Heterogeneity and interplay: the multifaceted role of cancer-associated fibroblasts in the tumor and therapeutic strategies.

The journey of cancer development is a multifaceted and staged process. The array of treatments available for cancer varies significantly, dictated by the disease's type and stage. Cancer-associated fibroblasts (CAFs), prevalent across various cancer types and stages, play a pivotal role in tumor genesis, progression, metastasis, and drug resistance. The strategy of concurrently targeting cancer cells and CAFs holds great promise in cancer therapy. In this review, we focus intently on CAFs, delving into their critical role in cancer's progression. We begin by exploring the origins, classification, and surface markers of CAFs. Following this, we emphasize the key cytokines and signaling pathways involved in the interplay between cancer cells and CAFs and their influence on the tumor immune microenvironment. Additionally, we examine current therapeutic approaches targeting CAFs. This article underscores the multifarious roles of CAFs within the tumor microenvironment and their potential applications in cancer treatment, highlighting their importance as key targets in overcoming drug resistance and enhancing the efficacy of tumor therapies.

Flavokawain C inhibits proliferation and migration of liver cancer cells through FAK/PI3K/AKT signaling pathway.

PURPOSE: This study investigated the potential applicability and the underlying mechanisms of flavokawain C, a natural compound derived from kava extracts, in liver cancer treatment. METHODS: Drug distribution experiment used to demonstrate the preferential tissues enrichment of flavokawain C. Cell proliferation, apoptosis and migration effect of flavokawain C were determined by MTT, colony formation, EdU staining, cell adhesion, transwell, flow cytometry and western blot assay. The mechanism was explored by comet assay, immunofluorescence assay, RNA-seq-based Kyoto encyclopedia of genes and genomes analysis, molecular dynamics, bioinformatics analysis and western blot assay. The anticancer effect of flavokawain C was further confirmed by xenograft tumor model. RESULTS: The studies first demonstrated the preferential enrichment of flavokawain C within liver tissues in vivo. The findings demonstrated that flavokawain C significantly inhibited proliferation and migration of liver cancer cells, induced cellular apoptosis, and triggered intense DNA damage along with strong DNA damage response. The findings from RNA-seq-based KEGG analysis, molecular dynamics, bioinformatics analysis, and western blot assay mechanistically indicated that treatment with flavokawain C notably suppressed the FAK/PI3K/AKT signaling pathway in liver cancer cells. This effect was attributed to the induction of gene changes and the binding of flavokawain C to the ATP sites of FAK and PI3K, resulting in the inhibition of their phosphorylation. Additionally, flavokawain C also displayed the strong capacity to inhibit Huh-7-derived xenograft tumor growth in mice with minimal adverse effects. CONCLUSIONS: These findings identified that flavokawain C is a promising anticancer agent for liver cancer treatment.

Revealing splenectomy-driven microRNA hsa-7b-5p's role in pancreatic cancer progression.

Splenectomy often accompanies distal pancreatectomy for pancreatic cancer. However, debates persist on splenic function loss impact. Prior studies in mice revealed splenectomy promotes pancreatic cancer growth by altering CD4/Foxp3 and CD8/Foxp3 ratios. The effect on other immune cells remains unclear. Clinical observations indicate splenectomy induces immunosuppression, heightening recurrence and metastasis risk. Here, we established an orthotopic pancreatic cancer model with splenectomy and observed a significant increase in tumor burden. Flow cytometry revealed elevated MDSCs, CD8+PD-1high+ T cells, and reduced CD4+ T cells, CD8+ T cells, and natural killer cells in tumors. Bulk sequencing identified increased MicroRNA (miRNA) hsa-7b-5p post-splenectomy, correlating with staging and immunosuppression. Similar results were obtained in vivo by constructing a KPC-miRNA hsa-7b-5p-sh cell line. These findings suggest that splenectomy enhances the expression of miRNA hsa-7b-5p, inhibits the tumor immune microenvironment, and promotes pancreatic cancer growth.

The neutrophil-lymphocyte ratio as a risk factor for all-cause and cardiovascular mortality among individuals with diabetes: evidence from the NHANES 2003-2016.

BACKGROUND: Evidence regarding the neutrophil-lymphocyte ratio (NLR) and mortality risk in diabetes patients is scarce. This study investigated the relationship of the NLR with all-cause and cardiovascular mortality risk in diabetes patients. METHODS: Diabetes patients (n = 3251) from seven National Health and Nutrition Examination Survey (NHANES) cycles (2003-2016) were included in this study. The cause of death and mortality status of the participants were obtained from National Death Index records. Restricted cubic spline (RCS) was used to visualize the association of the NLR with mortality risk. The maximally selected rank statistics method (MSRSM) was used to determine the optimal NLR cutoff value corresponding to the most significant association with survival outcomes. Weighted multivariable Cox regression models and subgroup analyses were adopted to assess the association of the NLR with all-cause and cardiovascular mortality. Time-dependent receiver operating characteristic curve (ROC) analysis was conducted to evaluate the accuracy of the NLR in predicting survival outcomes. RESULTS: During a median follow-up of 91 months (interquartile range, 55-131 months), 896 (27.5%) of the 3251 diabetes patients died, including 261 (8.0%) with cardiovascular deaths and 635 (19.5%) with noncardiovascular deaths. The RCS regression analysis showed a positive linear association between the NLR and all-cause and cardiovascular mortality (both p > 0.05 for nonlinearity) in diabetes patients. Participants were divided into higher (> 3.48) and lower (≤ 3.48) NLR groups according to the MSRSM. In the multivariable-adjusted model, compared with participants with a lower NLR, those with a higher NLR had a significantly higher risk of both all-cause (HR 2.03, 95% confidence interval (CI) 1.64-2.51, p < 0.0001) and cardiovascular mortality (HR 2.76, 95% CI 1.84-4.14, p < 0.0001). The association was consistent in subgroup analyses based on age, sex, smoking status, drinking status, and hypertension, with no significant interaction between the aforementioned characteristics and the NLR (p interaction > 0.05). The time-dependent ROC curve showed that the areas under the curve of the 1-, 3-, 5-, and 10-year survival rates were 0.72, 0.66, 0.64, and 0.64 for all-cause mortality and 0.69, 0.71, 0.69 and 0.65, respectively, for cardiovascular mortality. CONCLUSION: An elevated NLR is independently associated with increased all-cause and cardiovascular mortality in diabetes patients.

Impact of bariatric surgery on glucose and lipid metabolism and liver and kidney function in food-induced obese diabetic rats.

BACKGROUND: Obesity usually causes diabetes mellitus (DM) and is a serious danger to human health. Type 2 DM (T2DM) mostly occurs along with obesity. Foodborne obesity-induced DM is caused by an excessive long-term diet and surplus energy. Bariatric surgery can improve the symptoms of T2DM in some obese patients. But different types of bariatric surgery may have different effects. AIM: To investigate the effect of bariatric surgery on glucose and lipid metabolism and liver and kidney function in rats. METHODS: Male Sprague-Dawley rats aged 6-8 wk underwent Roux-en-Y gastric bypass surgery (RYGB), sleeve gastrectomy (SG), or gastric banding (GB). Glucose and insulin tolerance tests, analyses of biochemical parameters, histological examination, western blot, and quantitative real-time polymerase chain reaction were conducted. RESULTS: In comparison to the sham operation group, the RYGB, SG, and GB groups had decreased body weight and food intake, reduced glucose intolerance and insulin insensitivity, downregulated biochemical parameters, alleviated morphological changes in the liver and kidneys, and decreased levels of protein kinase C ß/ P66shc. The effect in the RYGB group was better than that in the SG and GB groups. CONCLUSION: These results suggest that RYGB, SG and GB may be helpful for the treatment of foodborne obesity-induced DM.

The level of macrophage migration inhibitory factor is negatively correlated with the efficacy of PD-1 blockade immunotherapy combined with chemotherapy as a neoadjuvant therapy for esophageal squamous cell carcinoma.

PURPOSE: This study aimed to screen biomarkers to predict the efficacy of programmed cell death 1 (PD-1) blockade immunotherapy combined with chemotherapy as neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC). METHODS: In the first stage of the study, the baseline concentrations of 40 tumor-related chemokines in the serum samples of 50 patients were measured to screen for possible biomarkers. We investigated whether the baseline concentration of the selected chemokine was related to the therapeutic outcomes and tumor microenvironment states of patients treated with the therapy. In the second stage, the reliability of the selected biomarkers was retested in 34 patients. RESULTS: The baseline concentration of macrophage migration inhibitory factor (MIF) was negatively correlated with disease-free survival (DFS) and overall survival (OS) in patients treated with the therapy. In addition, a low baseline expression level of MIF is related to a better tumor microenvironment for the treatment of ESCC. A secondary finding was that effective treatment decreased the serum concentration of MIF. CONCLUSION: Baseline MIF levels were negatively correlated with neoadjuvant therapy efficacy. Thus, MIF may serve as a predictive biomarker for this therapy. The accuracy of the prediction could be improved if the serum concentration of MIF is measured again after the patient received several weeks of treatment.

