Use of preclinical models for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive cancer most commonly caused by prior exposure to asbestos. Median survival is 12-18 months, since surgery is ineffective and chemotherapy offers minimal benefit. Preclinical models that faithfully recapitulate the genomic and histopathological features of cancer are critical for the development of new treatments. The most commonly used models of MPM are two-dimensional cell lines established from primary tumours or pleural fluid. While these have provided some important insights into MPM biology, these cell models have significant limitations. In order to address some of these limitations, spheroids and microfluidic chips have more recently been used to investigate the role of the three-dimensional environment in MPM. Efforts have also been made to develop animal models of MPM, including asbestos-induced murine tumour models, MPM-prone genetically modified mice and patient-derived xenografts. Here, we discuss the available in vitro and in vivo models of MPM and highlight their strengths and limitations. We discuss how newer technologies, such as the tumour-derived organoids, might allow us to address the limitations of existing models and aid in the identification of effective treatments for this challenging-to-treat disease.MS and JO are supported by BLF-Papworth Fellowships from the British Lung Foundation and the Victor Dahdaleh Foundation. MJG and HEF is supported by the British Lung Foundation and Wellcome Trust grant 206194. RCR is supported by the Cambridge Biomedical Research Centre, Cancer Research UK Cambridge Centre, British Lung Foundation and Royal Papworth Hospital. SJM is supported by the Medical Research Council, British Lung Foundation, Cambridge BRC, Royal Papworth Hospital, and the Alpha1-Foundatio

Biological basis for novel mesothelioma therapies

Funder: British Lung Foundation (BLF); doi: https://doi.org/10.13039/501100000351Funder: Royal Society through a University Research Fellowship and the Engineering and Physical Sciences Research Council (EPRSC)Funder: China Scholarship Council (CSC); doi: https://doi.org/10.13039/501100004543Abstract: Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies

Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation

International audienceAnterior 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

Endoplasmic reticulum proteostasis in glioblastoma-From molecular mechanisms to therapeutic perspectives

International audienceCellular stress induced by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) is a central feature of secretory cells and is observed in many tissues in various diseases, including cancer, diabetes, obesity, and neurodegenerative disorders. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the cytosol and nucleus to restore proteostasis. In the past decade, ER stress has emerged as a major pathway in remodeling gene expression programs that either prevent transformation or provide selective advantage in cancer cells. Controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, UPR signaling is a highly regulated process that leads to an integrated reprogramming of the cell. In this Review, we provide an overview of the regulatory mechanisms underlying UPR signaling and how this pathway modulates cancer progression, particularly the aggressiveness and chemotherapeutic resistance exhibited by glioblastoma, a form of brain cancer. We also discuss the emerging cross-talk between the UPR and related metabolic processes to ensure maintenance of proteostasis, and we highlight possible therapeutic opportunities for targeting the pathway with small molecules

Regulation of tumor-stroma interactions by the unfolded protein response

International audienceThe unfolded protein response (UPR) is a conserved adaptive pathway that helps cells cope with the protein misfolding burden within the endoplasmic reticulum (ER). Imbalance between protein folding demand and capacity in the ER leads to a situation called ER stress that is often observed in highly proliferative and secretory tumor cells. As such, activation of the UPR signaling has emerged as a key adaptive mechanism promoting cancer progression. It is becoming widely acknowledged that, in addition to its intrinsic effect on tumor biology, the UPR can also regulate tumor microenvironment. In this review, we discuss how the UPR coordinates the crosstalk between tumor and stromal cells, such as endothelial cells, normal parenchymal cells, and immune cells. In addition, we further describe the involvement of ER stress signaling in the response to current treatments as well as its impact on antitumor immunity mainly driven by immunogenic cell death. Finally, in this context, we discuss the relevance of targeting ER stress/UPR signaling as a potential anticancer approach

