CDKL3 is a targetable regulator of cell cycle progression in cancers.

Cell cycle regulation is largely abnormal in cancers. Molecular understanding and therapeutic targeting of the aberrant cell cycle are essentially meaningful. Here, we identified an under-appreciated Serine/Threonine kinase, CDKL3 (Cyclin-dependent kinase like 3), crucially drives the rapid cell cycle progression and cell growth in cancers. Mechanism-wise, CDKL3 localizes in the nucleus and associates with specific cyclin to directly phosphorylate Retinoblastoma (Rb) for quiescence exit. In parallel, CDKL3 prevents the ubiquitin-proteasomal degradation of CDK4 by direct phosphorylation on T172 to sustain G1 phase advancement. The crucial function of CDKL3 in cancers was demonstrated both in vitro and in vivo. We also designed, synthesized and characterized a first-in-class CDKL3-specific inhibitor, HZ1. HZ1 exhibits greater potency than CDK4/6 (Cyclin-dependent kinase 4/6) inhibitor in pan-cancer treatment by causing cell cycle arrest and overcomes the acquired resistance of the latter. In particular, CDKL3 has significant clinical relevance in colon cancer, and the effectiveness of HZ1 was demonstrated by murine and patient-derived cancer models. Collectively, this work presented an integrated paradigm of cancer cell cycle regulation and suggested CDKL3-targeting as a feasible approach in cancer treatment.

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer.

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

The emerging understanding of Frizzled receptors.

The Wnt signaling pathway is a huge network governing development and homeostasis, dysregulation of which is associated with a myriad of human diseases. The Frizzled receptor (FZD) family comprises receptors for Wnt ligands, which indispensably mediate Wnt signaling jointly with a variety of co-receptors. Studies of FZDs have revealed that 10 FZD subtypes play diverse roles in physiological processes. At the same time, dysregulation of FZDs is also responsible for various diseases, in particular human cancers. Enormous attention has been paid to the molecular understanding and targeted therapy of FZDs in the past decade. In this review, we summarize the latest research on FZD structure, function, regulation and targeted therapy, providing a basis for guiding future research in this field.

Progress in Research on White Organic Light-Emitting Diodes Based on Ultrathin Emitting Layers.

White organic light-emitting diodes (WOLEDs) hold vast prospects in the fields of next-generation displays and solid-state lighting. Ultrathin emitting layers (UEMLs) have become a research hotspot because of their unique advantage. On the basis of simplifying the device structure and preparation process, they can achieve electroluminescent performance comparable to that of doped devices. In this review, we first discuss the working principles and advantages of WOLEDs based on UEML architecture, which can achieve low cost and more flexibility by simplifying the device structure and preparation process. Subsequently, the successful applications of doping and non-doping technologies in fluorescent, phosphorescent, and hybrid WOLEDs combined with UEMLs are discussed, and the operation mechanisms of these WOLEDs are emphasized briefly. We firmly believe that this article will bring new hope for the development of UEML-based WOLEDs in the future.

A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.

The novel small molecule E0924G dually regulates bone formation and bone resorption through activating the PPARδ signaling pathway to prevent bone loss in ovariectomized rats and senile mice.

Osteoporosis is particularly prevalent among postmenopausal women and the elderly. In the present study, we investigated the effect of the novel small molecule E0924G (N-(4-methoxy-pyridine-2-yl)-5-methylfuran-2-formamide) on osteoporosis. E0924G significantly increased the protein expression levels of osteoprotegerin (OPG) and runt-related transcription factor 2 (RUNX2), and thus significantly promoted osteogenesis in MC3T3-E1 cells. E0924G also significantly decreased osteoclast differentiation and inhibited bone resorption and F-actin ring formation in receptor activator of NF-κB ligand (RANKL)-induced osteoclasts from RAW264.7 macrophages. Importantly, oral administration of E0924G in both ovariectomized (OVX) rats and SAMP6 senile mice significantly increased bone mineral density and decreased bone loss compared to OVX controls or SAMR1 mice. Further mechanistic studies showed that E0924G could bind to and then activate peroxisome proliferator-activated receptor delta (PPARδ), and the pro-osteoblast effect and the inhibition of osteoclast differentiation induced by E0924G were significantly abolished when PPARδ was knocked down or inhibited. In conclusion, these data strongly suggest that E0924G has the potential to prevent OVX-induced and age-related osteoporosis by dual regulation of bone formation and bone resorption through activation of the PPARδ signaling pathway.

Biomimetic MDSCs membrane coated black phosphorus nanosheets system for photothermal therapy/photodynamic therapy synergized chemotherapy of cancer.

Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4+, CD8+ T cells as well as CD103+ DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer.

Highly efficient fluorescent and hybrid white organic light-emitting diodes based on a bimolecular excited system: publisher's note.

