The Activity of Kv 11.1 Potassium Channel Modulates F-Actin Organization During Cell Migration of Pancreatic Ductal Adenocarcinoma Cells.

Sagar Manoli,Matteo Lulli,Thomas Schmidt,Nikolaj Nielsen,Albrecht Schwab,Nirmala Kuppalu,Annarosa Arcangeli,Claudia Duranti,Lara Magni,Andrea Becchetti,Stefano Coppola

doi:10.3390/cancers11020135

Abstract

Cell migration exerts a pivotal role in tumor progression, underlying cell invasion and metastatic spread. The cell migratory program requires f-actin re-organization, generally coordinated with the assembly of focal adhesions. Ion channels are emerging actors in regulating cell migration, through different mechanisms. We studied the role of the voltage dependent potassium channel KV11.1 on cell migration of pancreatic ductal adenocarcinoma (PDAC) cells, focusing on its effects on f-actin organization and dynamics. Cells were cultured either on fibronectin (FN) or on a desmoplastic matrix (DM) with the addition of a conditioned medium produced by pancreatic stellate cells (PSC) maintained in hypoxia (Hypo-PSC-CM), to better mimic the PDAC microenvironment. KV11.1 was essential to maintain stress fibers in a less organized arrangement in cells cultured on FN. When PDAC cells were cultured on DM plus Hypo-PSC-CM, KV11.1 activity determined the organization of cortical f-actin into sparse and long filopodia, and allowed f-actin polymerization at a high speed. In both conditions, blocking KV11.1 impaired PDAC cell migration, and, on cells cultured onto FN, the effect was accompanied by a decrease of basal intracellular Ca2+ concentration. We conclude that KV11.1 is implicated in sustaining pro-metastatic signals in pancreatic cancer, through a reorganization of f-actin in stress fibers and a modulation of filopodia formation and dynamics.

Highlights

Cell migration is a central feature of many physiological processes such as embryonic development, organ differentiation after birth, and the function of immune cells [1,2]
We addressed this point in pancreatic ductal adenocarcinoma (PDAC) cells, since PDAC is characterized by a peculiar desmoplastic and hypoxic tumor microenvironment that triggers a pro-migratory program which accounts for the highly malignant and invasive behavior of this cancer
F-Actin Organization and Migratory Activity of PANC-1, PDAC Cells Cultured on Fibronectin (FN): Role of KV 11.1 Channels

Summary

Introduction

Cell migration is a central feature of many physiological processes such as embryonic development, organ differentiation after birth, and the function of immune cells [1,2]. Cells are triggered to start a motility program by extracellular stimuli, in the form of either soluble molecules or adhesive interactions with the extracellular matrix (ECM). Such stimuli produce cyclical changes in cell adhesion and morphology, which overall underlie crawling motility [4]. Changes in cell morphology are driven by the constant remodeling of filamentous (f)-actin at specific sites, into structures (i.e., filopodia, lamellipodia, and stress fibers) that coordinate cell migration. They are regulated by different, specific signaling pathways [5,6]. The lamellipodium is characterized by a dense network of short, branched actin filaments, driven by activation of the

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