Deciphering pathogenic cellular module at single-cell resolution in checkpoint inhibitor-related pneumonitis.

Checkpoint inhibitor pneumonitis (CIP) is the most common fatal immune-related adverse event; however, its pathophysiology remains largely unknown. Comprehensively dissecting the key cellular players and molecular pathways associated with CIP pathobiology is critical for precision diagnosis and develop novel therapy strategy of CIP. Herein, we performed a comprehensive single-cell transcriptome analysis to dissect the complexity of the immunological response in the bronchoalveolar lavage fluid (BALF) microenvironment. CIP was characterized by a dramatic accumulation of CXCL13+ T cells and hyperinflammatory CXCL9+ monocytes. T-cell receptor (TCR) analysis revealed that CXCL13+ T cells exhibited hyperexpanded- TCR clonotypes, and pseudotime analysis revealed a potential differentiation trajectory from naïve to cytotoxic effector status. Monocyte trajectories showed that LAMP3+ DCs derived from CXCL9+ monocytes possessed the potential to migrate from tumors to the BALF, whereas the differentiation trajectory to anti-inflammatory macrophages was blocked. Intercellular crosstalk analysis revealed the signaling pathways such as CXCL9/10/11-CXCR3, FASLG-FAS, and IFNGR1/2-IFNG were activated in CIP+ samples. We also proposed a novel immune signature with high diagnostic power to distinguish CIP+ from CIP- samples (AUC = 0.755). Our data highlighted key cellular players, signatures, and interactions involved in CIP pathogenesis.

miR-32-5p induces hepatic steatosis and hyperlipidemia by triggering de novo lipogenesis.

BACKGROUND AND OBJECTIVES: MicroRNA-dependent regulation of hepatic lipid metabolism has been recognized recently as a key pathological mechanism contributing to the development of NAFLD. However, whether miR-32-5p (miR-32) plays a role in lipid metabolism or contributes to NAFLD remains unclear. METHODS AND RESULTS: A marked increase in miR-32 expression was observed in liver samples from patients and mice with NAFLD, as well as in palmitate-induced hepatocytes. Hepatocyte-specific miR-32 knockout (miR-32-HKO) dramatically ameliorated hepatic steatosis and metabolic disorders in high-fat diet-fed mice. Conversely, hepatic miR-32 overexpression markedly exacerbated the progression of these abnormalities. Further, combinational analysis of transcriptomics and lipidomics suggested that miR-32 was a key trigger for de novo lipogenesis in the liver. Mechanistically, RNA sequencing, luciferase assay and adenovirus-mediated downstream gene rescue assay demonstrated that miR-32 directly bound to insulin-induced gene 1 (INSIG1) and subsequently activated sterol regulatory element binding protein-mediated lipogenic gene programs, thereby promoting hepatic lipid accumulation and metabolic disorders. Notably, pharmacological administration of miR-32 antagonist significantly inhibited palmitate-induced triglyceride deposition in hepatocytes and markedly mitigated hepatic steatosis and metabolic abnormalities in obesity-associated NAFLD mice. CONCLUSION: miR-32 is an important checkpoint for lipogenesis in the liver, and targeting miR-32 could be a promising therapeutic approach for NAFLD treatment.

Neural network-based prognostic predictive tool for gastric cardiac cancer: the worldwide retrospective study.

