Mrakia polaris sp. nov. and Mrakia amundsenii sp. nov. (Mrakiaceae, Cystofilobasidiales), two novel psychrophilic yeast species isolated from Arctic habitats.

Four yeast strains belonging to the basidiomycetous yeast genus Mrakia were isolated from diverse habitats in the Ny-Ålesund region (Svalbard, High Arctic): two from vascular plants, one from seawater and one from freshwater. Phylogenetic analysis, based on the ITS region and the D1/D2 domain of the 28S rRNA gene, identified these four strains as representing two novel species within the genus Mrakia. The names Mrakia polaris sp. nov. (MycoBank number: MB 852063) and Mrakia amundsenii sp. nov. (MycoBank number: MB 852064) are proposed. These two new species show distinct psychrophilic adaptations, as they exhibit optimal growth at temperatures between 10 and 15°C, while being unable to grow at 25°C. The holotype of M. polaris sp. nov. is CPCC 300345T, and the holotype of M. amundsenii sp. nov. is CPCC 300572T.

Effect of different anaesthetic techniques on the prognosis of patients with colorectal cancer after resection: a systematic review and meta-analysis.

Background: The effect of total intravenous anaesthesia (TIVA) and inhalation anaesthesia (IA) on the prognosis of patients with colorectal cancer after resection is controversial. This study aimed to explore the effects of different anaesthesia methods on the postoperative prognosis of colorectal cancer. Methods: PubMed, Embase and Cochrane Library databases were searched for relevant literature from each database's inception until 18 November 2023. The literature topic was to compare the effects of TIVA and IA on the prognosis of patients undergoing colorectal cancer resection. Results: Six studies were selected for meta-analysis. The studies involved 111043 patients, with a trial size of 1001-88184 people. A statistically significant difference was observed in the overall survival (OS) between colorectal cancer patients administered TIVA and IA (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.70-0.99), but none in recurrence-free survival (RFS) (HR, 0.99; 95% CI, 0.90-1.08). In the subgroup analysis of OS, no statistically significant difference was observed between colorectal cancer patients administered TIVA and IA in Asia (HR, 0.77; 95% CI, 0.57-1.05), and not in Europe (HR, 0.99; 95% CI, 0.93-1.06). Regarding tumour location, no significant association was found between TIVA and IA in the colon, rectum and colorectum ((HR, 0.70; 95% CI, 0.38-1.28), (HR, 0.95; 95% CI, 0.83-1.08) and (HR, 0.99; 95% CI, 0.93-1.06), respectively). Conclusion: OS differed significantly between patients administered TIVA and IA when undergoing colorectal cancer resection, but no difference was observed in RFS. The prognostic effects of TIVA and IA differed. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023453185, identifier CRD42023453185.

Fabrication and in vitro/vivo evaluation of quercetin nanocrystals stabilized by glycyrrhizic acid for liver targeted drug delivery.

The purpose of this study was to design novel drug nanocrystals (NCs) stabilized by glycyrrhizic acid (GL) for achieving liver targeted drug delivery due to the presence of GL receptor in the hepatocytes. Quercetin (QT) exhibits good pharmacological activities for the treatment of liver diseases, including liver steatosis, fatty hepatitis, liver fibrosis, and liver cancer. It was selected as a model drug owing to its poor water solubility. QT NCs stabilized by GL (QT-NCs/GL) were fabricated by wet media milling technique and systemically evaluated. QT-NCs stabilized by poloxamer 188 (QT-NCs/P188) were prepared as a reference for comparison of in vitro and in vivo performance with QT-NCs/GL. QT-NCs/GL and QT-NCs/P188 with similar particle size around 130 nm were successfully fabricated by wet media milling technique. Both of QT-NCs/GL and QT-NCs/P188 showed irregular particles and short rods under SEM. XRPD revealed that QT-NCs/GL and QT-NCs/P188 remained in crystalline state with reduced crystallinity. QT-NCs/GL and QT-NCs/P188 exhibited significant solubility increase and drug release improvement of QT as compared to raw QT. No significant difference for the plasma concentration-time curves and pharmacokinetic parameters of QT were found following intravenous administration of QT-NCs/GL and QT-NCs/P188. However, a significantly higher liver distribution of QT following intravenous administration of QT-NCs/GL was observed in comparison to QT-NCs/P188, indicating QT-NCs stabilized by GL could achieve liver targeted delivery of QT. It could be concluded that GL used as stabilizer of QT NCs have a great potential for liver targeted drug delivery.

