Unknown,Transcriptomics,Genomics,Proteomics

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Spatial regulation of the glycocalyx component Podocalyxin is a switch for pro-metastatic function

ABSTRACT: The sialomucin Podocalyxin (PODXL) is required for normal tissue development and apicobasal cell polarity by promoting lumen formation. Strikingly, high PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumour types, such as prostate cancer. Utilising prostate cancer cell lines that have the highest RNA levels of PODXL (PC3), we identified subpopulations that do not differ drastically in their overall expression of PODXL but have the stable feature of either high or low surface localisation of PODXL. High surface PODXL promote robust invasion of cells into extracellular matrix. Notably, knockdown of PODXL gave the same effect - reduced invasion - as having PODXL expressed but not being localised to the surface. We performed transcriptional profiling via RNA-sequencing of PC3 cells (PC3 parental, PC3 High surface PODXL and PC3 Low surface PODXL) to uncover possible regulators of PODXL surface expression.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: Alvaro Roman-Fernandex

PROVIDER: E-MTAB-11793 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Inhibitors of Wnt signaling have been previously shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts (OBSOSTKO) promotes PC invasion while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells as quantified by TOPFLASH reporter and b-catenin activity, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts up-regulated under highly invasive conditions. Following further analysis we found that CRIM1 increases PC3 invasion, complexes with b-catenin, and promotes cell-adhesion, suggesting that elevated Wnt signaling secreted from the bone may promote PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of metastatic cancer cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via tail vein did not readily metastasize in NSG xenografts, suggesting that targeting the molecular bone environment may influence bone metastatic outcome in clinical settings. PC3 cells were cultured for 48 hours in specified conditions prior to RNA extraction and hybridization on Affymetrix Human Genome U133 Plus 2.0 Array. All experiments were performed in at least duplicates. Total RNA was collected from PC3 cells cultured in normal growth media, cocultured with WT mouse osteoblasts supplemented with recombinant human DKK1, cells cocultured with WT mouse osteoblasts supplemented with recombinant human SOST, or cocultured with SostKO mouse osteoblasts.

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Spatial regulation of the glycocalyx component Podocalyxin is a switch for pro-metastatic function

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