BACKGROUNDS: The incidence of gastric cardiac cancer (GCC) has obviously increased recently with poor prognosis. It's necessary to compare GCC prognosis with other gastric sites carcinoma and set up an effective prognostic model based on a neural network to predict the survival of GCC patients. METHODS: In the population-based cohort study, we first enrolled the clinical features from the Surveillance, Epidemiology and End Results (SEER) data (n = 31,397) as well as the public Chinese data from different hospitals (n = 1049). Then according to the diagnostic time, the SEER data were then divided into two cohorts, the train cohort (patients were diagnosed as GCC in 2010-2014, n = 4414) and the test cohort (diagnosed in 2015, n = 957). Age, sex, pathology, tumor, node, and metastasis (TNM) stage, tumor size, surgery or not, radiotherapy or not, chemotherapy or not and history of malignancy were chosen as the predictive clinical features. The train cohort was utilized to conduct the neural network-based prognostic predictive model which validated by itself and the test cohort. Area under the receiver operating characteristics curve (AUC) was used to evaluate model performance. RESULTS: The prognosis of GCC patients in SEER database was worse than that of non GCC (NGCC) patients, while it was not worse in the Chinese data. The total of 5371 patients were used to conduct the model, following inclusion and exclusion criteria. Neural network-based prognostic predictive model had a satisfactory performance for GCC overall survival (OS) prediction, which owned 0.7431 AUC in the train cohort (95% confidence intervals, CI, 0.7423-0.7439) and 0.7419 in the test cohort (95% CI, 0.7411-0.7428). CONCLUSIONS: GCC patients indeed have different survival time compared with non GCC patients. And the neural network-based prognostic predictive tool developed in this study is a novel and promising software for the clinical outcome analysis of GCC patients.

Prospective Study of a Modified Post-Transplantation Cyclophosphamide Regimen for Severe Aplastic Anemia Patients with HLA-Haploidentical Transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative modality for severe aplastic anemia (SAA). The availability of haploidentical donors has expanded valid options for SAA; however, previous post-transplantation cyclophosphamide (PTCy)-based protocols for HLA-haploidentical HSCT in SAA patients are associated with relatively delayed neutrophil and platelet engraftment. We prospectively studied HLA-haploidentical HSCT using bone marrow (BM) combined with peripheral blood stem cells (PBSC) as grafts and a modified PTCy regimen for treating SAA. We evaluated the efficacy and safety of this regimen, which had an increased dose (from 4.5 mg/kg to 6.0 mg/kg) and backward-adjusted timing (from day -9 to -7 to days -5 to -3) of antithymocyte globulin (ATG) compared with previous PTCy protocols. Seventy-one eligible patients were included in this prospective study between July 2019 and June 2022. The median time to neutrophil and platelet engraftment was 13 days (range, 11 to 19 days) and 12 days (range, 7 to 62 days), respectively, and the cumulative incidence (CuI) of neutrophil and platelet engraftment was 97.2 ± 2.2% and 94.4 ± 2.9%, respectively. Five patients experienced graft failure (GF), including 2 with primary GF and 3 with secondary GF. The CuI of GF was 7.0 ± 3.1%. A ≥1-year interval between diagnosis and transplantation was a risk factor for the development of GF (HR, 8.40; 95% confidence interval [CI], 1.40 to 50.47; P = .02). No patients developed grade IV acute graft-versus-host disease (aGVHD) or severe chronic graft-versus-host disease (cGVHD). The 100-day CuI of grade II-IV aGVHD was 13.4 ± 4.2%, and the 2-year CuI of cGVHD was 5.9 ± 2.9%. With a median follow-up of 580 days (range, 108 to 1014 days) for 63 survivors, the estimated 2-year overall survival (OS) and 2-year GVHD-free and failure-free survival (GFFS) were 87.3% (95% CI, 79.4% to 96.0%) and 83.8% (95% CI, 74.9% to 93.7%), respectively. In conclusion, the PTCy regimen with an increased dose and backward-adjusted timing of ATG is an effective and feasible choice for treatment with HLA-haploidentical HSCT using BM combined with PBSC as grafts, with a high rate of and faster engraftment, low rate and intensity of aGVHD and cGVHD, and prolonged OS and GFFS.

Multi-omics analysis uncovers tumor ecosystem dynamics during neoadjuvant toripalimab plus nab-paclitaxel and S-1 for esophageal squamous cell carcinoma: a single-center, open-label, single-arm phase 2 trial.

