Dataset Information

Selective activation of PERK signaling mediates fibroblast education and tumor progression by a CRELD2-dependent mechanism

ABSTRACT: It is now well-accepted that cancers co-opt the microenvironment to support their growth. However, the molecular mechanisms underlying cancer-microenvironment interactions remain poorly defined. We have found that Rho-associated kinase (ROCK) activity in the epithelial component of mammary tumors selectively actuates Protein kinase R-like endoplasmic reticulum kinase (Perk), causing the recruitment and persistent education of tumor-promoting cancer-associated fibroblasts (CAFs), a key component of the cancer microenvironment. Analysis of tumors from mice and human patients identified Cysteine-rich with EGF-like domains 2 (CRELD2), as the paracrine factor underlying PERK-mediated CAF-education downstream of ROCK. CRELD2 expression was found to be regulated by ATF4 downstream of the PERK pathway and knock-down of CRELD2 prevented tumor progression, demonstrating that the paracrine ROCK-PERK-ATF4-CRELD2 axis is a promoter of breast cancer progression and suggesting new therapeutic opportunities.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Suspension Culture, Fibroblast

DISEASE(S): Breast Cancer

SUBMITTER: Jarrod Sandow

LAB HEAD: Michael Samuel

PROVIDER: PXD018253 | Pride | 2020-05-27

REPOSITORIES: Pride

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Publications

ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism.

Boyle Sarah Theresa ST Poltavets Valentina V Kular Jasreen J Pyne Natasha Theresa NT Sandow Jarrod John JJ Lewis Alexander Charles AC Murphy Kendelle Joan KJ Kolesnikoff Natasha N Moretti Paul Andre Bartholomew PAB Tea Melinda Nay MN Tergaonkar Vinay V Timpson Paul P Pitson Stuart Maxwell SM Webb Andrew Ian AI Whitfield Robert John RJ Lopez Angel Francisco AF Kochetkova Marina M Samuel Michael Susithiran MS

Nature cell biology 20200525 7

It is well accepted that cancers co-opt the microenvironment for their growth. However, the molecular mechanisms that underlie cancer-microenvironment interactions are still poorly defined. Here, we show that Rho-associated kinase (ROCK) in the mammary tumour epithelium selectively actuates protein-kinase-R-like endoplasmic reticulum kinase (PERK), causing the recruitment and persistent education of tumour-promoting cancer-associated fibroblasts (CAFs), which are part of the cancer microenvironm ...[more]

PMID: 32451439

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Project description:Disruptions of protein homeostasis in the endoplasmic reticulum (ER) elicit activation of the unfolded protein response (UPR), a translation- and transcription-coupled proteostatic stress response pathway. The primary translational control arm of the UPR is initiated by the PERK-dependent phosphorylation of eIF2Î±, leading to a large-scale reprogramming of translation and subsequent activation of an ATF4-mediated transcriptional program. It has remained challenging, however, to accurately evaluate the contribution of each component of the eIF2Î±/ATF4 pathway to the remodelling of transcription and translation. Here, we have used mouse embryonic fibroblasts containing either a knock-in of the non-phosphorylatable eIF2Î± S51A mutant or knock-out for ATF4 by ribosome profiling and mRNA-seq to define the specific contributions of eIF2Î± phosphoryation and ATF4 in controlling the translational and transcriptional components of the UPR. These studies show that the transcriptional and translational targets of each P-eIF2Î±, ATF4, and the other UPR gene expression programs overlapped extensively, leading to a core set of UPR genes whose robust expression in response to ER stress is driven by multiple mechanisms. The identification of other, more factor-specific targets illustrated the potential for functional specialization of the UPR. As the UPR progressed temporally, cells employed distinct combinations of transcriptional and translational mechanisms, initiated by different factors, to adapt to ongoing stress. These effects were accompanied by a buffering effect where changes in mRNA levels were coupled to opposing changes in ribosome loading, a property which makes cooperation between transcription and translation essential to confer robust protein expression. Translational analysis by ribosome profiling and mRNA-seq of PERK pathways mutants during the UPR. Mouse embryonic fibroblasts (MEFs) lacking components of the PERK pathway (eIF2a phosphorylation and ATF4) were subjected to ER stress and analyzed by ribosome profiling.

Dataset Information

Selective activation of PERK signaling mediates fibroblast education and tumor progression by a CRELD2-dependent mechanism

Publications

ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism.

Similar Datasets

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