SK2 channels set a signalling hub bolstering CAF-triggered tumourigenic processes in pancreatic cancer

Abstract

ObjectiveIntercellular communication within pancreatic ductal adenocarcinoma (PDAC) dramatically contributes to metastatic processes. The underlying mechanisms are poorly understood, resulting in a lack of targeted therapy to counteract stromal-induced cancer cell aggressiveness. Here, we investigated whether ion channels, which remain understudied in cancer biology, contribute to intercellular communication in PDAC.DesignWe evaluated the effects of conditioned media from patient-derived cancer-associated fibroblasts (CAFs) on electrical features of pancreatic cancer cells (PCC). The molecular mechanisms were deciphered using a combination of electrophysiology, bioinformatics, molecular and biochemistry techniques in cell lines and human samples. An orthotropic mouse model where CAF and PCC were co-injected was used to evaluate tumour growth and metastasis dissemination. Pharmacological studies were carried out in the Pdx1-Cre, Ink4afl/fl LSL-KrasG12D (KICpdx1) mouse model.ResultsWe report that the K+ channel SK2 expressed in PCC is stimulated by CAF-secreted cues (8.84 vs 2.49 pA/pF) promoting the phosphorylation of the channel through an integrin–epidermal growth factor receptor (EGFR)–AKT (Protein kinase B) axis. SK2 stimulation sets a positive feedback on the signalling pathway, increasing invasiveness in vitro (threefold) and metastasis formation in vivo. The CAF-dependent formation of the signalling hub associating SK2 and AKT requires the sigma-1 receptor chaperone. The pharmacological targeting of Sig-1R abolished CAF-induced activation of SK2, reduced tumour progression and extended the overall survival in mice (11.7 weeks vs 9.5 weeks).ConclusionWe establish a new paradigm in which an ion channel shifts the activation level of a signalling pathway in response to stromal cues, opening a new therapeutic window targeting the formation of ion channel-dependent signalling hubs.

Insights into the mechanisms governing P01 scorpion toxin effect against U87 glioblastoma cells oncogenesis

“…Since P01 is highly active on SK2 channels and neither SK1 nor SK3 channels are expressed on U87 cells, we can suggest that SK2 channels are involved in the U87 cell tumorigenesis. This is in agreement with a recent paper demonstrating that SK2 channel, expressed in pancreatic ductal adenocarcinoma, increased invasiveness and metastasis formation, an effect that depends on cancer-associated fibroblasts (CAF) promoting SK2 phosphorylation through an integrin-epidermal growth factor receptor (EGFR)-AKT (Protein kinase B) axis (Rapetti-Mauss et al, 2022).…”

Plasma membrane SK2 channel activity regulates migration and chemosensitivity of high‐grade serous ovarian cancer cells

“…Finally, LPA can promote ovarian cancer cell migration by activating an epidermal growth factor receptor (EGFR)-dependent pathway. Indeed, it was recently reported that SK2 activity promoted cell migration and invasion in pancreatic cancer cells by enhancing an integrin-EGFR-AKT (Protein kinase B) pathway [22,43].…”

“…SK2 channels were also identified in intracellular compartments, such as mitochondria, the endoplasmic reticulum (ER), or vesicles, and notably controlling cell death [17][18][19][20]. Although there is little information on SKCa channels in cancers, these channels participated in cell proliferation and cell migration [21][22][23]. Our laboratory has described the role of plasma membrane SK3 in breast, melanoma, prostate, and colon cancer cell migration in vitro and in breast cancer metastasis in vivo [14 (p. 20), 15,21,24].…”

“…Our laboratory has described the role of plasma membrane SK3 in breast, melanoma, prostate, and colon cancer cell migration in vitro and in breast cancer metastasis in vivo [14 (p. 20), 15,21,24]. One recent article indicated that plasma membrane SK2 was responsible for pancreatic cancer cell migration and invasion [22] and involved in the proliferation of glioblastoma cells and in hypoxia-induced proliferation of melanoma cells [25,26]. To date, there is no data available on the role of SK2 channels in ovarian cancer cells and chemoresistance.…”

Currently Debated Topics on Surgical Treatment of Pancreatic Ductal Adenocarcinoma: A Narrative Review on Surgical Treatment of Borderline Resectable, Locally Advanced, and Synchronous or Metachronous Oligometastatic Tumor

“…The Fibroblast Activating Protein Inhibitor (FAPI) is a tumor-specific tracer on which we already have important clinical studies. This choice is because, in PDAC, more than 90% of the tumor volume consists of cancer-associated fibroblasts (CAFs) that are associated with the promotion of tumor growth, tissue invasion, metastasis development, immune escape, and resistance to therapy [142][143][144]. Considering the high expression of the FAP on the cell surfaces of CAFs and its limited expression in normal tissue, PET/CT imaging of CAFs with radiolabeled FAP inhibitors is an active field in nuclear medicine [137].…”