BACKGROUND: Immune checkpoint inhibitors combined with chemotherapy as a neoadjuvant therapy have been applied to the treatment of esophageal squamous cell carcinoma (ESCC). However, the optimal regimen needs to be further explored, particularly for older patients, and the mechanisms by which the immune checkpoint inhibitor combined with chemotherapy modulates the evolution of ESCC are unknown. METHODS: In this single-arm phase 2 trial, patients with resectable (stage II/III/IV without metastasis) ESCC were enrolled and received nanoparticle albumin-bound (nab) paclitaxel for two cycles and oral S-1 for 2 weeks, combined with intravenous toripalimab for two cycles before surgery. Combination postoperative adjuvant therapy was administered. The primary outcome was the major pathological response (MPR). Secondary outcomes included pathological complete response (pCR), overall response rate (ORR), disease control rate (DCR), disease-free survival (DFS), overall survival (OS), improvement in Stooler's dysphagia score and degree of daily living ability (dADL). Biopsies and plasma pre- and post-neoadjuvant therapy were performed using whole-exome sequencing, transcriptome sequencing, immunohistochemistry (IHC) for PD-L1, multiplex immunofluorescence (mIF) and proximity extension assay technology (PEA) for 92 proteins. FINDINGS: From November 2019 to July 2021, 60 patients were enrolled. After neoadjuvant therapy, R0 resection was achieved in 55 (98.21%) patients. MPR was identified in 27 patients (49.09%), and 16 patients (29.09%) achieved pCR. Patients with PR, SD and PD were 37 (61.67%), 21 (35.00%) and 2 (3.33%), respectively. The overall staging, Stooler dysphagia scores and dADL were significantly decreased after treatment. 11 patients (18.3%) experienced grade ≥3 AEs. Compared to PD-L1-Low patients, PD-L1-High patients had a significantly higher ratio of PR. During therapy, the tumor mutation burden (TMB) and tumor neoantigen burden (TNB) were significantly decreased in patients with PR. Differential clonal evolution within tumors was demonstrated by analysis of intratumoral heterogeneity. Transcriptome analyses revealed that the infiltration of CD4+ T lymphocytes at baseline was associated with clinical outcome. During therapy, CD8+ T cells and CD4+ T cells were increased in all patients; however, exhausted cells, nTregs and iTregs were significantly increased in patients with non-MPR. Protein analyses revealed that the levels of IFN-γ, Gal.1 and LAMP3 can predict the clinical benefit. In addition, the expression of CD83, TNFRSF4, TNFSF14, VEGFR2, ADA, ARG1, and HO-1 was associated with serious AEs. More importantly, the integration of CD4+ T cells with plasma protein of IFN-γ, Gal.1 or LAMP3 could further distinguish responders from non-responders. INTERPRETATION: In this study, neoadjuvant therapy with toripalimab, nab-paclitaxel and S-1 was less toxic and showed promising antitumor activity in patients with resectable ESCC. Changes in the genome, transcriptome, PD-L1 expression and serum proteins were comprehensively analyzed and correlated with clinical outcomes, which provides insight into the mechanism of action of toripalimab combined with nab-paclitaxel and S-1 in patients with ESCC. FUNDING: This study was funded by Major projects of the ministry of science and technology of the 13th five-year plan of China [grant number: 2018ZX09201013].

Retraction notice to "HIF-1α mediates tumor-nerve interactions through the up-regulation of GM-CSF in pancreatic ductal adenocarcinoma" [Cancer Lett. 453 (2019) 10-20].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief and Authors. Following concerns raised in the public domain, the authors contacted the journal to request the retraction of the article. Sections of panels from various figures appear similar to each other, particularly panels from Figs. 3G, 5B and 3G and 5F, 3F, S4D, S5D, S5C and S10C, as well as S10E.

Genome-wide CRISPR screen identifies MTA3 as an inducer of gemcitabine resistance in pancreatic ductal adenocarcinoma.

Gemcitabine (GEM) resistance is one of the major causes of treatment failure in pancreatic ductal adenocarcinoma (PDAC) in clinic. Here, through CRISPR/Cas9 activation library screen, we found that MTA3 mediates the GEM resistance of PDAC and thus might be a potential therapeutic target for combination chemotherapy. The CRISPR library screening showed that MTA3 is the most enriched gene in the surviving GEM-treated cells, and bioinformatic and histology analysis implied its high correlation with GEM resistance. MTA3 promoted GEM resistance of PDAC cells in in vitro and in vivo experiments. Mechanistically, as a component of the Mi-2/nucleosome remodeling and deacetylase transcriptional repression complex, MTA3 transcriptionally represses CRIP2, a transcriptional repressor of NF-κB/p65, activating NF-κB signaling and consequently leading to GEM resistance. Furthermore, the treatment of GEM increases MTA3 expression in PDAC cells via activating STAT3 signaling, thereby inducing the acquired chemoresistance of PDAC to GEM. In patients derived xenografts (PDX) mouse model, Colchicine suppresses the expression of MTA3 and increases the sensitivity of tumor cells to GEM. Based on these findings, MTA3 plays a key role in GEM resistance in pancreatic cancer and is a promising therapeutic target for reversing GEM chemotherapy resistance.

