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Metastasis and Survival of Breast Cancer Stem Cells Mediated by Cytoskeleton Remodeling and PI3K/mTOR Signaling transcription factors

ABSTRACT: Cancer metastasis is a fetal problem that claims life of over 90% of cancer patients. It is hypothesized that cancer stem cells (CSCs) mediate cancer metastasis and such cells are often resistant to chemotherapy. Studying BRCA1 associated cancers, we found that CSCs form fillopodia and protrusions enriching for active forms of ezrin/radixin/moesin proteins and they have a much higher potential to metastasize than non-CSCs. Microarray analysis indicated that many pathways related to cell adhesion, extracellular matrix and cytoskeleton were differentially regulated in CSCs. Although inhibition of cytoskeleton remodeling by cisplatin treatment retarded CSC motility and cancer metastasis, drug resistant cancers eventually emerge containing markedly increased number of CSCs. This event is at least partially attributed to the activation of PI3K/mTOR signaling, and can be significantly inhibited by the treatment of rapamycin. These results provide strong evidence that cytoskeletal rearrangement and PI3K/mTOR signaling play a distinct role in mediating CSC mobility and viability, and blocking of both pathways in CSCs synergistically inhibits primary and metastatic cancer growth in BRCA1 associated tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE26621 | GEO | 2012/04/14

SECONDARY ACCESSION(S): PRJNA136435

REPOSITORIES: GEO

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Metastasis and Survival of Breast Cancer Stem Cells Mediated by Cytoskeleton Remodeling and PI3K/mTOR Signaling transcription factors

Project description:Cancer metastasis is a fetal problem that claims life of over 90% of cancer patients. It is hypothesized that cancer stem cells (CSCs) mediate cancer metastasis and such cells are often resistant to chemotherapy. Studying BRCA1 associated cancers, we found that CSCs form fillopodia and protrusions enriching for active forms of ezrin/radixin/moesin proteins and they have a much higher potential to metastasize than non-CSCs. Microarray analysis indicated that many pathways related to cell adhesion, extracellular matrix and cytoskeleton were differentially regulated in CSCs. Although inhibition of cytoskeleton remodeling by cisplatin treatment retarded CSC motility and cancer metastasis, drug resistant cancers eventually emerge containing markedly increased number of CSCs. This event is at least partially attributed to the activation of PI3K/mTOR signaling, and can be significantly inhibited by the treatment of rapamycin. These results provide strong evidence that cytoskeletal rearrangement and PI3K/mTOR signaling play a distinct role in mediating CSC mobility and viability, and blocking of both pathways in CSCs synergistically inhibits primary and metastatic cancer growth in BRCA1 associated tumors. The sorted subpopulations based upon CD24, CD29 expression were used in the microarray analysis that was performed with 3 independent biologic sample sets.

2012-04-13 | E-GEOD-26621 | biostudies-arrayexpress

Transcriptomic analysis of Diffuse Intrinsic Pontine Glioma (DIPG) identifies a targetable ALDH-positive subset of highly tumorigenic cancer stem-like cells

Project description:Understanding the cancer stem-cell (CSC) landscape in diffuse intrinsic pontine glioma (DIPG) is desperately needed to address treatment resistance and identify novel therapeutic approaches. Patient derived DIPG cells demonstrated heterogeneous expression of aldehyde dehydrogenase (ALDH) and CD133 by flow cytometry. Transcriptome-level characterization identified elevated mRNA levels of MYC, E2F, DNA damage repair (DDR) genes, glycolytic metabolism and mTOR signaling in ALDH+ compared to ALDH- supporting a stem-like phenotype and indicating a druggable target. ALDH+ cells demonstrated increased proliferation and neurosphere formation and initiated tumors that resulted in decreased survival when orthotopically implanted. Pharmacological MAPK/PI3K/mTOR targeting downregulated MYC, E2F and DDR mRNAs and reduced glycolytic metabolism. In vivo PI3K/mTOR targeting inhibited tumor growth in both flank and an ALDH+ orthotopic tumor model likely by reducing cancer stemness. Characterization of DIPG CSCs coupled with targeting MAPK/PI3K/mTOR signaling provides an impetus for molecularly targeted therapy aimed at addressing the CSC phenotype in DIPG.

2020-11-03 | GSE149682 | GEO

Gene expression changes in a breast cancer stem cell model.

