P-035 - The plasminogen receptor P11 contributes to KRAS-driven invasiveness of pancreatic cancer cells and is upregulated in human pancreatic tumors

Date 04 July 2015
Event WorldGI 2015
Session Posters
Topics Basic Science
Pancreatic Cancer
Pathology/Molecular Biology
Presenter M. Bydoun
Citation Annals of Oncology (2015) 26 (suppl_4): 1-100. 10.1093/annonc/mdv233
Authors M. Bydoun1, W. Huang2, D. Waisman1
  • 1Dalhousie University, Halifax/CA
  • 2QEII Hospital, Halifax/CA

Abstract

Introduction

Despite its rarity, pancreatic cancer (PC) remains the deadliest cancer type among all cancers with a 5-yr survival rate of only 4%. PC patients are often diagnosed late at which point the cancer has spread to other organs and sabotaged their function leading to patient death.

Rationale: The Waisman group has previously shown that the plasminogen receptor p11 is important for cancers to grow and spread to other organs. In fact, p11 is highly active on invasive cancer cells and acts as a “hub” to activate proteolytic enzymes, which allow cancer cells to chew their way through neighboring fibrotic stroma, invade surrounding tissues, and metastasize to distant organs. However, the involvement of p11 in PC has not been addressed.

Methods

Here, the involvement of p11 in PC is being investigated using three different approaches:

1) culturing of human PC cell lines which were depleted of p11 (using RNAi technology) followed by in vitro evaluation of their ability to generate active enzymes (plasmin assays) and invade through an artificial matrix (invasion assays) compared to control cells.

2) utilizing a doxycycline-inducible PC mouse model that closely mimics the dynamics of PC in human patients.

3) examining p11 levels in tumors resected from PC patients admitted to the QEII hospital in Halifax, Nova Scotia, Canada.

Results

To examine whether p11 contributes to PC cell invasion, RNAi technology was used to deplete p11 protein levels. The results demonstrated that depletion of p11 in human PC cells hampers their ability to activate enzymes and invade by over 60%. Interestingly, p11 expression was found to be driven by oncogenic KRAS, a commonly mutated gene in PC (>95% of cases) and a well-established driver of oncogenesis. Immunohistochemical examination of pancreatic tumors isolated from the inducible mouse model revealed that p11 was highly expressed in tumorous ducts compared to normal ducts. This increase in expression along with expression pattern were also observed in tumors isolated from two patients with invasive PC.

Conclusion

In vitro results suggest that p11 contributes to the invasive properties of PC cells via enhancing the production of active proteases. This is further supported by the elevated p11 levels seen in mouse tumor samples as well as in patient samples with invasive PC. Currently, the full contribution of the KRas/p11 axis to PC is being studied using a larger cohort of patient samples (96 resected post-operative tumor samples). This may ultimately position p11 as a “druggable” target and a potential biomarker to predict outcome in newly diagnosed PC patients.