Prognostic value of depression and anxiety on colorectal cancer-related mortality: a systematic review and meta-analysis based on univariate and multivariate data.

BACKGROUND: Depression and anxiety are common mental disorders in patients with colorectal cancer (CRC); however, it remains unclear whether they are related to cancer mortality. METHOD: Based on a systematic literature search, 12 eligible studies involving 26,907 patients with CRC were included in this study. RESULTS: Univariate analysis revealed that anxiety was associated with an all-cause mortality rate of 1.42 (1.02, 1.96), whereas multivariate analysis revealed that anxiety was not associated with an all-cause mortality rate of 0.73 (0.39, 1.36). In univariate and multivariate analyses, depression was associated with all-cause mortality rates of 1.89 (1.68, 2.13) and 1.62 (1.27, 2.06), respectively, but not with the cancer-associated mortality rate of 1.16 (0.91, 1.48) in multivariate analyses. Multivariate subgroup analysis of depression and all-cause mortality showed that younger age (≤65 years), being diagnosed with depression/anxiety after a confirmed cancer diagnosis, and shorter follow-up time (<5 years) were associated with poor prognosis. CONCLUSIONS: Our study emphasizes the key roles of depression and anxiety as independent factors for predicting the survival of patients with CRC. However, owing to the significant heterogeneity among the included studies, the results should be interpreted with caution. Early detection and effective treatment of depression and anxiety in patients with CRC have public health and clinical significance.

Lactate acid promotes PD-1+ Tregs accumulation in the bone marrow with high tumor burden of Acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) displayed poor response to programmed death-1 (PD-1) blockade therapy. Regulatory T cells (Tregs) was one of major immunosuppressive components in Tumor microenvironment and plays a vital role in the resistance of immunotherapy. Coinhibitory receptors regulate function of regulatory Tregs and are associated with resistance of PD-1 blockade. However, the coinhibitory receptors expression and differentiated status of Tregs in AML patients remain to be unclear. METHODS: Phenotypic determination of Tregs and CD8+ T cells in bone marrow of healthy donors and AML patients was performed by flow cytometry. Coculture experiments of AML and Tregs in vitro were performed and the concentrations of lactate acid (LA) in the supernatant were examined by ELISA. RESULTS: More Tregs differentiated into effector subsets in AML patients. However, PD-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression on Tregs were comparable in healthy donors and AML patients. Further analysis showed that PD-1+ and PD-1+TIGIT+Tregs are more abundant in the bone marrow of patients with higher leukemic load. Moreover, PD-1+ Tregs accumulation was associated with higher level of senescent CD4+ T cells and increased frequencies of exhausted CD4+ as well as CD8+ T cells. Notably, neither Tregs nor their effector subsets were decreased among patients in complete remission. PD-1 expression was significantly downregulated in Tregs after achieving complete remission. Mechanistically, both AML cell line (KG-1α) and primary AML blasts produced high concentration of LA. Blockade of LA by lactate transporter inhibitor abrogated the upregulation of PD-1 by AML cells. CONCLUSION: PD-1+ Tregs accumulation in bone marrow in higher leukemic burden setting was linked to lactate acid secreted by AML blasts and decreased after disease remission. Our findings provided a novel insight into Tregs in AML and possible mechanism for resistance of PD-1 blockade in AML.

Group XIV C-type lectins: emerging targets in tumor angiogenesis.

C-type lectins, distinguished by a C-type lectin binding domain (CTLD), are an evolutionarily conserved superfamily of glycoproteins that are implicated in a broad range of physiologic processes. The group XIV subfamily of CTLDs are comprised of CD93, CD248/endosialin, CLEC14a, and thrombomodulin/CD141, and have important roles in creating and maintaining blood vessels, organizing extracellular matrix, and balancing pro- and anti-coagulative processes. As such, dysregulation in the expression and downstream signaling pathways of these proteins often lead to clinically relevant pathology. Recently, group XIV CTLDs have been shown to play significant roles in cancer progression, namely tumor angiogenesis and metastatic dissemination. Interest in therapeutically targeting tumor vasculature is increasing and the search for novel angiogenic targets is ongoing. Group XIV CTLDs have emerged as key moderators of tumor angiogenesis and metastasis, thus offering substantial therapeutic promise for the clinic. Herein, we review our current knowledge of group XIV CTLDs, discuss each's role in malignancy and associated potential therapeutic avenues, briefly discuss group XIV CTLDs in the context of two other relevant lectin families, and offer future direction in further elucidating mechanisms by which these proteins function and facilitate tumor growth.

