N6-methyladenine DNA Modification in Glioblastoma.

Genetic drivers of cancer can be dysregulated through epigenetic modifications of DNA. Although the critical role of DNA 5-methylcytosine (5mC) in the regulation of transcription is recognized, the functions of other non-canonical DNA modifications remain obscure. Here, we report the identification of novel N6-methyladenine (N6-mA) DNA modifications in human tissues and implicate this epigenetic mark in human disease, specifically the highly malignant brain cancer glioblastoma. Glioblastoma markedly upregulated N6-mA levels, which co-localized with heterochromatic histone modifications, predominantly H3K9me3. N6-mA levels were dynamically regulated by the DNA demethylase ALKBH1, depletion of which led to transcriptional silencing of oncogenic pathways through decreasing chromatin accessibility. Targeting the N6-mA regulator ALKBH1 in patient-derived human glioblastoma models inhibited tumor cell proliferation and extended the survival of tumor-bearing mice, supporting this novel DNA modification as a potential therapeutic target for glioblastoma. Collectively, our results uncover a novel epigenetic node in cancer through the DNA modification N6-mA.

USP33 deubiquitinates and stabilizes HIF-2alpha to promote hypoxia response in glioma stem cells.

Hypoxia regulates tumor angiogenesis, metabolism, and therapeutic response in malignant cancers including glioblastoma, the most lethal primary brain tumor. The regulation of HIF transcriptional factors by the ubiquitin-proteasome system is critical in the hypoxia response, but hypoxia-inducible deubiquitinases that counteract the ubiquitination remain poorly defined. While the activation of ERK1/2 also plays an important role in hypoxia response, the relationship between ERK1/2 activation and HIF regulation remains elusive. Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells. USP33 is preferentially induced in glioma stem cells by hypoxia and interacts with HIF-2alpha, leading to its stabilization through deubiquitination. The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33. Silencing of USP33 disrupted glioma stem cells maintenance, reduced tumor vascularization, and inhibited glioblastoma growth. Our findings highlight USP33 as an essential regulator of hypoxia response in cancer stem cells, indicating a novel potential therapeutic target for brain tumor treatment.

The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers.

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.

The role of ERp44 in glucose and lipid metabolism.

Endoplasmic Reticulum Protein 44 (ERp44) is a member of the PDI family, named for a molecular weight of 44 kD. White adipose tissue has metabolic and endocrine functions that are important to metabolism. The role of ERp44 in glucose and lipid metabolism is not known yet. The current study was undertaken to investigate the implication of ERp44 in glucose and lipid metabolism. In this study, we generated and characterized ERp44-/- mice. We used type 2 diabetes models and ERp44 knockout mice to show the implication of ERp44 in glucose and lipid metabolism. Knockout newborns had lower blood glucose compared to wild-type. Adult knockouts had abnormal intraperitoneal, glucose, insulin and pyruvic acid tolerance. Lipocytes were smaller and fewer in knockout mice compared to wild-type. Knockouts resisted to high-fat diet-induced obesity. ERp44 expression in white adipose tissue decreased significantly in type 2 diabetes models. Results suggest that ERp44 is closely associated with glucose and lipid metabolism.

Nitric oxide mediates stretch-induced Ca2+ oscillation in smooth muscle.

The stretching of smooth muscle tissue modulates contraction through augmentation of Ca(2+) transients, but the mechanism underlying stretch-induced Ca(2+) transients is still unknown. We found that mechanical stretching and maintenance of mouse urinary bladder smooth muscle strips and single myocytes at 30% and 18% beyond the initial length, respectively, resulted in Ca(2+) oscillations. Experiments indicated that mechanical stretching remarkably increased the production of nitric oxide (NO) as well as the amplitude and duration of muscle contraction. Stretch-induced Ca(2+) oscillations and contractility increases were completely abolished by the NO inhibitor L-NAME or eNOS (also known as NOS3) gene inactivation. Moreover, exposure of eNOS-knockout myocytes to exogenous NO donor induced Ca(2+) oscillations. The stretch-induced Ca(2+) oscillations were greatly inhibited by the selective inositol 1,4,5-trisphosphate receptor (IP3R) inhibitor xestospongin C and partially inhibited by ryanodine. Moreover, the stretch-induced Ca(2+) oscillations were also suppressed by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, but not by the soluble guanylyl cyclase (sGC) inhibitor ODQ. These results suggest that stretching myocyte and maintenance at a certain length results in Ca(2+) oscillations that are NO dependent , and sGC and cGMP independent, and results from the activation of PI3K in smooth muscle.