Pretreatment Neutrophil-to-Lymphocyte Ratio as a Prognostic Biomarker in Unresectable or Metastatic Esophageal Cancer Patients With Anti-PD-1 Therapy.

Background: The neutrophil-to-lymphocyte ratio (NLR) is an inflammatory index calculated by the absolute neutrophil count dividing the absolute lymphocyte count, and its prognostic role in esophageal cancer (EC) patients with anti-PD-1 therapy remains unclear. Methods: A total of 140 unresectable or metastatic EC patients receiving PD-1 inhibitor treatment were included from Jan 2016 to Mar 2020. Kaplan-Meier method and log-rank test were used for comparing overall survival (OS) and progression-free survival (PFS) between groups. Multivariate Cox analysis was performed to assess the prognostic value of NLR. Results: The cutoff value of NLR was set at 5, and the median follow-up time was 20.0 months. Patients with pretreatment NLR <5 had higher ORR (46.7% vs. 12.1%; p < 0.001) and DCR (85.0% vs. 69.7%; p = 0.047) than those with NLR ≥5. Kaplan-Meier curves showed that pretreatment NLR <5 was associated with longer PFS (median: 10.0 vs. 3.5 months, p < 0.0001) and OS (median: 22.3 vs. 4.9 months, p < 0.0001). Multivariate analysis demonstrated that pretreatment NLR ≥5 independently and significantly increased the risk of disease progression (hazard ratio (HR), 1.77 (95% confidence interval (CI), 1.12-2.82); p = 0.015) and death (HR, 4.01 (95% CI, 2.28-7.06); p < 0.001). Subgroup analysis showed that pretreatment NLR ≥5 was associated with poor efficacy and survival in most subsets. Conclusions: Our findings showed that pretreatment NLR was independently and significantly associated with the efficacy and prognosis of EC patients treated with PD-1 inhibitors. NLR could serve as a convenient and useful prognostic biomarker for EC patients with anti-PD-1 therapy.

Generation of a thrombopoietin-deficient thrombocytopenia model in zebrafish.

BACKGROUND: The production of platelets is tightly regulated by thrombopoietin (THPO). Mutations in the THPO gene cause thrombocytopenia. Although mice lacking Thpo present with thrombocytopenia, predicting phenotypes and pathogenicity of novel THPO mutations in mice is limited. Zebrafish can be a powerful tool for fast validation and study of candidate genes of human hematological diseases and have already been used as a model of human thrombocytopenia. OBJECTIVES: We aim to investigate the role of Thpo in zebrafish thrombopoiesis and to establish a Thpo-deficient zebrafish model. The model could be applied for illustrating the clinically discovered human THPO variants of which the clinical significance is not known and to evaluate the effect of THPO receptor agonists (THPO-Ras), as well as a screening platform for new drugs. METHODS: We generated a thpo loss-of-function zebrafish model using CRISPR/Cas9. After disruption of zebrafish thpo, thposzy6 zebrafish presented with a significant reduction of thpo expression and developed thrombocytopenia. Furthermore, we performed in vivo studies with zebrafish with the thposzy6 mutation and found two human clinical point mutations (c.091C > T and c.112C > T) that were responsible for the thrombocytopenia phenotype. In addition, effects of THPO-RAs used as therapeutics against thrombocytopenia were evaluated in the Tg(mpl:eGFP);thposzy6 line. RESULTS AND CONCLUSIONS: Zebrafish with the mutation thposzy6 presented with a significant reduction of thpo expression and developed thrombocytopenia. Thpo loss-of-function zebrafish model can serve as a valuable preclinical model for thrombocytopenia caused by thpo-deficiency, as well as a tool to study human clinical THPO variants and evaluate the effect of THPO-RAs.

Paracrine Regulation of Adipose Tissue Macrophages by Their Neighbors in the Microenvironment of Obese Adipose Tissue.

Obesity has recently been defined as a chronic low-grade inflammatory disease. Obesity-induced inflammation of adipose tissue (AT) is an essential trigger for insulin resistance (IR) and related metabolic diseases. Although the underlying molecular basis of this inflammation has not been fully identified, there is consensus that the recruited and activated macrophages in AT are the most important culprits of AT chronic inflammation. Adipose tissue macrophages (ATMs) are highly plastic and could be polarized from an anti-inflammatory M2 to proinflammatory M1 phenotypes on stimulation by microenvironmental signals from obese AT. Many efforts have been made to elucidate the molecular signaling pathways of macrophage polarization; however, the upstream drivers governing and activating macrophage polarization have rarely been summarized, particularly regulatory messages from the AT microenvironment. In addition to adipocytes, the AT bed also contains a variety of immune cells, stem cells, as well as vascular, neural, and lymphatic tissues throughout, which together orchestrate the AT microenvironment. Here, we summarize how the aforesaid neighbors of ATMs in the AT microenvironment send messages to ATMs and thus regulate its phenotype during obesity. Deciphering the biology and polarization of ATMs in the obese environment is expected to provide a precise immunotherapy for adipose inflammation and obesity-related metabolic diseases.

Mitochondrial Calcium Uniporter Drives Metastasis and Confers a Targetable Cystine Dependency in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with few effective treatments. Here we show that the mitochondrial calcium uniporter (MCU) promotes PDAC cell migration, invasion, metastasis, and metabolic stress resistance by activating the Keap1-Nrf2 antioxidant program. The cystine transporter SLC7A11 was identified as a druggable target downstream of the MCU-Nrf2 axis. Paradoxically, despite the increased ability to uptake cystine, MCU-overexpressing PDAC demonstrated characteristics typical of cystine-deprived cells and were hypersensitive to cystine deprivation-induced ferroptosis. Pharmacologic inhibitors of SLC7A11 effectively induced tumor regression and abrogated MCU-driven metastasis in PDAC. In patient-derived organoid models in vitro and patient-derived xenograft models in vivo, MCU-high PDAC demonstrated increased sensitivity to SLC7A11 inhibition compared with MCU-low tumors. These data suggest that MCU is able to promote resistance to metabolic stress and to drive PDAC metastasis in a cystine-dependent manner. MCU-mediated cystine addiction could be exploited as a therapeutic vulnerability to inhibit PDAC tumor growth and to prevent metastasis. SIGNIFICANCE: Elevated mitochondrial calcium uptake in PDAC promotes metastasis but exposes cystine addiction and ferroptosis sensitivity that could be targeted to improve pancreatic cancer treatment.

Potential molecular mechanisms and clinical progress in liver metastasis of breast cancer.

Breast cancer is the most common malignant tumor in women and the leading cause of cancer death in women. About 30% of breast cancer patients have metastasis every year, which greatly increases the mortality rate of breast cancer. The main target organs for metastasis are bone, brain, liver and lung. The breast cancer liver metastasis (BCLM) mechanism is not fully clarified. This is a complex process involving multiple factors, which is not only related to the microenvironment of the primary tumor and liver, but also regulated by a variety of signaling pathways. Clarifying these mechanisms is of great help to guide clinical treatment. With the in-depth study of BCLM, a variety of new treatment schemes such as targeted therapy and endocrine therapy provide new ideas for the cure of BCLM. In this review, we will summarize the molecular mechanism and treatment of BCLM.

Identification of DDX31 as a Potential Oncogene of Invasive Metastasis and Proliferation in PDAC.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignant tumors worldwide and has poor prognosis. DEAD box proteins31 (DDX31) participate in cellular processes involving RNA secondary structure changes. However, the functions of DDX31 in PDAC remain to be elucidated. Methods: The key gene DDX31 was identified using a combination of a risk model and weighted gene co-expression network analysis (WGCNA) with R software. The biological functions of DDX31 in PDAC were investigated through bioinformatics analysis and in vitro experiments. Results: Combining with WGCNA and risk model, DDX31 was identified as a potential factor of the invasive metastasis properties of PDAC, and its expression was closely related to the malignant differentiation of PDAC. The results of gene set enrichment analysis (GSEA) showed that DDX31 was correlated with cell invasive metastasis and proliferation by activating MAPK signaling pathway. The inhibition of DDX31 inhibited the invasion and migration of PDAC cells. Survival analysis showed that DDX31 expression was negatively associated with the poor prognosis in patients with PDAC. Interpretation: DDX31 may be a potential factor for PDAC. The inhibition of DDX31 may be a potential way to treat PDAC.