This publisher's note contains a correction to Opt. Lett.48, 5771 (2023)10.1364/OL.506371.

Identification of a sugarcane bacilliform virus promoter that is activated by drought stress in plants.

Sugarcane (Saccharum spp.) is an important sugar and biofuel crop in the world. It is frequently subjected to drought stress, thus causing considerable economic losses. Transgenic technology is an effective breeding approach to improve sugarcane tolerance to drought using drought-inducible promoter(s) to activate drought-resistance gene(s). In this study, six different promoters were cloned from sugarcane bacilliform virus (SCBV) genotypes exhibiting high genetic diversity. In ß-glucuronidase (GUS) assays, expression of one of these promoters (PSCBV-YZ2060) is similar to the one driven by the CaMV 35S promoter and >90% higher compared to the other cloned promoters and Ubi1. Three SCBV promoters (PSCBV-YZ2060, PSCBV-TX, and PSCBV-CHN2) function as drought-induced promoters in transgenic Arabidopsis plants. In Arabidopsis, GUS activity driven by promoter PSCBV-YZ2060 is also upregulated by abscisic acid (ABA) and is 2.2-5.5-fold higher when compared to the same activity of two plant native promoters (PScRD29A from sugarcane and PAtRD29A from Arabidopsis). Mutation analysis revealed that a putative promoter region 1 (PPR1) and two ABA response elements (ABREs) are required in promoter PSCBV-YZ2060 to confer drought stress response and ABA induction. Yeast one-hybrid and electrophoretic mobility shift assays uncovered that transcription factors ScbZIP72 from sugarcane and AREB1 from Arabidopsis bind with two ABREs of promoter PSCBV-YZ2060. After ABA treatment or drought stress, the expression levels of endogenous ScbZIP72 and heterologous GUS are significantly increased in PSCBV-YZ2060:GUS transgenic sugarcane plants. Consequently, promoter PSCBV-YZ2060 is a possible alternative promoter for genetic engineering of drought-resistant transgenic crops such as sugarcane.

A pan-PPAR agonist E17241 ameliorates hyperglycemia and diabetic dyslipidemia in KKAy mice via up-regulating ABCA1 in islet, liver, and white adipose tissue.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disease. Peroxisome proliferator-activated receptors (PPARs) play crucial roles in regulating glucolipid metabolism. Previous studies showed that E17241 could ameliorate atherosclerosis and lower fasting blood glucose levels in ApoE-/- mice. In this work, we investigated the role of E17241 in glycolipid metabolism in diabetic KKAy mice. APPROACH AND RESULTS: We confirmed that E17241 is a powerful pan-PPAR agonist with a potent agonistic activity on PPARγ, a high activity on PPARα, and a moderate activity on PPARδ. E17241 also significantly increased the protein expression of ATP-binding cassette transporter 1 (ABCA1), a crucial downstream target gene for PPARs. E17241 clearly lowered plasma glucose levels, improved OGTT and ITT, decreased islet cholesterol content, improved ß-cell function, and promoted insulin secretion in KKAy mice. Moreover, E17241 could significantly lower plasma total cholesterol and triglyceride levels, reduce liver lipid deposition, and improve the adipocyte hypertrophy and the inflammatory response in epididymal white adipose tissue. Further mechanistic studies indicated that E17241 boosts cholesterol efflux and insulin secretion in an ABCA1 dependent manner. RNA-seq and qRT-PCR analysis demonstrated that E17241 induced different expression of PPAR target genes in liver and adipose tissue differently from the PPARγ agonist rosiglitazone. In addition, E17241 treatment was also demonstrated to have an exhilarating cardiorenal benefits. CONCLUSIONS: Our results demonstrate that E17241 regulates glucolipid metabolism in KKAy diabetic mice while having cardiorenal benefits without inducing weight gain. It is a promising drug candidate for the treatment of T2DM.

Matched Redox Kinetics on Triazine-Based Carbon Nitride/Ni(OH)2 for Stoichiometric Overall Photocatalytic CO2 Conversion.

Mismatched reaction kinetics of CO2 reduction and H2 O oxidation is the main obstacle limiting the overall photocatalytic CO2 conversion. Here, a molten salt strategy is used to construct tubular triazine-based carbon nitride (TCN) with more adsorption sites and stronger activation capability. Ni(OH)2 nanosheets are then grown over the TCN to trigger a proton-coupled electron transfer for a stoichiometric overall photocatalytic CO2 conversion via "3CO2 + 2H2 O = CH4 + 2CO + 3O2 ." TCN reduces the energy barrier of H2 O dissociation to promote H2 O oxidation to O2 and supply sufficient protons to Ni(OH)2 , whereby the CO2 conversion is accelerated due to the enhanced proton-coupled electron transfer process enabled by the sufficient proton supply from TCN. This work highlights the importance of matching the reaction kinetics of CO2 reduction and H2 O oxidation by proton-coupled electron transfer on stoichiometric overall photocatalytic CO2 conversion.