Expression and function of phosphodiesterases (PDEs) in the rat urinary bladder.

BACKGROUND: It has been shown that hosphodiesterases (PDEs) play an important role in mediating the smooth muscle tone of rat urinary bladder. However, the gene expression profiles of them were still unknown. METHODS: Urinary bladder Strips were obtained from both neonatal and adult Sprague-Dawley rats. RT-PCR/western blot and organ bath were used to measure the expression and function of PDEs. RESULTS: Adult rat urinary bladder expressed various PDE mRNA with the following rank order: PDE5A ≈ PDE9A ≈ PDE10A > PDE2A ≈ PDE4A ≈ PDE4D > PDE4B ≈ PDE3B ≈ PDE8B ≈ PDE7A ≈ PDE7B > PDE1A. PDE1B, PDE1C, PDE3A, PDE4C, PDE8A, and PDE11A were not detected. Of interest, the mRNA and protein of PDE3A were significantly decreased in adult rat urinary bladder compared to neonatal rat urinary bladder. Cilostamide, a specific inhibitor for PDE3, significantly inhibited the amplitude and frequency of carbachol-enhanced phasic contractions of neonatal rat bladder strips by 38.8% and 12.1%, respectively. Compared to the neonatal rat bladder, the effect of cilostamide was significantly blunted in adult rat urinary bladder: the amplitude and frequency of carbachol-enhanced phasic contractions were decreased by 13.4% (P < 0.01 vs neonatal rat bladder) and 4.4%, respectively. However, the mRNA and the protein levels of PDE3B were similar between neonatal and adult rat bladder. CONCLUSION: We found that several PDE isoforms were expressed in the rat urinary bladder with distinct levels. Moreover, we showed that the function of PDE3 was blunted in adult rat bladder likely due to the decreased expression of PDE3A.

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice.

AIMS/HYPOTHESIS: CUG-binding protein 1 (CUGBP1) is a multifunctional RNA-binding protein that regulates RNA processing at several stages including translation, deadenylation and alternative splicing, as well as RNA stability. Recent studies indicate that CUGBP1 may play a role in metabolic disorders. Our objective was to examine its role in endocrine pancreas function through gain- and loss-of-function experiments and to further decipher the underlying molecular mechanisms. METHODS: A mouse model in which type 2 diabetes was induced by a high-fat diet (HFD; 60% energy from fat) and mice on a standard chow diet (10% energy from fat) were compared. Pancreas-specific CUGBP1 overexpression and knockdown mice were generated. Different lengths of the phosphodiesterase subtype 3B (PDE3B) 3' untranslated region (UTR) were cloned for luciferase reporter analysis. Purified CUGBP1 protein was used for gel shift experiments. RESULTS: CUGBP1 is present in rodent islets and in beta cell lines; it is overexpressed in the islets of diabetic mice. Compared with control mice, the plasma insulin level after a glucose load was significantly lower and glucose clearance was greatly delayed in mice with pancreas-specific CUGBP1 overexpression; the opposite results were obtained upon pancreas-specific CUGBP1 knockdown. Glucose- and glucagon-like peptide1 (GLP-1)-stimulated insulin secretion was significantly attenuated in mouse islets upon CUGBP1 overexpression. This was associated with a strong decrease in intracellular cAMP levels, pointing to a potential role for cAMP PDEs. CUGBP1 overexpression had no effect on the mRNA levels of PDE1A, 1C, 2A, 3A, 4A, 4B, 4D, 7A and 8B subtypes, but resulted in increased PDE3B expression. CUGBP1 was found to directly bind to a specific ATTTGTT sequence residing in the 3' UTR of PDE3B and stabilised PDE3B mRNA. In the presence of the PDE3 inhibitor cilostamide, glucose- and GLP-1-stimulated insulin secretion was no longer reduced by CUGBP1 overexpression. Similar to CUGBP1, PDE3B was overexpressed in the islets of diabetic mice. CONCLUSIONS/INTERPRETATION: We conclude that CUGBP1 is a critical regulator of insulin secretion via activating PDE3B. Repressing this protein might provide a potential strategy for treating type 2 diabetes.