Project description:Epithelial to mesenchymal transition (EMT) is activated during cancer invasion and metastasis, enriches for cancer stem cells (CSCs), and contributes to therapeutic resistance and disease recurrence. The epithelial cell line MCF7, can be induced to undergo EMT with the induction of PKC by PMA. 5-10% of the resulting cells have a CSC phenotype. This study looks at the transcriptome of these cells and how it differs from cells with a non-CSC phenotype. Epithelial to mesenchymal transition (EMT) is activated during cancer invasion and metastasis, enriches for cancer stem cells (CSCs), and contributes to therapeutic resistance and disease recurrence. The epithelial cell line MCF7, can be induced to undergo EMT with the induction of PKC by PMA. 5-10% of the resulting cells have a CSC phenotype. This study looks at the transcriptome of these cells and how it differs from cells with a non-CSC phenotype. MCF7 cells were stimulated with PMA and FACS sorted. 4 samples, no replicates

2014-06-22 | E-GEOD-53266 | biostudies-arrayexpress

PI3K/AKT/mTOR and Sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth

Project description:Cancer stem cells (CSCs) play major roles in cancer initiation, progression, and metastasis. It is evident from growing reports that PI3K/Akt/mTOR and Sonic Hedgehog (Shh) signaling pathway are aberrantly reactivated in pancreatic CSCs. Here, we examined the efficacy of combining NVP-LDE-225 (PI3K/mTOR inhibitor) and NVP-BEZ-235 (Smoothened inhibitor) on pancreatic CSCs characteristics, microRNA regulatory network, and tumor growth. NVP-LDE-225 cooperated with NVP-BEZ-235 in inhibiting pancreatic CSC’s characteristics and tumor growth in NOD/SCID IL2R null mice by acting at the level of Gli. Combination of NVP-LDE-225 and NVP-BEZ-235 inhibited self-renewal capacity of CSCs by suppressing the expression of pluripotency maintaining factors Nanog, Oct-4, Sox-2 and cMyc. NVP-LDE-225 cooperated with NVP-BEZ-235 to inhibit Lin28/Let7a/Kras axis in pancreatic CSCs. Furthermore, synergistic interaction of these drugs was observed on spheroid formation by pancreatic CSCs isolated from Pankras/p53 mice. The combination of these drugs also showed synergistic effects on the expression of proteins involved in cell survival and apoptosis. In addition, synergistic effects of these drugs were observed on inhibition of epithelial-to-mesenchymal transition (EMT) through modulation of cadherin, vimentin and transcription factors Snail, Slug and Zeb1. In conclusion, these data suggest that the combined inhibition of PI3K/Akt/mTOR and Shh pathways may be an effective strategy for the treatment of pancreatic cancer.

2017-06-19 | GSE70087 | GEO

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

Transcription profiling of human prostate cancer primary cell line vs metastasis cell line reveals Protein 4.1B suppresses prostate cancer progression and metastasis

Project description:Protein 4.1B is a 4.1/ezrin/radixin/moesin (FERM) domain-containing protein whose expression is frequently lost in a variety of human tumors, including meningiomas, non-small-cell lung cancers and breast carcinomas. However, its potential tumor suppressive function under in vivo conditions remains to be validated. In a screen for genes involved with prostate cancer metastasis, we found that 4.1B expression is reduced in highly metastatic tumors. Downregulation of 4.1B increased the metastatic propensity of poorly metastatic cells in an orthotopic model of prostate cancer. Furthermore, 4.1B-deficient mice displayed increased susceptibility for developing aggressive, spontaneous prostate carcinomas. In both cases, enhanced tumor malignancy was associated with reduced apoptosis. As expression of Protein 4.1B is frequently downregulated in human clinical prostate cancer, as well as in a spectrum of other tumor types, these results suggest a more general role for Protein 4.1B as a negative regulator of cancer progression to metastatic disease. Experiment Overall Design: primary cell line vs metastasis cell line