Phylogeny and Genetic Divergence among Sorghum Mosaic Virus Isolates Infecting Sugarcane.

Sorghum mosaic virus (SrMV, the genus Potyvirus of the family Potyviridae) is a causal agent of common mosaic in sugarcane and poses a threat to the global sugar industry. In this study, a total of 901 sugarcane leaf samples with mosaic symptom were collected from eight provinces in China and were detected via RT-PCR using a primer pair specific to the SrMV coat protein (CP). These leaf samples included 839 samples from modern cultivars (Saccharum spp. hybrids) and 62 samples from chewing cane (S. officinarum). Among these, 632 out of 901 (70.1%) samples were tested positive for SrMV. The incidences of SrMV infection were 72.3% and 40.3% in modern cultivars and chewing cane, respectively. Phylogenetic analysis showed that all tested SrMV isolates were clustered into three clades consisting of six phylogenetic groups based on 306 CP sequences (this study = 265 and GenBank database = 41). A total of 10 SrMV isolates from South America (the United States and Argentina) along with 106 isolates from China were clustered in group D, while the remaining 190 SrMV isolates from Asia (China and Vietnam) were dispersed in five groups. The SrMV isolates in group F were limited to Yunnan province in China, and those in group A were spread over eight provinces. A significant genetic heterogeneity was elucidated in the nucleotide sequence identities of all SrMV CPs, ranging from 69.0% to 100%. A potential recombination event was postulated among SrMV isolates based on CP sequences. All tested SrMV CPs underwent dominant negative selection. Geographical isolation (South America vs. Asia) and host types (modern cultivars vs. chewing cane) are important factors promoting the genetic differentiation of SrMV populations. Overall, this study contributes to the global understanding of the genetic evolution of SrMV and provides a valuable resource for the epidemiology and management of the mosaic in sugarcane.

Highly efficient fluorescent and hybrid white organic light-emitting diodes based on a bimolecular excited system.

A bimolecular excited system is considered as a promising candidate for developing white organic light-emitting diodes (WOLEDs) with reduced phosphorescent components. However, for actualizing high-performance WOLED, little attention has been paid to electromers compared to exciplexes. Herein, we construct the bimolecular excited system to prepare fluorescent WOLEDs by combining the electromer emission with the exciplex emission, achieving a maximum power efficiency of 11.8 lm/W with a color rendering index (CRI) of over 80. Furthermore, phosphorescent dopants are doped into an exciplex host to construct hybrid WOLEDs. The fabricated complementary-color and three-color devices achieve maximum efficiencies of 55.3 cd/A (46.8 lm/W) and 34.1 cd/A (26.8 lm/W), respectively. The spectral coverages of WOLEDs are broadened by the bimolecular excited system, and CRIs are further improved at high luminance. Our strategy may bring light to the future development of highly efficient WOLEDs with economy and sustainability.

Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth.

Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.

The deubiquitinase USP10 mediates crosstalk between the LKB1/AMPK axis and Wnt/ß-catenin signaling in cancer.

The liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) axis pivotally controls cell metabolism and suppresses abnormal growth in various cancers. Wnt/ß-catenin is a frequently dysregulated signaling pathway that drives oncogenesis. Here, we discovered a crosstalk mechanism between the LKB1/AMPK axis and Wnt/ß-catenin signaling. Activated AMPK phosphorylates the deubiquitinase USP10 to potentiate the deubiquitination and stabilization of the key scaffold protein Axin1. This phosphorylation also strengthens the binding between USP10 and ß-catenin and supports the phase transition of ß-catenin. Both processes suppress Wnt/ß-catenin amplitude in parallel and inhibit colorectal cancer growth in a clinically relevant manner. Collectively, we established a crosstalk route by which LKB1/AMPK regulates Wnt/ß-catenin signaling in cancer. USP10 acts as the hub in this process, thus enabling LKB1/AMPK to suppress tumor growth via regulation of both metabolism and cell proliferation.