Structural insight into CD93 recognition by IGFBP7.

The CD93/IGFBP7 axis proteins are key factors expressed in endothelial cells (EC) that mediate EC angiogenesis and migration. Their upregulation contributes to tumor vascular abnormality and a blockade of this interaction promotes a favorable tumor microenvironment for therapeutic interventions. However, the interactions of these proteins with each other remain unclear. In this study, we determined a partial structure of the human CD93-IGFBP7 complex comprising the EGF1 domain of CD93 and the IB domain of IGFBP7. Mutagenesis studies confirmed interactions and specificities. Cellular and mouse tumor studies demonstrated the physiological relevance of the CD93-IGFBP7 interaction in EC angiogenesis. Our study provides leads for the development of therapeutic agents to precisely disrupt unwanted CD93-IGFBP7 signaling in the tumor microenvironment. Additionally, analysis of the CD93 full-length architecture provides insights into how CD93 protrudes on the cell surface and forms a flexible platform for binding to IGFBP7 and other ligands.

The chromatin remodeling protein BRG1 regulates HSC-myofibroblast differentiation and liver fibrosis.

Excessive fibrogenic response in the liver disrupts normal hepatic anatomy and function heralding such end-stage liver diseases as hepatocellular carcinoma and cirrhosis. Myofibroblasts, derived primarily from hepatic stellate cells (HSCs), are the effector of liver fibrosis. In the present study we investigated the mechanism by which Brahma-related gene 1 (BRG1, encoded by Smarca4) regulates HSC-myofibroblast transition and the implication in intervention against liver fibrosis. We report that BRG1 expression was elevated during HSC maturation in cell culture, in animal models, and in human cirrhotic liver biopsy specimens. HSC-specific deletion of BRG1 attenuated liver fibrosis in several different animal models. In addition, BRG1 ablation in myofibroblasts ameliorated liver fibrosis. RNA-seq identified IGFBP5 as a novel target for BRG1. Over-expression of IGFBP5 partially rescued the deficiency in myofibroblast activation when BRG1 was depleted. On the contrary, IGFBP5 knockdown suppressed HSC-myofibroblast transition in vitro and mollified liver fibrosis in mice. Mechanistically, IGFBP5 interacted with Bat3 to stabilize the Bat3-TßR complex and sustain TGF-ß signaling. In conclusion, our data provide compelling evidence that BRG1 is a pivotal regulator of liver fibrosis by programming HSC-myofibroblast transition.

Glucose-induced and ChREBP: MLX-mediated lipogenic program promotes hepatocellular carcinoma development.

The Carbohydrate Response Element (ChoRE) Binding Protein (ChREBP) and its binding partner Max-like protein X (MLX) mediate transcription of lipogenic genes under glucose-rich conditions. Dysregulation of glucose and lipid metabolism frequently occurs in cancers, including Hepatocellular Carcinomas (HCCs). However, it is currently unclear whether the glucose-induced lipogenic program plays a role in the development of HCCs. Here, we show that MLX expression is elevated in HCC specimens and downregulation of MLX expression inhibits proliferation of HCC cells. In mice, liver-specific knockout of Mlx results in dramatic decrease in the expression of lipogenic genes and lipid levels in circulation. Interestingly, in the absence of Mlx, the development of tumors in multiple HCC models, such as diethylnitrosamine (DEN) treatment and hydrodynamic injection of oncogenes (AKT/RAS or CTNNB1/RAS), is robustly blocked. However, a high-fat diet can partially restore tumorigenesis in Mlx-deficient livers, indicating a critical role of lipid synthesis in HCC development. In addition, liver-specific expression of a dominant negative MLX (dnMLX) via adeno-associated virus effectively blocks tumorigenesis in mice. Thus, the glucose-induced lipogenic program is required in the development of HCC, and the ChREBP: MLX transcription factors serve as a potential target for cancer therapies.

Ubiquitin specific peptidase 47 contributes to liver regeneration.

