Epithelial-to-mesenchymal transition activates PERK-eIF2α and sensitizes cells to endoplasmic reticulum stress.
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.


CONCLUSIONS
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.
Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Yu-Xiong
YX
Feng
Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North CarolinaAuthors' Affiliations:Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina.
Ethan S
ES
Sokol
Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina.
Catherine A
CA
Del Vecchio
Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina.
Sandhya
S
Sanduja
Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina.
Jasper H L
JH
Claessen
Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina.
Theresa A
TA
Proia
Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North CarolinaAuthors' Affiliations:Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina.
Dexter X
DX
Jin
Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina.
Ferenc
F
Reinhardt
Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North CarolinaAuthors' Affiliations:Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina.
Hidde L
HL
Ploegh
Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina.
Qiu
Q
Wang
Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North CarolinaAuthors' Affiliations:Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts pgupta@wi.mit.edu.
Piyush B
PB
Gupta
D051701:Activating Transcription Factor 4 / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics* / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016513:Mice, SCID; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000235:genetics* / Q000378:metabolism
C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D015852:Eukaryotic Initiation Factor-2; D051701:Activating Transcription Factor 4; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase