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BackgroundSignet ring cell carcinoma (SRCC) is a particular histologic variant of gastric cancer (GC). However, the critical factor related to the aggressive characteristics of SRCC has not been determined.MethodsWe collected surgically resected tissues from 360 GC patients in the Kumamoto University cohort and generated survival curves via the Kaplan–Meier method. In vitro, we identified the specific transcript variant of MUC20 in SRCC cells by direct sequencing and investigated the role of MUC20 in GC progression using GC cells with MUC20 silencing and forced expression. In vivo, we examined chemoresistance using MUC20 variant 2 (MUC20v2)-overexpressing non-SRCC cells to construct a xenograft mouse model.ResultsWe analyzed a comprehensive GC cell line database to identify the specifically expressed genes in gastric SRCC. We focused on MUC20 and investigated its role in GC progression. Survival analysis revealed that GC patients with high MUC20 expression exhibited a poor prognosis and that MUC20 expression was significantly correlated with SRCC histological type. Moreover, we found that gastric SRCC cells specifically expressed MUC20v2, which was dominantly expressed in the cytoplasm. Silencing MUC20v2 caused cell death with characteristic morphological changes in gastric SRCC cells. To further determine the types of cell death, we examined apoptosis, pyroptosis and ferroptosis by detecting cleaved PARP, gasdermin E-N-terminal (GSDME-N), and lipid reactive oxygen species (ROS) levels, respectively. We found that apoptosis and pyroptosis occurred in MUC20-silenced gastric SRCC cells. In addition, MUC20v2-overexpressing GC cells exhibited chemoresistance to cisplatin (CDDP) and paclitaxel (PTX). RNA sequencing revealed that the pathways involved in intracellular calcium regulation were significantly upregulated in MUC20v2-overexpressing GC cells. Notably, forced expression of MUC20v2 in the cytoplasm of GC cells led to the maintenance of mitochondrial calcium homeostasis and mitochondrial membrane potential (MMP), which promoted cell survival and chemoresistance by suppressing apoptosis and pyroptosis. Finally, we investigated the significance of MUC20v2 in a xenograft model treated with CDDP and showed that MUC20v2 overexpression caused chemoresistance by inhibiting cell death.ConclusionThese findings highlight the novel functions of MUC20v2, which may confer cell survival and drug resistance in GC cells.SignificanceMUC20v2 protects GC cells from apoptosis and pyroptosis by maintaining mitochondrial calcium levels and mitochondrial membrane potential and subsequently induces drug resistance.

The arachidonic acid cascade is a major inflammatory pathway that produces prostaglandin E2 (PGE2). Although inhibition of 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) is reported to lead to PGE2 accumulation, the role of 15‐PGDH expression in the tumor microenvironment remains unclear. We utilized Panc02 murine pancreatic cancer cells for orthotopic transplantation into wild‐type and 15‐pgdh+/− mice and found that 15‐pgdh depletion in the tumor microenvironment leads to enhanced tumorigenesis accompanied by an increase in cancer‐associated fibroblasts (CAFs) and the promotion of fibrosis. The fibrotic tumor microenvironment is widely considered to be hypovascular; however, we found that the angiogenesis level is maintained in 15‐pgdh+/− mice, and these changes were also observed in a genetically engineered PDAC mouse model. Further confirmation revealed that fibroblast growth factor 1 (FGF1) is secreted by pancreatic cancer cells after PGE2 stimulation, consequently promoting CAF proliferation and vascular endothelial growth factor A (VEGFA) expression in the tumor microenvironment. Finally, in 15‐pgdh+/−Acta2‐TK mice, depletion of fibroblasts inhibited angiogenesis and cancer cell viability in orthotopically transplanted tumors. These findings highlighted the role of 15‐pgdh downregulation in enhancing PGE2 accumulation in the pancreatic tumor microenvironment and in subsequently maintaining the angiogenesis level in fibrotic tumors along with CAF expansion. Depletion of 15‐PGDH remodelling tumor microenvironment by promoting firosis and angiogenesis via the upregulation of FGF1 and VEGF.

Glycolysis is highly enhanced in pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for patients with PDAC, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL-6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides insight regarding the crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.