AIMS: Hepatocytes resume proliferation following liver injuries to compensate for the loss of liver mass. Robust liver regeneration is an intrinsic and pivotal process that facilitates restoration of liver anatomy and function. In the present study we investigated the role of ubiquitin-specific peptidase 47 (USP47) in liver regeneration. METHODS AND MATERIALS: Proliferation of hepatocytes was evaluated by Ki67 staining in vivo and EdU incorporation in vitro. DNA-protein interaction was evaluated by chromatin immunoprecipitation (ChIP). RESULTS: USP47 expression was up-regulated in hepatocytes isolated from mice subjected to partial hepatectomy (PHx) or exposed to HGF treatment. Ingenuity pathway analysis revealed E2F1 as a primary regulator of USP47 transcription. Reporter assay and ChIP assay confirmed that E2F1 directly bound to the USP47 promoter and activated USP47 transcription. Consistently, E2F1 knockdown abrogated USP47 induction by HGF. Compared to the wild type littermates, USP47 knockout mice displayed compromised liver regeneration following PHx. In addition, USP47 inhibition by a small-molecule compound impaired liver regeneration in mice. On the contrary, USP47 over-expression enhanced proliferation of hepatocytes in vitro and promoted liver regeneration in mice. Importantly, a positive correlation between USP47 expression and hepatocyte proliferation was identified in patients with acute liver failure (ALF). SIGNIFICANCE: Our data suggest that USP47, transcriptionally activated by E2F1, plays an essential role in liver regeneration.

Structural insight into CD93 recognition by IGFBP7.

The CD93/IGFBP7 axis are key factors expressed in endothelial cells (EC) that mediate EC angiogenesis and migration. Upregulation of them contributes to tumor vascular abnormality and blockade of this interaction promotes a favorable tumor microenvironment for therapeutic interventions. However, how these two proteins associated to each other remains unclear. In this study, we solved the human CD93-IGFBP7 complex structure to elucidate the interaction between the EGF 1 domain of CD93 and the IB domain of IGFBP7. Mutagenesis studies confirmed the binding interactions and specificities. Cellular and mouse tumor studies demonstrated the physiological relevance of the CD93-IGFBP7 interaction in EC angiogenesis. Our study provides hints for development of therapeutic agents to precisely disrupt unwanted CD93-IGFBP7 signaling in the tumor microenvironment. Additionally, analysis of the CD93 full-length architecture provides insights into how CD93 protrudes on the cell surface and forms a flexible platform for binding to IGFBP7 and other ligands.

Proteolytic activation of angiomotin by DDI2 promotes angiogenesis.

The scaffolding protein angiomotin (AMOT) is indispensable for vertebrate embryonic angiogenesis. Here, we report that AMOT undergoes cleavage in the presence of lysophosphatidic acid (LPA), a lipid growth factor also involved in angiogenesis. AMOT cleavage is mediated by aspartic protease DNA damage-inducible 1 homolog 2 (DDI2), and the process is tightly regulated by a signaling axis including neurofibromin 2 (NF2), tankyrase 1/2 (TNKS1/2), and RING finger protein 146 (RNF146), which induce AMOT membrane localization, poly ADP ribosylation, and ubiquitination, respectively. In both zebrafish and mice, the genetic inactivation of AMOT cleavage regulators leads to defective angiogenesis, and the phenotype is rescued by the overexpression of AMOT-CT, a C-terminal AMOT cleavage product. In either physiological or pathological angiogenesis, AMOT-CT is required for vascular expansion, whereas uncleavable AMOT represses this process. Thus, our work uncovers a signaling pathway that regulates angiogenesis by modulating a cleavage-dependent activation of AMOT.

Grb2-related adaptor protein GRAP is a novel regulator of liver fibrosis.

AIMS: Excessive liver fibrosis is frequently observed in chronic liver diseases and associated with decline of liver functions. Hepatic stellate cells (HSCs) are considered the principal mediator of liver fibrosis by trans-differentiating into myofibroblasts. In the present study we investigated the role of Grb2-related adaptor protein (GRAP) in HSC activation and liver fibrosis. METHODS AND MATERIALS: Liver fibrosis was induced by carbon tetrachloride (CCl4) injection. Gene expression was examined by quantitative PCR. Cell proliferation was evaluated by EdU incorporation. DNA-protein interaction was examined by chromatin immunoprecipitation (ChIP). KEY FINDINGS: GRAP expression was up-regulated during HSC-myofibroblast transition both in vivo and in vitro. Mechanistically, serum response factor (SRF) and myocardin-related transcription factor A (MRTF-A) formed a complex to bind to the GRAP promoter and activate GRAP transcription. Small interfering RNA (siRNA) mediated GRAP silencing blocked HSC-myofibroblast transition in vitro. Importantly, adeno-associated virus 6 (AAV6) mediated GRAP knockdown in myofibroblasts attenuated liver fibrosis in mice. Of note, inhibition of ERK signaling abrogated enhancement of HSC-myofibroblast transition by GRAP over-expression. SIGNIFICANCE: Our data suggest that GRAP, possibly via ERK activation, regulates HSC-myofibroblast transition and contributes to liver fibrosis. Screening for small-molecule GRAP inhibitors may yield novel therapeutic solutions against liver fibrosis.

