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Tumor microenvironment plays vital roles in shaping cancer diversity, and CD73 (ecto-5′-nucleotidase; NT5E) is an emerging immune checkpoint in modulating cancer progression via conversion of immunostimulatory ATP into immunosuppressive adenosine. However, how the CD73 is regulated and how it functions in the progression of cancer are largely unknown. Here, we showed that CD73 was overexpressed and correlated with poor prognosis of gastric cancer. CD73 links adenosinergic signaling in microenvironment switching to induction of epithelial-to-mesenchymal transition phenotype in gastric cancer during metastasis. Further pathway and gene set enrichment analysis of transcriptome data revealed the modulation role of CD73 in RICS/RhoA signaling by its extracellular function in adenosinergic pathway, which subsequently inhibited phosphorylation of LIMK/cofilin and promoted β-catenin activation. Pharmacological inhibition of CD73 adenosinergic signaling was found to induce RICS dysfunction. Dissemination and hematogenous metastasis model showed that targeting CD73 in gastric cancer could suppress experimental metastasis. To conclude, it substantiates CD73 as a target for treatment of gastric cancer metastasis and verifies RICS as an intracellular functional molecule linking CD73/adenosinergic signaling switching to RhoA/LIMK/cofilin pathway.

Background Tumors display a high rate of glucose metabolism and the SLC2A (also known as GLUT) gene family may be central regulators of cellular glucose uptake. However, roles of SLC2A family in mechanism of metabolite communication with immunity in gastric cancer remains unknown. Methods Bioinformatics analysis and IHC staining were used to reveal the expression of SLC2A3 in gastric cancer and the correlation with survival prognosis. Real-time PCR, western blots, OCR, ECAR, lactate production and glucose uptake assays were applied to determine the effect of SLC2A3 on glycolysis reprogramming. We then investigated the consequences of SLC2A3 upregulation or inhibition on aerobic glycolysis, also explored the underlying mechanism. Bioinformatics analysis and in vitro and in vivo research were used to reveal the role of SLC2A3 in macrophage infiltration and transition. Results Here, we show that SLC2A3 acts as a tumor promoter and accelerates aerobic glycolysis in GC cells. Mechanistically, the SLC2A3-STAT3-SLC2A3 feedback loop could promote phosphorylation of the STAT3 signaling pathway and downstream glycolytic targeting genes. Moreover, SLC2A3 potentially contributes to M2 subtype transition of macrophage infiltration in the GC microenvironment. Conclusions SLC2A3 could be used as a prognostic biomarker to determine prognosis and immune infiltration in GC and may provide an intervention strategy for GC therapy.

Background Single-incision plus one-port laparoscopic surgery (SILS + 1) has been demonstrated to be minimally invasive while possessing better cosmesis and less pain compared with conventional laparoscopic surgery (CLS). However, SILS + 1 as an alternative to CLS for colorectal cancer is still controversial. Methods A total of 1071 patients who underwent curative laparoscopic surgery for colon cancer between 2015 and 2018 were included. Of these patients, 258 SILS + 1 cases and 516 CLS cases were analyzed using propensity score matching. The baseline characteristics, surgical outcomes, pathologic findings and recovery course, morbidity and mortality within postoperative 30 days and 3-year disease-free and overall survival were compared. Results Baseline characteristics were balanced between the groups. The mean operating time was significantly shorter in SILS + 1 group, with less estimated blood loss. Tumor size, tumor differentiation, number of harvested lymph nodes, resection margin and pathologic T, N, TNM stage was similar between the groups. There was no significant difference in overall perioperative complications. Uni- and multivariate analyses revealed that SILS + 1 was not a risk factor for complications. Postoperatively, SILS + 1 group showed faster recovery than CLS group in terms of ambulation, bowel function, oral intake and discharge. The 3-year disease-free survival rates of SILS + 1 and CLS groups were 90.1% and 87.3%(p = 0.59), respectively and the 3-year overall survival rates were 93.3% vs. 89.8%(p = 0.172). Discussion Our study revealed that SILS + 1 is safe, feasible, oncologically efficient, and may be considered as a surgical option for selected patients with colorectal cancer.

BackgroundImmune checkpoint blockade (ICB) therapy, while transformative in cancer treatment, is frequently complicated by immune-related colitis (irColitis), driven by poorly understood mechanisms.MethodsAn integrated analysis of single-cell RNA sequencing (scRNA-seq), T cell receptor (TCR) sequencing, and spatial transcriptomics was conducted to identify immune cell populations and associated signaling pathways driving irColitis. In vivo murine models of irColitis, along with flow cytometry and qPCR, were used to further validate these findings. To assess the functional roles of specific signaling pathways and cell types in driving irColitis, in vivo blockade of IL-23 and CXCL9/10 signaling was performed using neutralizing antibodies, and intestinal macrophages were depleted using clodronate liposomes. Additionally, the potential impact of these immune cells and signaling pathways on ICB therapy was evaluated through the integration of scRNA-seq and TCR sequencing with qPCR and flow cytometry.ResultsA pathogenic IFNG+IL17+CD4+ T cell subset with dual Th1/Th17 features, high clonal expansion, and differentiation trajectories from tissue-resident memory T cells (TRM) was identified in human irColitis lesions and murine models. IL-23 blockade reduced the frequency of IFNG+IL17+CD4+ T cells and mitigated colitis severity. Mechanistically, IL-23 promoted the expansion and survival of pathogenic Th17 (pTh17) precursors, while CXCL9/10–CXCR3 signaling facilitated their differentiation into IFN-γ-secreting effector cells. Intestinal macrophages were identified as major producers of IL-23, CXCL9, and CXCL10. Macrophage depletion markedly alleviated colitis and reduced pathogenic T cells. Crucially, IFNG+IL17+CD4+ T cells showed no association with antitumor immunity in colorectal cancer immunotherapy responders, suggesting their targeting would not affect ICB efficacy.ConclusionsIFNG+IL17+CD4+ T cells and CXCL9/10-producing macrophages are key mediators of irColitis. Targeting IL-23 signaling and intestinal macrophages represents a promising strategy to alleviate gut immunopathology without compromising the efficacy of ICB therapy.

This study by Okuno et al. successfully identified eight exo‐miRNAs through exosome‐based discovery and established an exo‐miRNA‐based liquid biopsy assay for predicting therapeutic response in metastatic gastric cancer (mGC). Exosomes, a subpopulation of extracellular vesicles originating from endosomes, play a crucial role in this context. Liquid biopsy, analyzing blood for circulating tumor cells, extracellular vesicles, or cell‐free nucleic acid, has revolutionized cancer diagnosis and monitoring. It significantly contributes to early detection, staging, and relapse detection in various cancers. Numerous studies have highlighted the clinical significance of miRNA and lncRNA within extracellular vesicles. The authors developed a response‐prediction model for chemo‐responsiveness in mGC patients. This study's model predicts responses robustly, demonstrating its potential efficacy in clinical practice. It offers a non‐invasive and accessible method for therapeutic response prediction, crucial for precision medicine in mGC. Successful translation of these findings into clinical applications promises substantial benefits for patient care.

BackgroundMultiple mechanisms have been proposed that lead to reduced effectiveness of trastuzumab in HER2-positive gastric cancer (GC), yet resistance to trastuzumab remains a challenge in clinics.MethodsWe established trastuzumab-resistant cells and patient-derived xenografts models to measure metabolic levels and vascular density and shape. The HER2-positive GC patient samples were used to determine clinical significance. We also measured protein expression and phosphorylation modifications to determine those alterations related to resistance. In vivo studies combining inhibitor of PFKFB3 with trastuzumab corroborated the in vitro findings.ResultsThe 6-phosphofructo-2-kinase (PFKFB3)-mediated trastuzumab resistance pathways in HER2-positive GC by activating the glycolytic pathway. We also found vessels are chaotic and destabilised in the tumour during the trastuzumab resistance process. Inhibition of PFKFB3 significantly diminished tumour proliferation and promoted vessel normalisation in the patient-derived xenograft model. Mechanistically, PFKFB3 promoted the secretion of CXCL8 into the tumour microenvironment, and phosphorylated Ser1151 of ERBB2, enhancing the transcription of CXCL8 by activating the PI3K/AKT/NFκB p65 pathway.ConclusionsOur current findings discover that PFKFB3 inhibitors might be effective tools to overcome adjuvant therapy resistance in HER2-positive GC and reshaping the microenvironment by normalising tumour vessels is a novel strategy to overcome trastuzumab resistance.

