Hepatocellular adenomas (HCA) are benign liver tumors predominantly developed in women using oral contraceptives. Here, exome sequencing identified recurrent somatic FRK mutations that induce constitutive kinase activity, STAT3 activation, and cell proliferation sensitive to Src inhibitors. We also found uncommon recurrent mutations activating JAK1, gp130, or β-catenin. Chromosome copy number and methylation profiling revealed patterns that correlated with specific gene mutations and tumor phenotypes. Finally, integrative analysis of HCAs transformed to hepatocellular carcinoma revealed β-catenin mutation as an early alteration and TERT promoter mutations as associated with the last step of the adenoma-carcinoma transition. In conclusion, we identified the genomic diversity in benign hepatocyte proliferation, several therapeutic targets, and the key genomic determinants of the adenoma-carcinoma transformation sequence.

We found that spadin, a natural peptide derived from sortilin, blocks the mouse TREK-1 channel and might be an efficient and fast-acting antidepressant.

e ATF6␣, a membrane-anchored transcription factor from the endoplasmic reticulum (ER) that modulates the cellular response to stress as an effector of the unfolded-protein response (UPR), is a key player in the development of tumors of different origin. ATF6␣ activation has been linked to oncogenic transformation and tumor maintenance; however, the mechanism(s) underlying this phenomenon remains elusive. Here, using a phenotypic small interfering RNA (siRNA) screening, we identified a novel role for ATF6␣ in chemoresistance and defined the protein disulfide isomerase A5 (PDIA5) as necessary for ATF6␣ activation upon ER stress. PDIA5 contributed to disulfide bond rearrangement in ATF6␣ under stress conditions, thereby leading to ATF6␣ export from the ER and activation of its target genes. Further analysis of the mechanism demonstrated that PDIA5 promotes ATF6␣ packaging into coat protein complex II (COPII) vesicles and that the PDIA5/ATF6␣ activation loop is essential to confer chemoresistance on cancer cells. Genetic and pharmacological inhibition of the PDIA5/ATF6␣ axis restored sensitivity to the drug treatment. This work defines the mechanisms underlying the role of ATF6␣ activation in carcinogenesis and chemoresistance; furthermore, it identifies PDIA5 as a key regulator ATF6␣-mediated cellular functions in cancer. P rotein folding in the endoplasmic reticulum (ER) can be particularly affected by the presence of mutations in secretory proteins or by dynamic changes in the cellular microenvironment, events which are often encountered in cancers. In the ER, these events are sensed by specific sensors, which in turn trigger select signaling pathways, collectively named the unfolded-protein response (UPR) (1). The UPR is an adaptive response that allows the cells to either overcome the stress or promote cell death in the case of overwhelming burden (1). Three ER-resident proteins, namely, the protein kinase PKR-like ER kinase (PERK), the inositol-requiring protein 1 alpha (IRE1␣), and the activating transcription factor 6 alpha (ATF6␣), have been identified as the major transducers of the UPR in mammals. They display an ER luminal domain that senses misfolded proteins and are activated by a common mechanism involving the dissociation of the ER chaperone BiP/GRP78. PERK is responsible for translational attenuation through the phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2␣) (2). IRE1␣ mediates the unconventional splicing of X-box binding protein 1 (Xbp1) mRNA (3) as well as mRNA expression levels through regulated IRE1␣-dependent mRNA decay (RIDD) (4) and controls the activation of the c-jun N-terminal kinase (JNK) pathway. The third arm of the UPR is controlled by ATF6␣. This membrane-anchored transcription factor is a type II transmembrane protein regulated by intramembrane proteolysis by the Golgi apparatuslocalized site 1 and site 2 proteases (S1P and S2P) upon ER stress (5). Indeed, upon ER stress, BiP dissociates from the luminal domain of ATF6␣, thereby unmaski...