Loss of CD28 expression associates with severe T-cell exhaustion in acute myeloid leukemia.

Introduction: Despite accumulated evidence in T-cell exhaustion in acute myeloid leukemia (AML), the immunotherapeutic targeting exhausted T cells such as programmed cell death protein 1 (PD-1) blockade in AML failed to achieve satisfying efficacy. Characteristics of exhausted T cells in AML remained to be explored. Methods: Phenotypic analysis of T cells in bone marrow (BM) using flow cytometry combining senescent and exhausted markers was performed in de novo AML patients and healthy donors as well as AML patients with complete remission (CR). Functional analysis of T-cell subsets was also performed in de novo AML patients using flow cytometry. Results: T cells experienced a phenotypic shift to terminal differentiation characterized by increased loss of CD28 expression and decrease of naïve T cells. Additionally, lack of CD28 expression could help define a severely exhausted subset from generally exhausted T cells (PD-1+TIGIT+). Moreover, CD28- subsets rather than CD28+ subsets predominantly contributed to the significant accumulation of PD-1+TIGIT+ T cells in AML patients. Further comparison of de novo and CR AML patients showed that T-cell exhaustion status was improved after disease remission, especially in CD28+ subsets. Notably, higher frequency of CD28-TIGIT-CD4+ T cells correlated with the presence of minimal residual disease in AML-CR group. However, the correlation between CD28- exhausted T cells and cytogenetic risk or white blood cell count was not observed, except for that CD28- exhausted CD4+ T cells correlated with lymphocyte counts. Intriguingly, larger amount of CD28-TGITI+CD8+ T cells at diagnosis was associated with poor treatment response and shorter leukemia free survival. Discussion: In summary, lack of CD28 expression defined a severely exhausted status from exhausted T cells. Accumulation of CD28- exhausted T cells was linked to occurrence of AML, and correlated to poor clinical outcome. Our data might facilitate the development of combinatory strategies to improve the efficacy of PD-1 blockade in AML.

Two Hippo signaling modules orchestrate liver size and tumorigenesis.

The Hippo pathway is a central regulator of organ size and tumorigenesis and is commonly depicted as a kinase cascade, with an increasing number of regulatory and adaptor proteins linked to its regulation over recent years. Here, we propose that two Hippo signaling modules, MST1/2-SAV1-WWC1-3 (HPO1) and MAP4K1-7-NF2 (HPO2), together regulate the activity of LATS1/2 kinases and YAP/TAZ transcriptional co-activators. In mouse livers, the genetic inactivation of either HPO1 or HPO2 module results in partial activation of YAP/TAZ, bile duct hyperplasia, and hepatocellular carcinoma (HCC). On the contrary, inactivation of both HPO1 and HPO2 modules results in full activation of YAP/TAZ, rapid development of intrahepatic cholangiocarcinoma (iCCA), and early lethality. Interestingly, HPO1 has a predominant role in regulating organ size. HPO1 inactivation causes a homogenous YAP/TAZ activation and cell proliferation across the whole liver, resulting in a proportional and rapid increase in liver size. Thus, this study has reconstructed the order of the Hippo signaling network and suggests that LATS1/2 and YAP/TAZ activities are finetuned by HPO1 and HPO2 modules to cause different cell fates, organ size changes, and tumorigenesis trajectories.

Gas Diffusion Layer for Proton Exchange Membrane Fuel Cells: A Review.

Proton exchange membrane fuel cells (PEMFCs) are an attractive type of fuel cell that have received successful commercialization, benefitted from its unique advantages (including an all solid-state structure, a low operating temperature and low environmental impact). In general, the structure of PEMFCs can be regarded as a sequential stacking of functional layers, among which the gas diffusion layer (GDL) plays an important role in connecting bipolar plates and catalyst layers both physically and electrically, offering a route for gas diffusion and drainage and providing mechanical support to the membrane electrode assemblies. The GDL commonly contains two layers; one is a thick and rigid macroporous substrate (MPS) and the other is a thin microporous layer (MPL), both with special functions. This work provides a brief review on the GDL to explain its structure and functions, summarize recent progress and outline future perspectives.