2008-06-15 | E-GEOD-7930 | biostudies-arrayexpress

Tenascin-C Protects Cancer Stem-Like Cells from Immune Surveillance

Project description:Precociously disseminated cancer cells may seed quiescent sites of future metastasis if they can protect themselves from immune surveillance. However, there is little knowledge about how such sites might be achieved. Here we present evidence that prostate cancer stem-like cells (CSC) can be found in histopathologically negative prostate draining lymph nodes (PDLN) in mice harboring oncogene-driven prostate intraepithelial neoplasia (mPIN). PDLN-derived CSC were phenotypically and functionally identical to CSC obtained from mPIN lesions, but distinct from CSCs obtained from frank prostate tumors. CSC derived from either PDLN or mPIN used the extracellular matrix protein Tenascin-C (TNC) to inhibit T cell receptor-dependent T cell activation, proliferation and cytokine production. Mechanistically, TNC interacted with Î±5Î²1 integrin on the cell surface of T cells, inhibiting reorganization of the actin-based cytoskeleton therein required for proper T cell activation. CSC from both PDLN and mPIN lesions also expressed CXCR4 and migrated in response to its ligand CXCL12, which was overexpressed in PDLN upon mPIN development. CXCR4 was critical for the development of PDLN-derived CSC, as in vivo administration of CXCR4 inhibitors prevented establishment in PDLN of an immunosuppressive microenvironment. Taken together, our work establishes a pivotal role for TNC in tuning the local immune response to establish equilibrium between disseminated nodal CSC and the immune system. A total of six sample of TPIN (N = 3) and TNE (N = 3) cultured cells from TRAMP mouse model were analyzed

2015-02-03 | E-GEOD-65502 | biostudies-arrayexpress

Gene expression changes in a breast cancer stem cell model.

2014-06-22 | GSE53266 | GEO

A Phase I/II Study of Active Immunotherapy With Cancer Stem Cells Vaccine for Colorectal Cancer

Project description:Most studies of cancer stem cells (CSC) involve the inoculation of cells from human tumors into immunosuppressed mice, preventing an assessment on the immunologic interactions and effects of CSCs. In this study, the investigators examined the vaccination effects produced by CSC-enriched populations from histologically distinct murine tumors after their inoculation into different syngeneic immunocompetent hosts. Enriched CSCs were immunogenic and more effective as an antigen source than unselected tumor cells in inducing protective antitumor immunity.Immune sera from CSC-vaccinated hosts contained high levels of IgG which bound to CSCs, resulting in CSC lysis in the presence of complement.CTLs generated from peripheral blood mononuclear cells or splenocytes harvested from CSC-vaccinated hosts were capable of killing CSCs in vitro. Mechanistic investigations established that CSC-primed antibodies and T cells were capable of selective targeting CSCs and conferring anti-tumor immunity.

| 2169532 | ecrin-mdr-crc

Cancer stem cell features shift during skin squamous cell carcinoma progression

Project description:Cancer stem cells (CSCs) play a key role in tumour growth and metastasis. Although an expansion of CSC population was previously described in advanced cutaneous squamous cell carcinoma (SCC), it remains unknown whether CSC regulatory mechanisms also change through tumour progression to promote malignancy. Here, we generate mouse models of skin SCCs to study alterations in CSC regulation over progression. We found that features of CSCs change at late stage of progression, correlating with a switch from epithelial to mesenchymal tumour shape. beta-catenin and EGFR signalling are down-regulated, whereas autocrine FGFR1 and PDGFR alpha pathways are up-regulated in CSCs of advanced tumours. Inhibition of FGFR and PDGFR signalling repress malignant SCCs growth and metastasis, respectively. An enhanced epithelial-to-mesenchymal transition (EMT) program and over-expression of PDGFR alpha and FGFR1 are observed in malignant human skin SCCs, suggesting that these pathways are also induced over human SCC progression. Therefore, uncover signalling pathways controlling CSCs at specific stage of progression may improve the selection of more accurate targeted therapeutic strategies according to tumour stage, blocking SCC relapse and metastasis. Mouse models of skin SCCs progression were first generated. For that, individual samples of spontaneous or DMBA-TPA induced skin SCCs generated in K14-HPV16 mice were orthotopically engrafted in immunodeficient mice and then serially transplanted, generating lineages in which the progression from WD-SCCs to PD-SCCs was observed. Then, tumour cells expressing CD34 and alpha 6-integrin, previously identified as cutaneous cancer stem cells, were isolated by flow cytometry-sorter from WD-SCCs and PD-SCCs of different tumour lineages. RNA extraction and hybridization on Affymetrix microarrays was carried out to compare whole gene profiling of these populations of CSCs.

2016-01-08 | E-GEOD-59439 | biostudies-arrayexpress

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