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CD90 is a membrane GPI-anchored protein with one Ig V-type superfamily domain that was initially described in mouse T cells. Besides the specific expression pattern and functions of CD90 that were described in normal tissues, i.e., neurons, fibroblasts and T cells, increasing evidences are currently highlighting the possible involvement of CD90 in cancer. This review first provides a brief overview on CD90 gene, mRNA and protein features and then describes the established links between CD90 and cancer. Finally, we report newly uncovered functional connections between CD90 and endoplasmic reticulum (ER) stress signaling and discuss their potential impact on cancer development.

Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1‐dependent decay (RIDD) of RNA. Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1‐dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression. Synopsis The IRE1 arm of the Unfolded Protein Response (UPR) plays a major role in cancer development. Dissecting IRE1 signals in human glioblastoma tumors, primary and established cell lines reveals the dual role of XBP1 mRNA splicing and RIDD in tumor aggressiveness. GBM tumors cluster into two groups exhibiting low or high IRE1 activity. XBP1s elicits pro‐tumorigenic signals and promotes angiogenesis and macrophage recruitment to the tumor. RIDD dampens angiogenesis and tumor cell migration. Patients bearing tumors with high XBP1s low RIDD features show lower survival than those with low XBP1s high RIDD, thereby providing potential therapeutic avenues. Graphical Abstract The IRE1 arm of the Unfolded Protein Response (UPR) plays a major role in cancer development. Dissecting IRE1 signals in human glioblastoma tumors, primary and established cell lines reveals the dual role of XBP1 mRNA splicing and RIDD in tumor aggressiveness.

Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein–protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses. Synopsis This study provides molecular insights into the anterior gradient 2 (AGR2) mode of action in the endoplasmic reticulum (ER) with an emphasis on the regulation of AGR2 dimers. Dysregulation of AGR2 dimer formation leads to inflammation as seen in inflammatory bowel disease (IBD) and Crohn's disease. AGR2 is a chaperone involved in the regulation of protein quality control in the ER. We have developed and used a novel cellular protein‐protein interaction screen to identify cellular regulators of AGR2 dimerization. We identify specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. Modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of AGR2, respectively. In IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses. Graphical Abstract This study provides molecular insights into the anterior gradient 2 (AGR2) mode of action in the endoplasmic reticulum (ER) with an emphasis on the regulation of AGR2 dimers. Dysregulation of AGR2 dimer formation leads to inflammation as seen in inflammatory bowel disease (IBD) and Crohn's disease.

The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis. Cancer cells multiply abnormally fast and therefore produce protein molecules faster than normal cells. To avoid becoming stressed by this overproduction, cancer cells make use of proteins that fold the new proteins inside the cell. One of these protein folders is called anterior gradient-2 (or AGR2 for short) and is produced at high levels in so-called epithelial cancers, such as breast and lung cancer. Previous research has shown that AGR2 inside cancer cells can help them grow and survive and AGR2 can also be found outside cells, such as in the blood or the urine of cancer patients. Therefore some researchers have suggested that measuring the levels of AGR2 in bodily fluids may be a useful marker for detecting cancers. Fessart et al. hypothesized that – apart from becoming a promising diagnostic tool – the AGR2 protein itself, specifically when found outside cells, might make cancer cells more aggressive. Fessart et al. used a range of techniques to test this hypothesis. For example, healthy lung cells and lung cancer cells were grown into miniature replicas of lung organs in the laboratory, and in a key experiment, AGR2 was added to the lung organoids grown from the healthy cells. The addition of AGR2 protein was enough to change the non-tumor organoids into tumor organoids and boosted their growth about ten-fold. Further experiments then revealed that AGR2 also makes cells more invasive and capable of moving, both important features of aggressive cancer cells. Overall, Fessart et al. have proven that AGR2 is a signalling molecule found outside cancer cells that makes them more aggressive. In future, more research addressing how AGR2 achieves this may lead to new therapeutic strategies against some forms of cancer.

