Ion channels in control of pancreatic stellate cell migration.

Hannah Storck,Angela Zaccagnino,Sandra Schimmelpfennig,Benedikt Hild,Ivana Novak,Sarah Sargin,Albrecht Schwab,Nikolaj Nielsen,Thomas Budde,Holger Kalthoff

doi:10.18632/oncotarget.13647

Hannah Storck, Angela Zaccagnino + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.13647

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Abstract

Pancreatic stellate cells (PSCs) play a critical role in the progression of pancreatic ductal adenocarcinoma (PDAC). Once activated, PSCs support proliferation and metastasis of carcinoma cells. PSCs even co-metastasise with carcinoma cells. This requires the ability of PSCs to migrate. In recent years, it has been established that almost all “hallmarks of cancer” such as proliferation or migration/invasion also rely on the expression and function of ion channels. So far, there is only very limited information about the function of ion channels in PSCs. Yet, there is growing evidence that ion channels in stromal cells also contribute to tumor progression. Here we investigated the function of KCa3.1 channels in PSCs. KCa3.1 channels are also found in many tumor cells of different origin. We revealed the functional expression of KCa3.1 channels by means of Western blot, immunofluorescence and patch clamp analysis. The impact of KCa3.1 channel activity on PSC function was determined with live-cell imaging and by measuring the intracellular Ca2+ concentration ([Ca2+]i). KCa3.1 channel blockade or knockout prevents the stimulation of PSC migration and chemotaxis by reducing the [Ca2+]i and calpain activity. KCa3.1 channels functionally cooperate with TRPC3 channels that are upregulated in PDAC stroma. Knockdown of TRPC3 channels largely abolishes the impact of KCa3.1 channels on PSC migration. In summary, our results clearly show that ion channels are crucial players in PSC physiology and pathophysiology.

Highlights

Pancreatic stellate cells (PSCs) constitute a small fraction of cells in the periacinar space that are normally quiescent
The main findings of our study are that (i) pancreatic stellate cells functionally express KCa3.1 channels whose activity (ii) is required for migration by (iii) regulating the [Ca2+]i and thereby (iv) calpain activity
We showed that (v) the role of KCa3.1 channels in cell migration depends on cooperation with transient receptor potential cation channel (TRPC3) channels which are upregulated in the stroma of pancreatic ductal adenocarcinoma (PDAC) tissue samples

Summary

INTRODUCTION

Pancreatic stellate cells (PSCs) constitute a small fraction of cells in the periacinar space that are normally quiescent. PSCs are the predominant mesenchymal cells within the PDAC stroma [4] They are activated by growth factors and cytokines (e.g. PDGF and TGF-β, IL8 and TNF-a) produced by tumor cells or by themselves (autocrine stimulation [5, 6]). Based on the critical role of ion channels in other tumors [18], it is reasonable to predict that they are important drivers of PDAC progression as well. In analogy to other cell types of the tumor stroma it is very likely that altered ion channel expression and function in stimulated PSCs contribute to processes that are critical for PDAC progression such as cell migration and invasion, growth factor signaling, or proliferation and apoptosis [25]. We show that KCa3.1 channels are expressed in PSCs and contribute in cooperation with TRPC3 channels to their migratory activity

RESULTS

DISCUSSION

MATERIALS AND METHODS