Nitric oxide enhances extracellular ATP induced Ca²âº oscillation in HeLa cells.

Calcium (Ca(2+)) oscillations play a central role in varieties of cellular processes including fertilization and immune response, but controversy over the regulation mechanisms still exists. It has been known that nitric oxide (NO) dependently regulates Ca(2+) signaling in most physiopathological processes. Previous study indicated that eNOS translocation during some pathological process influences intracellular Ca(2+) homeostasis. In this study, we investigated the role and mechanism of NO on Ca(2+) release by overexpressing eNOS in cytoplasm (Cyto-eNOS) and endoplasmic reticulum (ER-eNOS) of HeLa cells. We found that the properties of Ca(2+) release were altered by the overexpression of eNOS. The amplitude and frequency of extracellular ATP (eATP)-induced Ca(2+) oscillation were enhanced in both Cyto-eNOS and ER-eNOS cells, respectively. Especially, the enhancement of the amplitude and frequency of the Ca(2+) oscillation was much more significant in the ER-eNOS cells than that of Cyto-eNOS cells. Further study indicated that this effect was abrogated by NO inhibitor, L-NAME, suggesting it was not an artificial result induced by ER stress. Furthermore, an up-regulated phosphorylation of phospholamban (PLB) was observed and the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) function was activated followed by the significant increase in the ER Ca(2+) load. Taken together, we revealed a novel regulatory mechanism of Ca(2+) oscillation.

Intratumoral Delivery of Chimeric Antigen Receptor T Cells Targeting CD133 Effectively Treats Brain Metastases.

PURPOSE: Brain metastases (BM) are mainly treated palliatively with an expected survival of less than 12 months after diagnosis. In many solid tumors, the human neural stem cell marker glycoprotein CD133 is a marker of a tumor-initiating cell population that contributes to therapy resistance, relapse, and metastasis. EXPERIMENTAL DESIGN: Here, we use a variant of our previously described CD133 binder to generate second-generation CD133-specific chimeric antigen receptor T cells (CAR-T) to demonstrate its specificity and efficacy against multiple patient-derived BM cell lines with variable CD133 antigen expression. RESULTS: Using both lung- and colon-BM patient-derived xenograft models, we show that a CD133-targeting CAR-T cell therapy can evoke significant tumor reduction and survival advantage after a single dose, with complete remission observed in the colon-BM model. CONCLUSIONS: In summary, these data suggest that CD133 plays a critical role in fueling the growth of BM, and immunotherapeutic targeting of this cell population is a feasible strategy to control the outgrowth of BM tumors that are otherwise limited to palliative care. See related commentary by Sloan et al., p. 477.

The Emerging Roles and Mechanisms of PAQR3 in Human Cancer: Pathophysiology and Therapeutic Implications.

Cancer was one of the common causes of death in the world, and it was increasing year by year. At present, Progestin and AdipoQ receptor family member 3 (PAQR3) was widely studied in cancer. It has been found that PAQR3 was down regulated in various cancers, such as the gastric cancer, osteosarcoma, glioma, hepatocellular carcinoma, acute lymphoblastic leukemia, laryngeal squamous cell carcinoma, esophageal cancer, breast cancer, non-small cell lung cancer, and colorectal cancer. The decreased expression of PAQR3 was associated with short overall survival and disease-free survival in patients with gastric cancer, hepatocellular carcinoma, laryngeal squamous cell carcinoma, esophageal cancer, breast cancer, and non-small cell lung cancer. PAQR3 could inhibit cancer progression by using the Ras/Raf/MEK/ERK, PI3/AKT, EMT and other mechanisms, and was negatively regulated by the miR-543, miR-15b-5p and miR-15b. The roles and signaling mechanisms of PAQR3, and the relationship between the expression of PAQR3 and prognosis in cancer progression are reviewed in this article, and provides new tumor marker and idea to guide cancer treatment.

