Epithelial-to-Mesenchymal Transition Activates PERK–eIF2α and Sensitizes Cells to Endoplasmic Reticulum Stress

Abstract

Epithelial-to-mesenchymal transition (EMT) promotes both tumor progression and drug resistance, yet few vulnerabilities of this state have been identifi ed. Using selective small molecules as cellular probes, we show that induction of EMT greatly sensitizes cells to agents that perturb endoplasmic reticulum (ER) function. This sensitivity to ER perturbations is caused by the synthesis and secretion of large quantities of extracellular matrix (ECM) proteins by EMT cells. Consistent with their increased secretory output, EMT cells display a branched ER morphology and constitutively activate the PERK-eIF2α axis of the unfolded protein response (UPR). Protein kinase RNA-like ER kinase (PERK) activation is also required for EMT cells to invade and metastasize. In human tumor tissues, EMT gene expression correlates strongly with both ECM and PERK-eIF2α genes, but not with other branches of the UPR. Taken together, our fi ndings identify a novel vulnerability of EMT cells, and demonstrate that the PERK branch of the UPR is required for their malignancy. SIGNIFICANCE:EMT drives tumor metastasis and drug resistance, highlighting the need for therapies that target this malignant subpopulation. Our fi ndings identify a previously unrecognized vulnerability of cancer cells that have undergone an EMT: sensitivity to ER stress. We also fi nd that PERK-eIF2α signaling, which is required to maintain ER homeostasis, is also indispensable for EMT cells to invade and metastasize. Cancer Discov; 4(6);

NACA deficiency reveals the crucial role of somite-derived stromal cells in haematopoietic niche formation

“…We found that NACA deficiency does trigger the UPR in zebrafish larvae, and that treatment of naca mutants with the chemical chaperon 4-PBA significantly suppressed SRC apoptosis, and restored CHT haematopoiesis. Interestingly, EMT-derived mesenchymal cells in general were recently shown to be exquisitely sensitive to ER stress-induced apoptosis 30 . This feature was shown to be linked to their high level of extracellular matrix secretory activity, which involves steady ER development.…”

SMARCE1 is required for the invasive progression of in situ cancers

“…In vivo and 3D hydrogel studies were performed as previously described (18,28). All computational analyses, reagents, public datasets used, and other protocols are described in SI Materials and Methods.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…This molecule induces cell death in a CHOP-dependent manner in a number of cell lines, and there is enthusiastic support to develop this molecule for cancer therapy. A recent study also suggests that modulation of ER stress could be a selective target for cancer cells that undergo EMT (Feng et al 2014). During EMT, cells secrete more secretory molecules, such as extracellular matrix proteins, which provokes eIF2α phosphorylation and subsequent ATF4 induction.…”

“…Thus, cells undergoing EMT are more sensitive to ER stress compared with cells without EMT. This selective toxicity of cells stressed by a harsh environment or protein misfolding offers a selective advantage to using these agents to uniquely destroy tumor cells (Feng et al 2014).…”