-β-Catenin activation to enhance TEM capacity of Cd-pericytes for intravasation and extravasation, two critical steps during tumor metastasis. Furthermore, selective disruption of Cd-pericytes, GPR124 or Wnt7-β-Catenin signaling markedly reduced brain and liver metastases of lung ADC. Our findings uncover an unappreciated cellular and molecular paradigm driving tumor metastasis.
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