Introduction: Endoplasmic reticulum (ER) stress signals can be transmitted between cancer cells and tumour-associated cells (e.g., immune cells or stellate cells). This novel concept is known as transmissible ER stress (TERS).
Objective: The aims of this project are to determine the effect of TERS on the proliferation, chemoresistance and migration of pancreatic cancer and pancreatic stellate cells.
Methods and Results: The KPC pancreatic cancer cell line and pancreatic stellate cells (PSCs) were derived from C5BL/6 mice. Both cell types were treated separately with control media or the ER stress inducer Thapsigargin, washed, and new media was added for 16 h to produce conditioned media (CM) or ER stress conditioned media (TgCM). Mass spectrometry was used to confirm there was no Thapsigargin present in the TgCM. TgCM or CM was incubated with the heterologous cell type, alongside relevant controls. In contrast to the CM and control media, TgCM significantly (p<0.001-0.05) induced ER stress in receiver cells of both cell types (i.e., upregulation of BiP, XBP-1s and CHOP). Alamar Blue assays demonstrated that TgCM significantly (p<0.001-0.01) reduced the cellular viability of KPC cells or PSCs at 24 h. TgCM improved the efficacy of the ER stress inducing chemotherapeutic, Bortezomib, at 48 h. Real-Time xCELLligence data showed that both CM and TgCM derived from PSCs increased the migratory capacity of KPC cells at 16 h.
Conclusions: TERS was induced between the KPC cancer cells and the PSC stromal cells. This stress transmission between cells reduced the viability of both cell types. In fact, TERS improved the efficacy of the ER-stress inducing chemotherapeutic Bortezomib. TERS enhanced the migratory capacity of the KPC cancer cells. This demonstrates that TERS communication can impact proliferation, chemoresistance and migration of cancer and stromal cells. Understanding the effect and mechanisms of TERS may provide novel targets and therapeutics.