Pancreatic cancer: bioelectricity illuminates intercellular communication within the tumor

Deciphering the relationships between cancer cells and the tumor ecosystem is a major challenge for understanding the development of the disease and identifying therapeutic avenues in pancreatic adenocarcinoma (AdKP), one of the most aggressive solid cancers, with a 5-year survival rate of less than 10%.

In this study, the teams of Olivier Soriani, Professor at Université Côte d’Azur (Nice, iBV, Institut de Biologie Valrose) and Richard Tomasini, Inserm Research Director (Marseille, CRCM, Centre de Recherches sur le Cancer) unveil how a potassium channel (SK2) stimulates the formation of metastases by sensitizing cancer cells to signals from the tumor microenvironment. This work is soon to be published in the journal GUT.

Pancreatic cancer or pancreatic adenocarcinoma (AdKP) is a cancer whose prognosis remains serious with a 5-year survival rate of less than 10%. It is a solid tumor whose particular structure is partly responsible for its resistance to treatment. It is composed of few cancer cells (<20% of cells) dispersed within a very dense, poorly vascularized compartment, the stroma, which is mostly composed of cancer-associated fibroblastic cells (CAF).

CAFs are key elements of the stroma and are derived from normal fibroblasts, which are naturally present in the pancreas. Under the influence of tumor cells, these fibroblasts proliferate, secrete chemical signals and proteins that form a network, the extracellular matrix. This very particular environment controls the tumor cells in return by stimulating their pro-invasive functions. More aggressive, cancer cells form metastases that will colonize distant organs, and in particular the liver.

What are the actors of the dialogue between CAFs and tumor cells?

Olivier Soriani’s team has focused its research on a family of proteins that is still little studied in cancer research, that of ion channels, which includes more than 300 members.

An ion channel is a protein integrated in the cell membrane, allowing the passage of small electrically charged molecules, the ions. The passage of ions through ion channels induces small currents that determine an electric field across the membrane of living cells. This phenomenon of “bioelectricity” is the basis of the transmission of information in many organs such as the nervous system, the heart, the muscles, or the endocrine system.

Three questions are at the basis of this study: Are ion channels involved in the dialogue between CAFs and cancer cells? If so, are they able to control the behavior of cancer cells? Finally, can these channels be targeted specifically in the tumor for therapeutic purposes, without altering the normal function of other organs?

To answer these questions, the Nice researchers of Olivier Soriani’s team, specialists in ion channels, joined forces with Richard Tomasini’s team from Marseille, known for its work on the role of CAFs in pancreatic cancer.

First, they showed that the stimulation of cancer cells by CAFs taken from patients induces an electric current in the tumor cells, generated by the opening of a particular ion channel, the SK2 potassium channel. Moreover, experiments on tumor cells in culture indicate that inhibition of the SK2 channel activity protects them from the pro-invasive influence of CAF. These results are confirmed in vivo, since CAFs are no longer able to induce metastasis in the liver of SK2 channel-deficient mouse models.

Finally, analysis of human pancreatic tumor libraries shows that SK2 channel expression is associated with liver metastasis.

By what mechanism is the SK2 channel able to increase the response of tumor cells to the influence of CAF?

The researchers observed that CAFs, by secreting certain proteins necessary for the formation of the extracellular matrix (collagen and fibronectin), stimulated a signaling pathway in cancer cells that is crucial for tumor aggressiveness: the AKT-dependent pathway, an enzyme that regulates the activity of many cellular proteins. The detailed exploration of this pathway by the Nice researchers revealed two major facts: first, the SK2 channel is a direct target of AKT: it is through this pathway that the channel is activated in the presence of CAF. Second, the channel behaves as a signal amplifier whose activity significantly increases the efficiency of the AKT pathway, and thus the sensitivity of cells to pro-metastatic signals from CAFs. The use of quantitative microscopy techniques has shown that stimulation of tumor cells by CAFs induces physical coupling between SK2 and AKT.

How to act on SK2 without altering the function of the channel in healthy tissues (brain, blood vessels, heart)?

Olivier Soriani’s team has been interested in several years in a protein that helps many ion channels: SigmaR1. SigmaR1 is an intracellular protein expressed in all tissues. Silent under normal conditions, it is activated in injured tissues to accompany partner proteins, thus contributing to the survival of cells under stress. In this way, SigmaR1 contributes to slowing down the progression or limiting cell death in pathologies such as neurodegenerative diseases, strokes, or myocardial infarction.

By analyzing tumors from pancreatic cancer patients, Olivier Soriani and Richard Tomasini noticed that the distribution of SigmaR1 was the same as that of the SK2 channel.

In this configuration, could SigmaR1 contribute to the mobilization of SK2 in pancreatic cancer cells? The answer is positive: the presence of SigmaR1 is even necessary for the stimulation of SK2 by CAFs, and for good reason: it is SigmaR1 that drives the physical association between AKT and the SK2 channel!

The researchers from Nice and Marseille then turned to Patricia Melnyk, a chemist from Lille who specializes in the synthesis of small molecule ligands for targets involved in CNS pathologies, among them SigmaR1. The results obtained with one of the sigma ligands she is developing in her laboratory are extremely promising: this molecule inhibits, in cancer cells, the activation of SK2 by CAFs by preventing the AKT/SK2 association via SigmaR1.

But the most spectacular results were observed in vivo, in a mouse model genetically modified to spontaneously develop pancreatic cancers.

This work demonstrates for the first time the role of ion channels in the dialogue between tumor cells and the actors of their ecosystem. Further studies will clarify the place of this new therapeutic pathway using sigma ligands as an adjuvant to reference treatments or as a first-line treatment. The prospects offered by these results could be extended to other cancers in which the role of the stroma is predominant (breast or colon cancer).