Extracellular AGR3 regulates breast cancer cells migration via Src signaling

International audienceHuman anterior gradient proteins AGR2 and AGR3 are overexpressed in a variety of adenocarcinomas and are often secreted in cancer patients' specimens, which suggests a role for AGR proteins in intra and extracellular compartments. Although these proteins exhibit high sequence homology, AGR2 is predominantly described as a pro-oncogene and a potential prognostic biomarker. However, little is known about the function of AGR3. Therefore, the aim of the present study was to investigate the role of AGR3 in breast cancer. The results demonstrated that breast cancer cells secrete AGR3. Furthermore, it was revealed that extracellular AGR3 (eAGR3) regulates tumor cell adhesion and migration. The current study indicated that the pharmacological and genetic perturbation of Src kinase signaling, through treatment with Dasatinib (protein kinase inhibitor) or investigating cells that express a dominant-negative form of Src, significantly abrogated eAGR3-mediated breast cancer cell migration. Therefore, the results indicated that eAGR3 may control tumor cell migration via activation of Src kinases. The results of the present study indicated that eAGR3 may serve as a microenvironmental signaling molecule in tumor-associated processes

Enhancing Drug Delivery Efficacy Through Bilayer Coating of Zirconium-Based Metal-Organic Frameworks: Sustained Release and Improved Chemical Stability and Cellular Uptake for Cancer Therapy.

Publication status: PublishedThe development of nanoparticle (NP)-based drug carriers has presented an exciting opportunity to address challenges in oncology. Among the 100,000 available possibilities, zirconium-based metal-organic frameworks (MOFs) have emerged as promising candidates in biomedical applications. Zr-MOFs can be easily synthesized as small-size NPs compatible with intravenous injection, whereas the ease of decorating their external surfaces with functional groups allows for targeted treatment. Despite these benefits, Zr-MOFs suffer degradation and aggregation in real, in vivo conditions, whereas the loaded drugs will suffer the burst effect-i.e., the fast release of drugs in less than 48 h. To tackle these issues, we developed a simple but effective bilayer coating strategy in a generic, two-step process. In this work, bilayer-coated MOF NU-901 remained well dispersed in biologically relevant fluids such as buffers and cell growth media. Additionally, the coating enhances the long-term stability of drug-loaded MOFs in water by simultaneously preventing sustained leakage of the drug and aggregation of the MOF particles. We evaluated our materials for the encapsulation and transport of pemetrexed, the standard-of-care chemotherapy in mesothelioma. The bilayer coating allowed for a slowed release of pemetrexed over 7 days, superior to the typical 48 h release found in bare MOFs. This slow release and the related performance were studied in vitro using both A549 lung cancer and 3T mesothelioma cells. Using high-resolution microscopy, we found the successful uptake of bilayer-coated MOFs by the cells with an accumulation in the lysosomes. The pemetrex-loaded NU-901 was indeed cytotoxic to 3T and A549 cancer cells. Finally, we demonstrated the general approach by extending the coating strategy using two additional lipids and four surfactants. This research highlights how a simple yet effective bilayer coating provides new insights into the design of promising MOF-based drug delivery systems

Tamoxifen-Dependent Induction of <i>AGR2</i> Is Associated with Increased Aggressiveness of Endometrial Cancer Cells

<p>Tamoxifen treatment in breast cancer patients is associated with increased risk of endometrial malignancies. Significantly, higher <i>AGR2</i> expression was found in endometrial cancers that developed in women previously treated with tamoxifen compared to those who had not been exposed to tamoxifen. An association of elevated <i>AGR2</i> level with myometrial invasion occurrence and invasion depth was also found. <i>In vitro</i> analyses identified a stimulatory effect of <i>AGR2</i> on cellular proliferation. Although adverse tamoxifen effects on endometrial cells remain elusive, our work identifies elevated <i>AGR2</i> as a candidate tamoxifen-dependent mechanism of action responsible for increased incidence of endometrial cancer.</p

Dual ire1 rnase functions dictate glioblastoma 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 IRE1 alpha (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