Trastuzumab is the only target to be approved as the first-line treatment of HER2 positive metastatic gastric cancer, but ubiquitous resistance decreases its therapeutic benefit. In this study, we found HER4, phosphorylation HER4 (p-HER4) and the mesenchymal marker Vimentin increased in trastuzumab-resistant cells (MKN45TR and NCI-N87TR), while epithelial markers expressions in trastuzumab-resistant cell lines and animal models decreased. Additionally, silencing HER4 prevented the epithelial-mesenchymal transition and led to decreased proliferation and migration in vitro and in vivo. The expression of YAP1, a vital downstream interacted target of HER4, decreased when HER4 was knocked down. Interestingly, stimulation of NRG1 could compromise the inhibitory impact and rescue cell survival; whereas, transfection of siYAP1 sensitized trastuzumab-treated cells. Expression analysis of the proteins in patient-derived xenograft model (PDX) mice showed that HER4, p-HER4, YAP1, and Vimentin were clearly upregulated in the trastuzumab-resistant mice compared to mice without trastuzumab resistance. However, HER2 and E-cadherin were downregulated in response to continuous treatment with trastuzumab. These findings elucidated that the central role of the HER4-YAP1 axis in trastuzumab resistance of HER2-positive gastric cancer cells through induction of EMT. Hence, regulating the HER4-YAP1 axis might be a promising strategy for clinical interventions in patients with HER2-positive gastric cancer.

Epithelial–mesenchymal transition (EMT)-induced metastasis contributes to human colorectal cancer (CRC) progression, especially in advanced CRC. However, the underlying mechanism of β-catenin in this process is elusive. We identified that LIM domain kinase (LIMK)2 was progressively downregulated with tumor progression from precancerous lesions to advanced cancer. Gain- and loss-of-function assays revealed that LIMK2 inhibits cell proliferation via cell cycle arrest at the G1–S transition and suppresses the ability of cell metastasis by restricting the EMT process. Reduced LIMK2 expression enhanced the nuclear accumulation of β-catenin and activated the Wnt signaling pathway, thus contributing to tumor progression. A homolog of the LIMK family, LIMK1, which was overexpressed throughout tumor progression, served as a competitive inhibitor of LIMK2 via β-catenin nuclear translocation. The imbalanced expression of LIMK1 and LIMK2 is important in CRC progression, and the combined effects provide a new insight into the mechanism of CRC progression. These findings provide a new understanding for LIMK-based anticancer therapy.

LIM and SH3 protein 1 (LASP1) can promote colorectal cancer (CRC) progression and metastasis, but the direct evidence that elucidates the molecular mechanism remains unclear. Here, our proteomic data showed that LASP1 interacted with 14-3-3σ and decreased the expression of 14-3-3σ in CRC. Deletion of 14-3-3σ was required for LASP1-mediated CRC cell aggressiveness. In vitro gain- and loss-of-function assays showed that 14-3-3σ suppressed the ability of cell migration and decreased the phosphorylation of AKT in CRC cells. We further observed clearly co-localization between AKT and 14-3-3σ in CRC cells. Treatment of PI3K inhibitor LY294002 markedly prevented phosphorylation of AKT and subsequently counteract aggressive phenotype mediated by siRNA of 14-3-3σ. Clinically, 14-3-3σ is frequently down-regulated in CRC tissues. Down-regulation of 14-3-3σ is associated with tumor progression and poor prognosis of patients with CRC. Multivariate analysis confirmed low expression of 14-3-3σ as an independent prognostic factor for CRC. A combination of low 14-3-3σ and high LASP1 expression shows a worse trend with overall survival of CRC patients. Our research paves the path to future investigation of the LASP1-14-3-3σ axis as a target for novel anticancer therapies of advanced CRC.

LIM and SH3 protein 1 (LASP1) can promote colorectal cancer (CRC) progression and metastasis, but the direct evidence that elucidates the molecular mechanism remains unclear. Here, our proteomic data showed that LASP1 interacted with 14-3-3σ and decreased the expression of 14-3-3σ in CRC. Deletion of 14-3-3σ was required for LASP1-mediated CRC cell aggressiveness. In vitro gain- and loss-of-function assays showed that 14-3-3σ suppressed the ability of cell migration and decreased the phosphorylation of AKT in CRC cells. We further observed clearly co-localization between AKT and 14-3-3σ in CRC cells. Treatment of PI3K inhibitor LY294002 markedly prevented phosphorylation of AKT and subsequently counteract aggressive phenotype mediated by siRNA of 14-3-3σ. Clinically, 14-3-3σ is frequently down-regulated in CRC tissues. Down-regulation of 14-3-3σ is associated with tumor progression and poor prognosis of patients with CRC. Multivariate analysis confirmed low expression of 14-3-3σ as an independent prognostic factor for CRC. A combination of low 14-3-3σ and high LASP1 expression shows a worse trend with overall survival of CRC patients. Our research paves the path to future investigation of the LASP1-14-3-3σ axis as a target for novel anticancer therapies of advanced CRC.