Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Direct Signaling Between Platelets and Cancer Cells Induces an Epithelial-Mesenchymal-Like Transition and Promotes Metastasis

ABSTRACT: Interactions of cancer cells with the primary tumor microenvironment are important determinants of cancer progression towards metastasis but it is unknown whether additional prometastatic signals are provided during the intravascular transit to the site of metastasis. Here, we show that transient platelet-tumor cell interactions are sufficient to prime tumor cells for subsequent metastasis. Platelet-derived TGF-beta and direct platelet-tumor cell contacts synergistically activate the TGF-beta/Smad and NF-kappaB pathways in cancer cells, resulting in their transition to an invasive mesenchymal-like phenotype and enhanced metastasis in vivo. Inhibition of NF-kappaB signaling in cancer cells or ablation of TGF-beta1 expression solely in platelets protects against lung metastasis in vivo. Thus, cancer cells rely on platelet-derived signals outside of the primary tumor for efficient metastasis. MoEx-1_0-st: Five replicates of Ep5 tumor cells cultured alone, five replicates of tumor cells cultured in combination with platelets, and three replicates of tumor cells combined with platelets just prior to RNA isolation to control for the presence of platelet RNAs. MoGene-1_0-st: Three replicates of tumor cells cultured alone, three replicates of tumor cells cultured in combination with platelets, three replicates of tumor cells cultured with centrifuged platelets and three replicates of tumor cells cultured with supernate (releasate) from centrifuged platelets.

ORGANISM(S): Mus musculus

SUBMITTER: Charles Whittaker

PROVIDER: E-GEOD-27456 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis.

Labelle Myriam M Begum Shahinoor S Hynes Richard O RO

Cancer cell 20111101 5

Interactions of cancer cells with the primary tumor microenvironment are important determinants of cancer progression toward metastasis but it is unknown whether additional prometastatic signals are provided during the intravascular transit to the site of metastasis. Here, we show that platelet-tumor cell interactions are sufficient to prime tumor cells for subsequent metastasis. Platelet-derived TGFβ and direct platelet-tumor cell contacts synergistically activate the TGFβ/Smad and NF-κB pathwa ...[more]

PMID: 22094253

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Project description:Despite the high prevalence and poor outcome of patients with metastatic lung cancer, the mechanisms of tumour progression and metastasis remain largely uncharacterized. We modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS1 and inactivation of the p53-pathway2, using conditional alleles in mice3-5. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of KrasLSL-G12D/+;p53flox/flox mice initiates lung adenocarcinoma development4. Although tumours are initiated synchronously by defined genetic alterations, only a subset become malignant, suggesting that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK-2 related homeobox transcription factor Nkx2-1 (Ttf-1/Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1-negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1 regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically-restricted chromatin regulator Hmga2. While focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function6-9, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability, and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor. 23 cell lines derived from primary tumor or metastasis. 6 samples analyzed to determine the effect of Nkx2-1 knockdown on gene expression

Dataset Information

Direct Signaling Between Platelets and Cancer Cells Induces an Epithelial-Mesenchymal-Like Transition and Promotes Metastasis

Publications

Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis.

Similar Datasets

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