Background Remodeling the tumor microenvironment (TME) to benefit cancer cells is crucial for tumor progression. Although diffuse-type gastric cancer (DGC) preferentially interacts with the TME, the precise mechanism of the complicated network remains unknown. This study aimed to investigate the mutual activation mechanism underlying DGC progression. Methods Mass cytometry analysis of co-cultured macrophages, noncancerous fibroblasts (NFs), and DGC cells was performed. RNA sequencing was applied to examine gene expression in fibroblasts. DGC cells were treated with cytokines to examine their effect on characteristic changes. The TCGA and Kumamoto University cohorts were used to evaluate the clinical relevance of the in vitro findings. Results Cohort analysis revealed that DGC patients had a poor prognosis. The fibroblasts and macrophages interacted with DGC cells to form a cell cluster in the invasive front of DGC tissue. The original 3D triple co-culture system determined the promotional effects of nonmalignant cells on DGC invasive growth. We notably identified a mixed-polarized macrophage cell type with M1/M2 cell surface markers in a triple co-culture system. IL-1β from mixed-polarized macrophages induced the conversion of NFs to cancer-associated fibroblast-like (CAF-like) cells, promoting the malignant phenotype of DGC cells by inducing the secretion of IL-6, IL-24, and leukemia inhibitory factor (LIF). Moreover, IL-6 and colony stimulating factor 2 (GM-CSF) cooperated to maintain the stable state of mixed-polarized macrophages. Finally, we found that mixed-polarized macrophages were frequently detected in DGC tissues. Conclusion These findings demonstrated that mixed-polarized macrophages exist as a novel subtype through the reciprocal interaction between DGC cells and nonmalignant cells. Graphical Abstract

The accumulation of prostaglandin E2 (PGE 2 ) during chronic inflammation has been implicated in the progression of several cancers. Cyclooxygenase is the key synthesizing enzyme of PGE 2 , although the degradation enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has received considerable attention recently. We investigated the molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) progression via 15-PGDH downregulation. Here, we found that 15-PGDH expression was inversely correlated with ALDH1, an important cancer stem cell-associated marker indicative of poor prognosis in humans. Moreover, we demonstrated that pharmacological inhibition of 15-PGDH enhanced CYP26A1 expression, leading to depletion of all- trans retinoic acid (ATRA) and expansion of the ALDH1-positive subset in both human PDAC cells and tumor cells of Kras LSL -G12D /+ ; Ptf1a Cre/+ (KC) mice. Furthermore, genetic deletion of 15-Pgdh in KC mice showed PGE 2 accumulation and ATRA depletion in the pancreas, resulting in PDAC with high levels of Aldh1 and Ki-67. Finally, ATRA replacement suppressed 15-PGDH inhibition-induced tumor progression in KC mice, and ATRA treatment attenuated Aldh1 activity in tumor cells isolated from the pancreas of 15-Pgdh −/− KC mice. These findings provide evidence that 15-PGDH inhibition enhances KRAS -driven tumor progression via ATRA depletion in the pancreas. Therefore, ATRA replacement could be a potential strategy for PDAC treatment.

Cancer-associated fibroblasts (CAFs) are major stromal components of the tumor microenvironment (TME) and play diverse roles in gastrointestinal (GI) cancer progression, immunity, and therapeutic resistance. However, the heterogeneity, tissue specificity, and clinical relevance of CAFs across GI cancers remain incompletely defined. We integrated 14 independent single-cell RNA-sequencing datasets comprising 239 GI adenocarcinoma samples to define the subtypes of CAFs. Machine learning-based deconvolution was applied to 18 bulk transcriptomic cohorts (3396 patients) to estimate CAF subtype abundance and assess prognostic associations by meta-analysis. Functional states, differentiation trajectories, cell-cell communication, and spatial organization were analyzed using gene-set enrichment, transcription factor activity inference, pseudotime modeling, ligand-receptor analysis, and spatial transcriptomics. We identified eight CAF subtypes with distinct transcriptional programs and organ-specific distributions. Two myofibroblastic CAF subtypes (myCAF1 and myCAF2) were consistently associated with poor prognosis, characterized by extracellular matrix remodeling, TGF-β signaling, hypoxia adaptation, and close crosstalk with immunosuppressive macrophages, as well as tumor cells displaying epithelial-mesenchymal transition and hypoxia signatures. In contrast, inflammatory CAF (iCAF) 1 was associated with a favorable prognosis and increased infiltration of antitumor immune cells. Spatial transcriptomic analyses further revealed that distinct CAF subtypes preferentially occupied discrete spatial domains within the GI TME. Our study demonstrated that the functional state and spatial context of CAFs jointly affect tumor progression and outcomes in patients with GI cancers. myCAF-driven stromal niches promote immune suppression and poor prognosis, whereas a balanced inflammatory CAF program may support antitumor immunity.