CD44+ lung cancer stem cell-derived pericyte-like cells cause brain metastases through GPR124-enhanced trans-endothelial migration.

Brain metastasis of lung cancer causes high mortality, but the exact mechanisms underlying the metastasis remain unclear. Here we report that vascular pericytes derived from CD44+ lung cancer stem cells (CSCs) in lung adenocarcinoma (ADC) potently cause brain metastases through the G-protein-coupled receptor 124 (GPR124)-enhanced trans-endothelial migration (TEM). CD44+ CSCs in perivascular niches generate the majority of vascular pericytes in lung ADC. CSC-derived pericyte-like cells (Cd-pericytes) exhibit remarkable TEM capacity to effectively intravasate into the vessel lumina, survive in the circulation, extravasate into the brain parenchyma, and then de-differentiate into tumorigenic CSCs to form metastases. Cd-pericytes uniquely express GPR124 that activates Wnt7-ß-catenin signaling to enhance TEM capacity of Cd-pericytes for intravasation and extravasation, two critical steps during tumor metastasis. Furthermore, selective disruption of Cd-pericytes, GPR124, or the Wnt7-ß-catenin signaling markedly reduces brain and liver metastases of lung ADC. Our findings uncover an unappreciated cellular and molecular paradigm driving tumor metastasis.

Overexpression of TWF1 promotes lung adenocarcinoma progression and is associated with poor prognosis in cancer patients through the MMP1 signaling pathway.

Background: It has been reported that twinfilin actin binding protein 1 (TWF1) is associated with the progression of breast and pancreatic cancers. However, the roles and mechanisms of TWF1 in lung adenocarcinoma (LUAD) have not been reported. Methods: The expression levels of TWF1 in LUAD and normal tissues were analyzed using The Cancer Genome Atlas (TCGA) database, and validation was carried out with 12 clinical samples. The relationship between TWF1 expression and LUAD patients' clinical indices and immunity was investigated. Cell Counting Kit-8 (CCK-8) and migration and invasion assays were employed to explore the effects of downregulated TWF1 on LUAD cell proliferation and metastasis. Results: TWF1 was upregulated in LUAD tissues, and upregulated TWF1 was correlated with the tumor (T) stage, node (N) stage, clinical classification, overall survival (OS), and progression-free interval (PFI) of LUAD patients. Moreover, the Cox regression analysis showed that TWF1 overexpression was an independent risk factor for the poor prognosis of LUAD patients. TWF1 expression was associated with tumor immune infiltration (such as dendritic cells resting, eosinophils, macrophages M0, and others), drug sensitivity (such as A-770041, Bleomycin, and BEZ235), tumor mutation burden (TMB), and sensitivity to immunotherapy. In the cell model, TWF1 expression interference significantly prohibited LUAD cell proliferation, migration, and invasion, which might be relevant to aberrant MMP1 protein downregulation. Conclusions: TWF1 overexpression was correlated with poor prognoses and immune status of LUAD patients. Inhibited TWF1 expression delayed the growth and migration of cancer cells by downregulating MMP protein, implying that TWF1 is a promising biomarker for the prognoses of LUAD patients.

Novel INHAT repressor drives glioblastoma growth by promoting ribosomal DNA transcription in glioma stem cells.