Comparison of laparoscopic and open pancreaticoduodenectomy for the treatment of distal cholangiocarcinoma: A propensity score matching analysis.

Background: There are few studies comparing the oncological outcomes of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) for distal cholangiocarcinoma (DCC). Our objective was to assess the short-term efficacy and long-term survival of LPD and OPD in patients with DCC. Methods: The data of 124 DCC patients who underwent LPD or OPD at the Third Affiliated Hospital of Soochow University from May 2010 to May 2021 were retrospectively analyzed. Propensity score matching was performed to balance the two groups of baseline characteristics. After 1:1 matching, the overall survival (OS) of the two groups was compared by the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were used to identify independent predictors of OS. Results: The original cohort consisted of 124 patients. Nineteen patients were excluded because of incomplete baseline or follow-up data, and the remaining 105 patients were divided into two cohorts (45 in the LPD group and 60 in the OPD group). The LPD group showed more favorable results in OS analysis (LPD vs. OPD, 56.4 [46.2-66.5] vs. 48.9 [36.4-61.4], months, P=0. 01). PSM analysis identified 30 pairs of patients, and differences between matching groups were still significant (LPD vs. OPD, 67.9[58.2-77.6] vs. 47.4[31.4-67.5], months, P=0.002). Moreover, the LPD group experienced less intraoperative bleeding (LPD vs. OPD, 292.67 vs. 519.17 mL, P=0.002). Univariate analysis showed that surgical modality (P=0.012), carbohydrate antigen 19-9 (P=0.043), carcinoembryonic antigen (P=0.003), neutrophil-to-lymphocyte ratio (P=0.012), blood transfusion (P=0.031), clinically relevant postoperative pancreatic fistula (P<0.001) and lymphatic metastasis (P=0.004) were predictors of OS. Multivariate Cox analysis demonstrated that carbohydrate antigen 19-9 (P=0.048), carcinoembryonic antigen (P=0.031) and lymphatic metastasis (P=0.023) were independent predictive factors of OS. However, adjuvant therapy had no significant effect on the OS of DCC patients after radical pancreaticoduodenectomy (P>0.05). Conclusions: For DCC patients, LPD may be a more recommended procedure because of its advantages over OPD in terms of intraoperative bleeding and long-term survival.

Atypical chemokine receptors: emerging therapeutic targets in cancer.

Atypical chemokine receptors (ACKRs) regulate the availability of chemokines via chemokine scavenging, while also having the capacity to elicit downstream function through ß-arrestin coupling. This contrasts with conventional chemokine receptors that directly elicit immune cell migration through G protein-coupled signaling. The significance of ACKRs in cancer biology has previously been poorly understood, but recent findings have highlighted the multifaceted role of these receptors in tumorigenesis and immune response modulation within the tumor microenvironment (TME). Additionally, recent research has expanded our understanding of the function of several receptors including GPR182, CCRL2, GPR1, PITPNM3, and C5aR2 that share similarities with the ACKR family. In this review, we discuss these recent developments, and highlight the opportunities and challenges of pharmacologically targeting ACKRs in cancer.

Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a therapeutic target in YAP/TAZ-active cancers.

The Hippo tumor-suppressor pathway is frequently dysregulated in human cancers and represents a therapeutic target. However, strategies targeting the mammalian Hippo pathway are limited because of the lack of a well-established cell-surface regulator. Here, we show that transmembrane protein KIRREL1, by interacting with both SAV1 and LATS1/2, promotes LATS1/2 activation by MST1/2 (Hippo kinases), and LATS1/2 activation, in turn, inhibits activity of YAP/TAZ oncoproteins. Conversely, YAP/TAZ directly induce the expression of KIRREL1 in a TEAD1-4-dependent manner. Indeed, KIRREL1 expression positively correlates with canonical YAP/TAZ target gene expression in clinical tumor specimens and predicts poor prognosis. Moreover, transgenic expression of KIRREL1 effectively blocks tumorigenesis in a mouse intrahepatic cholangiocarcinoma model, indicating a tumor-suppressor role of KIRREL1. Hence, KIRREL1 constitutes a negative feedback mechanism regulating the Hippo pathway and serves as a cell-surface marker and potential drug target in cancers with YAP/TAZ dependency.