Cachexia is a devastating and multifactorial syndrome characterized by progressive loss of body weight, skeletal muscle wasting, and systemic inflammation, frequently observed in patients with advanced gastric cancer (GC) with peritoneal dissemination. Despite its clinical significance, the molecular mechanisms underlying cancer-associated cachexia remain poorly understood. In this study, comparative transcriptomic analysis using the GEMINI database identified bone morphogenetic protein 7 (BMP7) as a novel candidate cachexia-inducing factor, along with the known cachexia mediators, growth differentiation factor 11 (GDF11) and growth differentiation factor 15 (GDF15). Functional studies demonstrated that BMP7 acts as an upstream regulator that drives cachectic phenotypes by inducing the expression of GDF11 and GDF15. Knockdown of BMP7, GDF11, or GDF15 in the cachexia-inducing GC cell line, MKN45 significantly attenuated weight loss and muscle wasting in vivo. Conversely, overexpression of BMP7 in the non-cachectic GC cell line, NUGC3 induced cachexia and upregulated GDF11 and GDF15 in tumor tissues. Furthermore, clinical analysis revealed that high BMP7 expression in tumor specimens from patients with advanced GC was associated with significantly poorer overall survival. These findings identify BMP7 as a master regulator of cancer-associated cachexia through the induction of GDF11 and GDF15 and suggest its potential as a promising therapeutic target for mitigating cachexia in GC.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Figure 4 was newly assembled by relocating the BMP7 knockdown, recombinant BMP7 rescue, and SMAD1/5 signaling data previously presented in Figure 3H-J to Figure 4A-C. New panels Figure 4D and 4E were added to show the JASPAR SMAD5 motif used for FIMO scanning and the in silico analysis of candidate SMAD-responsive regions in the GDF11 and GDF15 promoters, together with publicly available SMAD1 ChIP-seq peaks. Figure 3 was reorganized, and Figure 4 was newly assembled accordingly. The corresponding Results, Materials and Methods, Discussion, and figure legends were also revised.Funder Information DeclaredFOREST program of the Japan Science and Technology Agency, JPMJFR200HThe P-PROMOTE program of Japan Agency for Medical Research and Development, 25ama221442h0001The Japan Society for the Promotion of Science, 26K02477, 24K22151, 24KK0162, 23H02772The Uehara Memorial Foundation and the Vehicle Racing Commemorative Foundation

In the chronic phase after intracerebral hemorrhage (ICH), the aftereffect-associated lowering of motivation burdens many patients; however, the pathogenic mechanism is unclear. Here, we revealed for the first time that indoleamine 2, 3-dioxygenase (IDO) expression and enzyme activity are increased in the collagenase-induced murine ICH model. IDO is a rate-limiting enzyme situated at the beginning of the kynurenine pathway and converts tryptophan, a source of serotonin (5-hydroxytryptamine; 5-HT), to kynurenine. In this study, we showed that IDO is localized in 5-HTergic neurons. After ICH, the synaptosomal 5-HT level decreased, but this effect was neutralized by subcutaneous injections of 1-methyl tryptophan (MT), a specific IDO inhibitor. These results suggest that ICH-induced IDO weakens the activity of 5-HTergic neurons. Accordingly, we next investigated whether the IDO increase contributes to the depression-like behaviors of ICH mice. The immobility times of tail suspension and forced swimming tests were significantly prolonged after ICH but shortened by the administration of 1-MT. In conclusion, the increased IDO after ICH was found to decrease 5-HT levels and subsequently reduce stress tolerance. These findings indicate that IDO is a novel therapeutic target for the ICH aftereffect-associated lowering of motivation.

BackgroundAppearance care enables cancer patients to maintain social connections during treatment, but it remains an unmet need in Japan. We surveyed healthcare professionals in Japan to collect information on their awareness of appearance care and their institutions’ appearance care systems.MethodsFrom November 1 to December 13, 2022, we performed an online survey of 16,838 members of the Japan Society of Clinical Oncology.ResultsWe received responses from 807 members (671(83%) physicians; 65(8%) pharmacists; 45(6%) nurses; 22(3%) dentists; and 4(0.5%) others), 72% of whom were men and 28%, women. Among respondents, 93% (n = 749//807) had been asked by patients about appearance care, and 46% (n = 318/693) of the physicians and dentists had refused to perform treatment or changed it because of its effects on physical appearance. Only 59% (n = 410) of physicians and dentists were familiar with the term appearance care, but 100% (n = 45) of nurses and 97% (n = 63) of pharmacists were. Among all respondents, 26% reported that their institution had a specialized department and specific personnel for appearance care. In some cases, physicians and dentists had difficulty communicating correct information to patients, and other healthcare professionals compensated for this deficit.ConclusionThe survey revealed that physicians have low awareness of appearance care. It was suggested that communication and a team approach between physicians and other healthcare professionals is recommended. Each medical facility may be encouraged to establish a sustainable system for providing information on appearance care in that patients or medical personnel themselves can easily consult. Activities are also needed to raise awareness about appearance care among physicians.