Background Glioblastoma (GB) is a highly invasive primary brain tumor that nearly always systematically recurs at the site of resection despite aggressive radio-chemotherapy. Previously, we reported a gene expression signature related to tumor infiltration. Within this signature, the EMX2 gene encodes a homeodomain transcription factor that we found was down regulated in glioblastoma. As EMX2 is reported to play a role in carcinogenesis, we investigated the impact of EMX2 overexpression in glioma-related cell lines. Methods For that purpose, we constructed tetracycline-inducible EMX2 expression lines. Transfected cell phenotypes (proliferation, cell death and cell cycle) were assessed in time-course experiments. Results Restoration of EMX2 expression in U87 glioblastoma cells significantly inhibited cell proliferation. This inhibition was reversible after EMX2 removal from cells. EMX2-induced proliferative inhibition was very likely due to cell cycle arrest in G1/S transition and was not accompanied by signs of cell death. Conclusion Our results suggest that EMX2 may constitute a putative therapeutic target for GB treatment. Further studies are required to decipher the gene networks and transduction signals involved in EMX2’s effect on cell proliferation.

The legend to Fig 8A has been updated from “Western blot analysis of the expression of WT or Q780* IRE1 in RNS85, RNS87, RNS96, and RNS130 primary GBM lines.” The reference to Appendix Fig S8C has been added to and updated from “The lines were selected on the basis of IRE1 mRNA expression (Appendix Fig S8A) and then analyzed by Western blot with anti-IRE1 antibodies (Fig 8A). Subsequently, Western blot using IRE1 antibodies was performed on the corresponding lysates to look for the presence of (A) an increased intensity band in the case of the WT overexpression and the presence of an additional band in the case of Q780* overexpression.

Glioblastoma (GB) is a highly infiltrative tumor recurring in 90% of cases within a few centimeters of the resection cavity, even in cases of complete tumor resection and adjuvant chemo/radiotherapy. This observation highlights the importance of understanding this special zone of brain tissue surrounding the tumor. It is becoming clear that the nonneoplastic stromal compartment of most solid cancers plays an active role in tumor proliferation, invasion, and metastasis. Very little information, other than that concerning angiogenesis and immune cells, has been collected for stromal cells from GB. As part of a translational research program, we have isolated a new stromal cell population surrounding GB by computer-guided stereotaxic biopsies and primary culture. We named these cells GB-associated stromal cells (GASCs). GASCs are diploid, do not display the genomic alterations typical of GB cells, and have phenotypic and functional properties in common with the cancer-associated fibroblasts (CAFs) described in the stroma of carcinomas. In particular, GASCs express markers associated with CAFs such as fibroblast surface protein, alpha-smooth muscle actin (α-SMA), and platelet-derived growth factor receptor-beta (PDGFRβ). Furthermore, GASCs have a molecular expression profile different from that of control stromal cells derived from non-GB peripheral brain tissues. GASCs were also found to have tumor-promoting effects on glioma cells in vitro and in vivo. The isolation of GASCs in a tumor of neuroepithelial origin was unexpected, and further studies are required to determine their potential as a target for antiglioma treatment.

Graphical Abstract

High grade gliomas (HGG) including glioblastomas (GBM) are the most common and devastating primary brain tumours. Despite important progresses in GBM treatment that currently includes surgery combined to radio‐ and chemotherapy, GBM patients′ prognosis remains very poor. Immunotherapy is one of the new promising therapeutic approaches that can specifically target tumour cells. Such an approach could also maintain long term antitumour responses without inducing neurologic defects. Since the past 25 years, adoptive and active immunotherapies using lymphokine‐activated killer cells, cytotoxic T cells, tumour‐infiltrating lymphocytes, autologous tumour cells, and dendritic cells have been tested in phase I/II clinical trials with HGG patients. This paper inventories these cellular immunotherapeutic strategies and discusses their efficacy, limits, and future perspectives for optimizing the treatment to achieve clinical benefits for GBM patients.

Endoplasmic reticulum stress can drive chronic pain, revealing a new target The control of chronic pain has become a major public health concern because frequent prescriptions for opioids to control pain leads to increasing risks for abuse and overdose-related deaths. Therefore, in order to develop new therapeutic approaches that are as efficient as current treatments but with reduced adverse effects, a better understanding of the underlying cellular and molecular mechanisms involved in chronic pain is required. On page 248 of this issue, Chopra et al. ( 1 ) demonstrate that signaling by inositol-requiring enzyme 1α (IRE1α)–X-box binding protein spliced (XBP1s), which is induced by endoplasmic reticulum (ER) stress, enhances prostaglandin synthesis and release by myeloid cells, contributing to chronic pain in mouse models. This study reveals a new therapeutic approach for attenuating chronic pain behavior.