Matrisomics: Beyond the extracellular matrix for unveiling tumor microenvironment.

The matrisome, a group of proteins constituting or interacting with the extracellular matrix (ECM), has garnered attention as a potent regulator of cancer progression. An increasing number of studies have focused on cancer matrisome utilizing diverse -omics approaches. Here, we present diverse patterns of matrisomal populations within cancer tissues, exploring recent -omics studies spanning different '-omics' levels (epigenomics, genomics, transcriptomics, and proteomics), as well as newly developed sequencing techniques such as single-cell RNA sequencing and spatial transcriptomics. Some matrisome genes showed uniform patterns of upregulated or downregulated expression across various cancers, while others displayed different expression patterns according to the cancer types. This matrisomal dysregulation in cancer was further examined according to their originating cell type and spatial location in the tumor tissue. Experimental studies were also collected to demonstrate the identified roles of matrisome genes during cancer progression. Interestingly, many studies on cancer matrisome have suggested matrisome genes as effective biomarkers in cancer research. Although the specific mechanisms and clinical applications of cancer matrisome have not yet been fully elucidated, recent techniques and analyses on cancer matrisomics have emphasized their biological importance in cancer progression and their clinical implications in deciding the efficacy of cancer treatment.

Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells.

Auranofin (AF), a gold (I)-containing phosphine compound, is being investigated for oncological application as a repurposed drug. We show here that 4~5 µM AF induces paraptosis, a non-apoptotic cell death mode characterized by dilation of the endoplasmic reticulum (ER) and mitochondria, in breast cancer cells. Although the covalent inhibition of thioredoxin reductase (TrxR), an enzyme that critically controls intracellular redox homeostasis, is considered the primary mechanism of AF's anticancer activity, knockdown of TrxR1 did not induce paraptosis. Instead, both TrxR1 knockdown plus the proteasome inhibitor (PI), bortezomib (Bz), and 2 µM AF plus Bz induced paraptosis, thereby mimicking the effect of 5 µM AF. These results suggest that the paraptosis induced by 5 µM AF requires the inhibition of both TrxR1 and proteasome. We found that TrxR1 knockdown/Bz or subtoxic doses of AF and Bz induced paraptosis selectively in breast cancer cells, sparing non-transformed MCF10A cells, whereas 4~5 µM AF killed both cancer and MCF10A cells. GSH depletion was found to be more critical than ROS generation for the paraptosis induced by dual TrxR1/proteasome inhibition. In this process, the ATF4/CHAC1 (glutathione-specific gamma-glutamylcyclotransferase 1) axis leads to GSH degradation, contributing to proteotoxic stress possibly due to the accumulation of misfolded thiol-containing proteins. These results suggest that the paraptosis-inducing strategy of AF plus a PI may provide an effective therapeutic strategy against pro-apoptotic therapy-resistant cancers and reduce the potential side effects associated with high-dose AF.

ISRIB plus bortezomib triggers paraptosis in breast cancer cells via enhanced translation and subsequent proteotoxic stress.

Despite the success of proteasome inhibitors (PIs) in treating hematopoietic malignancies, including multiple myeloma (MM), their clinical efficacy is limited in solid tumors. In this study, we investigated the involvement of the integrated stress response (ISR), a central cellular adaptive program that responds to proteostatic defects by tuning protein synthesis rates, in determining the fates of cells treated with PI, bortezomib (Bz). We found that Bz induces ISR, and this can be reversed by ISRIB, a small molecule that restores eIF2B-mediated translation during ISR, in both Bz-sensitive MM cells and Bz-insensitive breast cancer cells. Interestingly, while ISRIB protected MM cells from Bz-induced apoptosis, it enhanced Bz sensitivity in breast cancer cells by inducing paraptosis, the cell death mode that is accompanied by dilation of the endoplasmic reticulum (ER) and mitochondria. Combined treatment with ISRIB and Bz may shift the fate of Bz-insensitive cancer cells toward paraptosis by inducing translational rescue, leading to irresolvable proteotoxic stress.

The Frequency of Axial Deposition in Korean Patients With Gout at a Tertiary Spine Center.

Objectives: This study aimed to describe the frequency of axial deposition (axial gout) and determine the associated factors in patients with gout who presented to a spine clinic in Korea. Methods: We enrolled 95 Korean patients who visited our spine center from March 2012 to February 2016 and who had been previously diagnosed with gout and had available computed tomography (CT) images of the vertebral columns. Axial gout was defined as the presence of erosions or tophi in the vertebral endplate or facet joint. The clinical and laboratory data of these patients were retrieved from medical records. Results: Out of 95 patients, 15 [15.8%; 95% confidence interval (CI), 9.4-25.0%] had a conventional CT evidence suggestive of axial gout. In these 15 patients, 12 (80%) had lumbar spine involvement (95% CI, 51.4-94.7%). Fifteen patients had erosions of the vertebral column, and two presented with tophi that exhibited erosive changes of the facet joints. The presence of axial gout was not associated with the patients' age, duration of gout, laboratory findings, inflammatory back pain symptoms, identification of monosodium urate crystals in the peripheral joints, current use of urate-lowering drugs, hypertension, and end-stage renal disease; however, there was a significant association with the presence of diabetes (P = 0.008). Conclusions: The frequency of axial deposition in Korean patients with gout and spinal symptoms was 15.8%, with the lumbar region being the most commonly involved section of the spine. In addition, diabetes was associated with evidence of axial gout on imaging.

Comparison of Clinical Outcomes between Idiopathic Frozen Shoulder and Diabetic Frozen Shoulder After a Single Ultrasound-Guided Intra-Articular Corticosteroid Injection.

There is no consensus on the use of intra-articular corticosteroid injections in diabetic frozen shoulder (FS). Thus, we aimed to compare clinical outcomes after intra-articular corticosteroid injections in patients with diabetic FS and idiopathic FS. Data collected from 142 FS patients who received glenohumeral joint intra-articular corticosteroid injections were retrospectively reviewed. Thirty-two patients were diagnosed with diabetic FS and 110 patients with idiopathic FS. Data including visual analog scale (VAS) for pain, American Shoulder and Elbow Surgeons (ASES) score, subjective shoulder value (SSV), and passive range of motion (ROM) were compared before the injection and at 3, 6, and 12 weeks after the injection. There were significant improvements in all outcomes (p < 0.001 for all parameters) through 12 weeks in both groups. There were no significant differences in all outcomes, except for ASES scores, between both groups at 3 weeks. However, there were significant differences in VAS score, SSVs, ASES scores, and passive ROMs, except for angle of abduction, between the two groups at 6 weeks and 12 weeks after injection. A single intra-articular steroid injection can be used as a conservative treatment for diabetic FS, but less effective than for idiopathic FS.