Dataset Information

Wnt5a Drives The State Transition To An Invasive Phenotype In Human Glioblastoma Cancer Stem Cells

ABSTRACT: Numerous pathways underlie brain invasion by tumors, a critical element underpinning recurrence and lethality in human glioblastomas (hGBMs). The identification of the master factors that elicit these pathways globally, driving invasion altogether, eludes us. We report that high expression levels of non-canonical Wnt5a characterize the most invasive gliomas, epitomize dismal prognosis and discriminate the most infiltrating mesenchymal hGBMs from proneural and classical ones. Exacerbated Wnt5a defines mesenchymal hGBM cells (Wnt5aHigh) possessing prototypical invasiveness and tumor-promoting stem-like characteristics (TPCs), but not their Wnt5aLow siblings. While inhibition of Wnt5a suppresses infiltration in mesenchymal hGBM TPCs, administration or over-expression of Wnt5a elicits the opposite effects, turning on infiltrative “mesenchymal-like” molecular programs in poorly motile, classical hGBM TPCs and Wnt5aLow mesenchymal TPCs, ex vivo and intracranially. Anti-Wnt5a antibodies or antagonist Wnt5a peptides block invasion, increasing survival in clinically relevant intracranial hGBM models. Wnt5a emerges as a master regulator in gliomatous invasion, endowing hGBM TPCs with archetypal, infiltratory transcriptional and functional profiles, providing a unique target to tackle brain invasion by hGBM cancer stem cells. Overall design: A total of 12 samples were analyzed. Each experimental group was made of two biological replicates. Each biological replicate had two technical replicates. Sorted hGBM specimens were compared with unsorted hGBM specimens.

INSTRUMENT(S): [HTA-2_0] Affymetrix Human Transcriptome Array 2.0 [transcript (gene) version]

SUBMITTER: Tommaso Mazza

PROVIDER: GSE76422 | GEO | 2017-03-07

SECONDARY ACCESSION(S): PRJNA307251

REPOSITORIES: GEO

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Dataset's files

Source:

			Action	DRS
	GSE76422_Additonal_Probeset_information.txt.gz	Txt
	GSE76422_HTA-2_0.na35.hg19.probeset.csv.zip.gz	Csv
	GSE76422_HTA-2_0.na35.hg19.transcript.csv.gz	Csv
	GSE76422_RAW.tar	Raw
	GSE76422_normalized_data_all_na35.hg19.txt.gz	Txt

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Publications

Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells.

Binda Elena E Visioli Alberto A Giani Fabrizio F Trivieri Nadia N Palumbo Orazio O Restelli Silvia S Dezi Fabio F Mazza Tommaso T Fusilli Caterina C Legnani Federico F Carella Massimo M Di Meco Francesco F Duggal Rohit R Vescovi Angelo L AL

Cancer research 20161223 4

Brain invasion by glioblastoma determines prognosis, recurrence, and lethality in patients, but no master factor coordinating the invasive properties of glioblastoma has been identified. Here we report evidence favoring such a role for the noncanonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal glioblastoma from poorly motile proneural and classical g ...[more]

PMID: 28011620

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Project description:Wnt5a is a non-canonical secreted glycoprotein of the Wnt family that plays an important role in cancer development and progression. Previous studies report that Wnt5a is upregulated in prostate cancer and suggested that Wnt5a affects migration and invasion of prostate tumor cell. This study aimed to evaluate the prognostic value of Wnt5a protein expression in prostate cancer tissue and its potential to predict outcome after radical prostatectomy in patients with localized prostate cancer.Immunohistochemical analysis of a tissue microarray containing prostate specimens of 503 patients with localized prostate cancer showed significantly higher Wnt5a protein expression in cancer compared to benign cores from the same patients (p<0.0001). Patients with high expression of Wnt5a protein had significantly better outcome in terms of time to biochemical recurrence compared to patients with low expression levels (p?=?0.001, 95%CI 1.361-3.570, Hazard's ratio 2.204). A combination of high Wnt5a expression with low levels of Ki-67 or androgen receptor expression had even better outcome compared to all other groups. Furthermore, we found that Wnt5a expression significantly correlated with VEGF and with Ki-67 and androgen receptor expression, although not highly significant. In vitro, we demonstrated that recombinant Wnt5a decreased invasion of 22Rv1 and DU145 cells and that siRNA knockdown of endogenous Wnt5a protein led to increased invasion of 22Rv1 and LNCaP cells.We demonstrate that preserved overexpression of Wnt5a protein in patients with localized prostate cancer predicts a favorable outcome after surgery. This finding together with our in vitro data demonstrating the ability of Wnt5a to impair the invasive properties of prostate cancer cells, suggests a tumor suppressing effect of Wnt5a in localized prostate cancer. These results indicate that Wnt5a can be used as a predictive marker and that it also is a plausible therapeutic target for treatment of localized prostate cancer.