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S100P is a metastasis-associated gene that facilitates transendothelial migration of pancreatic cancer cells

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the 5th most common cause of cancer death in the UK and the 4th in the US. The vast majority of deaths following pancreatic cancer are due to metastatic spread, hence understanding the metastatic process is vital for identification of critically needed novel therapeutic targets. An enriched set of 33 genes differentially expressed in common between primary PDAC and liver metastases, when compared to normal tissues, was obtained through global gene expression profiling. This metastasis-associated gene set comprises transcripts from both cancer (S100P, S100A6, AGR2, etc.) and adjacent stroma (collagens type I, III, and V, etc.), thus reinforcing the concept of a continuous crosstalk between the two compartments in both primary tumours and their metastases. The expression of S100P, SFN, VCAN and collagens was further validated in additional primary PDACs and matched liver metastatic lesions, while the functional significance of one of the most highly expressed genes, S100P, was studied in more detail. We show that this protein increases the transendothelial migration of PDAC cancer cells in vitro, which was also confirmed in vivo experiments using a zebrafish embryo model. Thus S100P facilitates cancer cell intravasation/extravasation, critical steps in the hematogenous dissemination of pancreatic cancer cells.

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Acknowledgments

We thank G. Elia for help with collagen staining and Prof. I. Hart for critical reading of the manuscript. This work is funded by the Barts and the London Charitable Foundation (SB), Cancer Research UK C355/A6253 (CC, TCJ, NRL) and HEFCE (TCJ). We are grateful to Dr. Iacobuzio-Donahue for kindly providing us with pancreatic cancer primary and liver metastatic samples from the GICRMDP at John Hopkins University, Baltimore, USA.

Conflicts of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK

    Sayka Barry, Claude Chelala, Kate Lines, Nicholas R. Lemoine & Tatjana Crnogorac-Jurcevic

  2. First Department of Surgery, Tohoku University School of Medicine, Sendai, Japan

    Makoto Sunamura

  3. Immunology Department, Imperial College, London, UK

    Amu Wang

  4. Centre for Biochemical Pharmacology, William Harvey Heart Centre, Barts and the London SMD, Queen Mary University of London, London, EC1M 6BQ, UK

    Federica M. Marelli-Berg

  5. School of Biological Sciences, Queen Mary University of London, Mile End Road, London, E1 4NS, UK

    Caroline Brennan

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  1. Sayka Barry
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  2. Claude Chelala
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  3. Kate Lines
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Correspondence to Tatjana Crnogorac-Jurcevic.

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Sayka Barry and Claude Chelala equally contributed to this study.

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Supplementary Fig. 1

Dendrogram displaying clustering of analysed tissue specimens. It is evident that normal liver (NL1-3, NL2-3 representing technical replicates; all underlined yellow), normal pancreas (N1-3; all underlined blue), pancreatic cancer (P1/2/5/6; underlined violet) and liver metastatic (M1-5; underlined dark blue) samples cluster separately, with normal liver forming the most distant group. The distance between the liver metastases and PDAC was probably potentiated by the fact that the samples were not matched. Of note, out of an initial 12 liver metastatic samples, seven did not pass through the RNA quality control assessments and three out of seven PDAC samples did not pass through the Affymetrix quality control assessment for data analysis and were therefore omitted from further analysis (PDF 111 kb)

Supplementary Fig. 2

Collagen expression in normal pancreas and primary PDAC. A Dense, organised collagen fibres are seen surrounding normal ducts and PanIN lesions (I, IV ×50; II, V ×100; III, VI ×200); pancreatic cancer displaying heterogeneous regions with differing amounts of less well organised collagens (VII, X ×50; VIII, XI ×100; IX, XII ×200) (PDF 396 kb)

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Barry, S., Chelala, C., Lines, K. et al. S100P is a metastasis-associated gene that facilitates transendothelial migration of pancreatic cancer cells. Clin Exp Metastasis 30, 251–264 (2013). https://doi.org/10.1007/s10585-012-9532-y

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  • DOI: https://doi.org/10.1007/s10585-012-9532-y

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