Abstract
Epithelial-to-mesenchymal transition (EMT) promotes both tumor progression and drug resistance, yet few vulnerabilities of this state have been identified. 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 findings identify a novel vulnerability of EMT cells, and demonstrate that the PERK branch of the UPR is required for their malignancy. EMT drives tumor metastasis and drug resistance, highlighting the need for therapies that target this malignant subpopulation. Our findings identify a previously unrecognized vulnerability of cancer cells that have undergone an EMT: sensitivity to ER stress. We also find that PERK-eIF2α signaling, which is required to maintain ER homeostasis, is also indispensable for EMT cells to invade and metastasize.
Highlights
Carcinoma cells acquire key malignant traits by reprogramming their differentiation state via an epithelial-to-mesenchymal transition (EMT; refs. 1, 2)
To determine whether increased extracellular matrix (ECM) secretion is a general feature of EMT, we examined the expression of ECM genes identified to be upregulated upon EMT (Fig. 3A) in basal-B and luminal breast cancer lines [35]
Primary cancer cells expressing EMT markers were more sensitive to the endoplasmic reticulum (ER) stressor thapsigargin as indicated by unfolded protein response (UPR) pathway activation (Fig. 7B). Consistent with this, these cells exhibited significantly reduced viability upon treatment with ER stressors (Fig. 7C and Supplementary Fig. S8). To assess whether these findings extended to other tumor types, we analyzed gene-expression microarray data from patient tumors to test for associations between the expression of EMT, ECM, and UPR pathway genes
Summary
Carcinoma cells acquire key malignant traits by reprogramming their differentiation state via an epithelial-to-mesenchymal transition (EMT; refs. 1, 2). EMT cells must remodel the extracellular matrix (ECM) by secreting matrix proteases and large scaffolding proteins that facilitate their migration. These scaffolding proteins, which include collagens, fibronectin (FN1), plasminogen activator inhibitor 1 (PAI1), and periostin 6), interact to form networks that provide tensional forces and signals that are essential for migration. These quaternary interactions are often initiated within the cell before secretion. Collagens are partially assembled into triple-helical fibers within the endoplasmic reticulum (ER) before their secretion into the extracellular space
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