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

ABSTRACT: 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

ORGANISM(S): Mus musculus

SUBMITTER: Ignazio Piras

PROVIDER: E-GEOD-65502 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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 α5β1 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.

2015-02-03 | GSE65502 | GEO

Diffusible factors released from human prostate carcinoma cells restrained cancer stem cells from contributing to tumor progression

Project description:The growth and progression of many cancers is thought to be driven by small subpopulations of cancer stem cells (CSC). Long-term cultures of CSC have been established to develop therapeutic strategies aimed at eradicating these tumorigenic cells. To evaluate the contribution of CSC to the progression of prostate cancer we isolated a CD44+CD24- tumor cell population from the DU145 cell line, derived from a brain metastasis of human prostate carcinoma, and established their CSC properties. The behaviour of selected CSC was then investigated with respect to the bulk DU145 cells. Interestingly, CSC were able to generate very aggressive tumors in immunodeficient mice, but this capacity was interfered by the presence of differentiated DU145 cells, resulting in the growth of scarcely aggressive tumors. To understand the influence of DU145 cells on CSC we performed co-culture experiments, demonstrating that signals released from differentiated tumor cells interfered with CSC acquisition of an aggressive phenotype. Our findings highlight that the fate of prostate CSC can be controlled by microenvironmental signals that restrain CSC from contributing to prostate cancer progression. Finally, we identified several molecules possibly involved in this cell-to-cell signaling, hypothesizing their potential value as novel prognostic markers or therapeutic targets. To investigate the cellular response involved in tumorigenesis both at the level of gene expression and at the pre-mRNA splicing level we performed a whole genome microarray analysis of two paradigmatic experimental conditions, DU145 cells and their selected CSC.

2013-03-01 | E-GEOD-28313 | biostudies-arrayexpress

Diffusible factors released from human prostate carcinoma cells restrained cancer stem cells from contributing to tumor progression

2013-03-01 | GSE28313 | GEO

Comparing gene-expression profiles between bone-metastatic vs. non bone-metastatic human prostate cancer cells

Project description:Disseminated prostate cancer cells colonize the skeleton to progress into macroscopic lesions only if they successfully adapt to the bone microenvironment. We previously reported that the ability of prostate cancer cells to generate skeletal tumors in animal models correlated with the expression of the alpha-receptor for Platelet-Derived Growth Factor (PDGFRa). In this study we aimed to identify PDGFRa-regulated genes responsible for the acquisition of a bone-metastatic prostate phenotype. We performed genome-wide expression comparative analyses of human prostate cancer cell lines that differ for PDGFRa expression and propensity to establish tumors in the skeleton of animal models. We investigated the genes that were differentially regulated in the highly bone-metastatic PC3-ML cells and their low-metastatic counterpart PC3-N cells, and the genes differentially regulated between PC3-N and PC3-N with overexpression of PDGFRa (PC3NRa). We have previously shown that DU-145 cells lack PDGFRa and fail to survive longer than three days as disseminated tumor cells after homing to the mouse bone marrow. Interestingly, and in contrast to PC3-N cells, the exogenous expression of PDGFRa did not promote metastatic bone-tropism of DU-145 cells in our model. Thus, we examined the genes that were differentially regulated between DU-145 and DU-145(Ra) and excluded them from our candidate genes. Finally, to refine our findings and compensate for PC3 and DU-145 genetic disparity, we performed a comparative analysis of the genes differentially regulated between two bone metastatic single-cell progenies that were derived from PC3-ML cells. Seven human prostate cancer cell lines were analyzed in total for this study. Each cell line was analyzed in duplicate from two different passages in culture.

2013-03-30 | E-GEOD-43332 | biostudies-arrayexpress

Expression data from human metastatic adrenocortical carcinoma

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2017-11-24 | GSE90713 | GEO

The Marrow Niche Controls The Cancer Stem Cell Phenotype Of Disseminated Prostate Cancer

Project description:Dissemination of cancer stem cells (CSCs) serves as the basis of metastasis. Recently, we demonstrated that circulating prostate cancer (PCa) targets the hematopoietic stem cell (HSCs) ‘niche’ in marrow during dissemination. Once in the niche, disseminated tumor cells (DTCs) may remain dormant for extended periods. As the major function of the HSC niche is to maintain stem cell functions, we hypothesized that the niche regulates CSC activities of DTCs. We show that DTCs recovered from marrow were significantly enriched for a CSC phenotype. Critically, the conversion of DTCs to CSCs is regulated by niche. The data demonstrate that the niche plays a significant role in maintaining tumor-initiating PCa in marrow and suggests a functional relationship between CSCs and dormancy. Understanding how the marrow niche regulates the conversion of DTCs to CSCs is critical for the development of therapeutics specifically targeting skeletal bone metastasis and dormancy. We used microarrays to determine the global changes in gene expression underlying the significant roles of the marrow niche in activating cancer stem-like cell programs of prostate caner.

2016-01-30 | GSE77379 | GEO

Comparing gene-expression profiles between bone-metastatic vs. non bone-metastatic human prostate cancer cells

2013-03-30 | GSE43332 | GEO

Co-culture of human prostate cancer cells and mouse osteoblasts as a model for tumor dormancy in bone metastasis

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2023-10-23 | GSE210751 | GEO

Gene expression data from MDSC subsets, cell lines and tumor cells

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2016-05-21 | GSE81701 | GEO

Human expression data from iPSCs, motor neurons derived from iPSCs and ESCs, and fetal spinal cords

Project description:We compare transcriptomic profiles of human induced pluripotent stem cells (iPSCs), motor neurons (MNs) in vitro differentiated from iPSCs or human ESCs containing a HB9::GFP reporter for MNs, and human fetal spinal cords. The purpose of this comparison is to assess the extent of molecular similarities between in vitro differentiated MNs and in vivo fetal or adult spinal cord MNs. Data for adult spinal cord MNs are published from other studies: GSE3526, GSE19332, GSE20589, and GSE40438. Human induced pluripotent stem cells, pluripotent stem cell derived motor neurons, and fetal spinal cords for RNA extraction and hybridization on Affymetrix arrays.

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