BACKGROUND: Cancer cells including cancer stem cells exhibit a higher rate of ribosome biogenesis than normal cells to support rapid cell proliferation in tumors. However, the molecular mechanisms governing the preferential ribosome biogenesis in glioma stem cells (GSCs) remain unclear. In this work, we show that the novel INHAT repressor (NIR) promotes ribosomal DNA (rDNA) transcription to support GSC proliferation and glioblastoma (GBM) growth, suggesting that NIR is a potential therapeutic target for GBM. METHODS: Immunoblotting, immunohistochemical and immunofluorescent analysis were used to determine NIR expression in GSCs and human GBMs. Using shRNA-mediated knockdown, we assessed the role and functional significance of NIR in GSCs and GSC-derived orthotopic GBM xenografts. We further performed mass spectrometry analysis, chromatin immunoprecipitation, and other biochemical assays to define the molecular mechanisms by which NIR promotes GBM progression. RESULTS: Our results show that high expression of NIR predicts poor survival in GBM patients. NIR is enriched in the nucleoli of GSCs in human GBMs. Disrupting NIR markedly suppresses GSC proliferation and tumor growth by inhibiting rDNA transcription and pre-ribosomal RNA synthesis. In mechanistic studies, we find that NIR activates rDNA transcription to promote GSC proliferation by cooperating with Nucleolin (NCL) and Nucleophosmin 1 (NPM1), 2 important nucleolar transcription factors. CONCLUSIONS: Our study uncovers a critical role of NIR-mediated rDNA transcription in the malignant progression of GBM, indicating that targeting this axis may provide a novel therapeutic strategy for GBM.

Interfering with ITGB1-DT expression delays cancer progression and promotes cell sensitivity of NSCLC to cisplatin by inhibiting the MAPK/ERK pathway.

Long non-coding RNA ITGB1-DT is involved in the regulation of cancer growth and metastasis. However, the roles of ITGB1-DT in non-small cell lung cancer (NSCLC) progression and sensitivity to cisplatin has not been elucidated. ITGB1-DT expression in NSCLC tissues, and the relationship between ITGB1-DT expression with NSCLC diagnosis, prognosis, clinicopathological features, and immune cell infiltration were investigated in The Cancer Gene Atlas (TCGA) database. The roles and mechanisms of ITGB1-DT in cell growth, migration, and drug sensitivity of NSCLC cells were explored in the cell model. The prognostic nomograms of ITGB1-DT-related genes were evaluated using bioinformatics. ITGB1-DT was overexpressed in NSCLC. Elevated ITGB1-DT expression was related to the late T stage, N stage, M stage, short overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) of NSCLC patients. ITGB1-DT was the independent risk factors for poor prognosis, and had diagnostic value for NSCLC patients. Interfering with the ITGB1-DT expression can inhibit the proliferation, migration, and invasion of A549, H1299, and drug-resistant A549/DDP, possibly due to the inhibition of p38 MAPK and ERK phosphorylation levels. ITGB1-DT expression was correlated with the levels of NSCLC immune infiltration cells, such as the TReg, Th, and NK cells. ITGB1-DT-related gene nomograms were associated with the prognosis, and were expected to evaluate the prognosis of NSCLC patients. In conclusion, inhibition of ITGB1-DT expression delayed the growth and metastasis of NSCLC using the MAPK/ERK signaling mechanism and enhanced the sensitivity of NSCLC to cisplatin drugs. These results indicate that ITGB1-DT might be a biomarker for evaluating the diagnosis and prognosis of NSCLC patients.

ERp44 is required for endocardial cushion development by regulating VEGFA secretion in myocardium.

OBJECTIVES: Endocardial cushions are precursors of the valve septum complex that separates the four heart chambers. Several genes have been implicated in the development of endocardial cushions. Specifically, ERp44 has been found to play a role in the early secretory pathway, but its function in heart development has not been well studied. MATERIALS AND METHODS: In this study, we established conditional and tissue-specific knockout mouse models. The morphology, survival rate, the development of heart and endocardial cushion were under evaluation. The relationship between ERp44 and VEGFA was investigated by transcriptome, qPCR, WB, immunofluorescence and immunohistochemistry. RESULTS: ERp44 knockout (KO) mice were smaller in size, and most mice died during early postnatal life. KO hearts exhibited the typical phenotypes of congenital heart diseases, such as abnormal heart shapes and severe septal and valvular defects. Similar phenotypes were found in cTNT-Cre+/- ; ERp44fl / fl mice, which indicated that myocardial ERp44 principally controls endocardial cushion formation. Further studies demonstrated that the deletion of ERp44 significantly decreased the proliferation of cushion cells and impaired the endocardial-mesenchymal transition (EndMT), which was followed by endocardial cushion dysplasia. Finally, we found that ERp44 was directly bound to VEGFA and controlled its release, further regulating EndMT. CONCLUSION: We demonstrated that ERp44 plays a specific role in heart development. ERp44 contributes to the development of the endocardial cushion by affecting VEGFA-mediated EndMT.

Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma.

MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here, we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on target, leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell-cycle arrest and apoptosis. We further show that an orally available small-molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.

Thoracic endometriosis: a case report and review of the literature.

Thoracic endometriosis is characterized by the presence of normal functioning endometrial tissues in normal pleural, diaphragm, or lung parenchyma, and main clinical symptoms include pneumothorax, menstrual hemothorax, menstrual hemoptysis, and pulmonary nodules. Chest X-ray (CXR), computed tomography (CT), magnetic resonance imaging (MRI), bronchoscopy, and surgical biopsy could be applied to the diagnosis of TE. Both drug therapy and surgical treatment were widely used to treat this disease, but no theory was used to guide the choice of treatment options. This paper introduces a case of menstrual hemoptysis due to endometriosis, and the final surgical treatment was chosen. The patient recovered well postoperatively and reported no hemoptysis during 2 months of follow-up. Reexamination of the chest through CT showed no ground-glass lesions or pulmonary exudative lesions. We make the following recommendations for patient selection when considering a surgical approach to the treatment of TE. Patients for whom surgery should be considered are those who (I) do not respond to drug therapy or relapse once drug therapy is withdrawn, (II) cannot tolerate drug therapy or who may wish to get pregnant in the near future (III) have limited lesions which are able to be completely removed during surgery. Patients in whom surgery is not recommended include those who have extensive lesions which cannot be surgically removed, including those with diaphragm or pleural involvement as the diseased tissues must be completely removed to avoid recurrence, and those who are unfit for surgery.

Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells.

Glioblastoma (GBM) contains abundant tumor-associated macrophages (TAMs). The majority of TAMs are tumor-promoting macrophages (pTAMs), while tumor-suppressive macrophages (sTAMs) are the minority. Thus, reprogramming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small-molecule compounds, we find that inhibiting ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) with MK-8931 potently reprograms pTAMs into sTAMs and promotes macrophage phagocytosis of glioma cells; moreover, low-dose radiation markedly enhances TAM infiltration and synergizes with MK-8931 treatment to suppress malignant growth. BACE1 is preferentially expressed by pTAMs in human GBMs and is required to maintain pTAM polarization through trans-interleukin 6 (IL-6)-soluble IL-6 receptor (sIL-6R)-signal transducer and activator of transcription 3 (STAT3) signaling. Because MK-8931 and other BACE1 inhibitors have been developed for Alzheimer's disease and have been shown to be safe for humans in clinical trials, these inhibitors could potentially be streamlined for cancer therapy. Collectively, this study offers a promising therapeutic approach to enhance macrophage-based therapy for malignant tumors.

ERp44/CG9911 promotes fat storage in Drosophila adipocytes by regulating ER Ca2+ homeostasis.

Fat storage is one of the important strategies employed in regulating energy homeostasis. Impaired lipid storage causes metabolic disorders in both mammals and Drosophila. In this study, we report CG9911, the Drosophila homolog of ERp44 (endoplasmic reticulum protein 44) plays a role in regulating adipose tissue fat storage. Using the CRISPR/Cas9 system, we generated a CG9911 mutant line deleting 5 bp of the coding sequence. The mutant flies exhibit phenotypes of lower bodyweight, fewer lipid droplets, reduced TAG level and increased expression of lipolysis related genes. The increased lipolysis phenotype is enhanced in the presence of ER stresses and suppressed by a reduction of the ER Ca2+. Moreover, loss of CG9911 per se results in a decrease of ER Ca2+ in the fat body. Together, our results reveal a novel function of CG9911 in promoting fat storage via regulating ER Ca2+ signal in Drosophila.