Citrus peel extract protects against diesel exhaust particle-induced chronic obstructive pulmonary disease-like lung lesions and oxidative stress.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and characterized by emphysema, small airway remodeling and mucus hypersecretion. Citrus peels have been widely used as food spices and in traditional Chinese medicine for chronic lung disease. Given that citrus peels are known for containing antioxidants and anti-inflammatory compounds, we hypothesize that citrus peel intake can suppress oxidative stress and inflammatory response to air pollution exposure, thereby alleviating COPD-like pathologies. This study aimed to investigate the efficacy of citrus peel extract, namely Guang Chenpi (GC), in preventing the development of COPD induced by diesel exhaust particles (DEPs) and its potential mechanism. DEP-induced COPD-like lung pathologies, inflammatory responses and oxidative stress with or without GC treatment were examined in vivo and in vitro. Our in vivo study showed that GC was effective in decreasing inflammatory cell counts and inflammatory mediator (IL-17A and TNF-α) concentrations in bronchoalveolar lavage fluid (BALF). Pretreatment with GC extract also significantly decreased oxidative stress in the serum and lung tissue of DEP-induced COPD rats. Furthermore, GC pretreatment effectively reduced goblet cell hyperplasia (PAS positive cells) and fibrosis of the small airways, decreased macrophage infiltration as well as carbon loading in the peripheral lungs, and facilitated the resolution of emphysema and small airway remodeling in DEP-induced COPD rats. An in vitro free radical scavenging assay revealed robust antioxidant potential of GC in scavenging DPPH free radicals. Moreover, GC demonstrated potent capacities in reducing ROS production and enhancing SOD activity in BEAS-2B cells stimulated by DEPs. GC treatment significantly attenuated the increased level of IL-8 and MUC5AC from DEP-treated BEAS-2B cells. Mechanistically, GC treatment upregulated the protein level of Nrf-2 and could function via MAPK/NF-κB signaling pathways by suppressing the phosphorylation of p38, JNK and p65. Citrus peel extract is effective in decreasing oxidative stress and inflammatory responses of the peripheral lungs to DEP exposure. These protective effects further contributed to the resolution of COPD-like pathologies.

Management of Exciton Distribution for High-Performance Organic Light-Emitting Diodes Based on Interfacial Exciplex Architecture.

Interfacial exciplex has recently been adopted as an effective host to achieve phosphorescent organic light-emitting diodes (OLEDs) with high efficiencies and low driving voltages. However, a systematic understanding of exciton recombination behavior in either host of interfacial exciplex is still deficient. Herein, the strategic design rule of interfacial exciplex host is proposed to overcome the negative effects of direct trapping recombination by systematically investigating exciton recombination behavior in interfacial exciplex hosts. As a result, blue and orange phosphorescent devices acquire peak external quantum efficiencies of 23.5% and 29.2% with low turn-on voltages. These results provide a simple method to realize highly efficient OLEDs aiming for general lighting and display applications.

USP10 strikes down ß-catenin by dual-wielding deubiquitinase activity and phase separation potential.

Wnt/ß-catenin signaling is a conserved pathway crucially governing development, homeostasis, and oncogenesis. Discoveries of its regulators hold great values in both basic and translational research. Through screening, we identified a deubiquitinase, USP10, as a critical modulator of ß-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination. Surprisingly, USP10 physically tethers Axin1 and ß-catenin and promotes the phase separation for ß-catenin suppression regardless of the enzymatic activity. Function-wise, USP10 enzymatic activity preferably regulates embryonic development and both the enzymatic activity and physical function jointly control intestinal homeostasis by antagonizing ß-catenin. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical promotion of phase separation and correlates with Wnt/ß-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against ß-catenin and unearthed the enzyme-dependent and -independent "dual-regulating" mechanism. These two functions of USP10 work in parallel and are context dependent.

Exosomal PGAM1 promotes prostate cancer angiogenesis and metastasis by interacting with ACTG1.

Tumor-derived exosomes and their contents promote cancer metastasis. Phosphoglycerate mutase 1 (PGAM1) is involved in various cancer-related processes. Nevertheless, the underlying mechanism of exosomal PGAM1 in prostate cancer (PCa) metastasis remains unclear. In this study, we performed in vitro and in vivo to determine the functions of exosomal PGAM1 in the angiogenesis of patients with metastatic PCa. We performed Glutathione-S-transferase pulldown, co-immunoprecipitation, western blotting and gelatin degradation assays to determine the pathway mediating the effect of exosomal PGAM1 in PCa. Our results revealed a significant increase in exosomal PGAM1 levels in the plasma of patients with metastatic PCa compared to patients with non-metastatic PCa. Furthermore, PGAM1 was a key factor initiating PCa cell metastasis by promoting invadopodia formation and could be conveyed by exosomes from PCa cells to human umbilical vein endothelial cells (HUVECs). In addition, exosomal PGAM1 could bind to γ-actin (ACTG1), which promotes podosome formation and neovascular sprouting in HUVECs. In vivo results revealed exosomal PGAM1 enhanced lung metastasis in nude mice injected with PCa cells via the tail vein. In summary, exosomal PGAM1 promotes angiogenesis and could be used as a liquid biopsy marker for PCa metastasis.

Anti-Pan-Rspo Chimeric Protein-Conjugated Albumin Nanoparticle Provides Promising Opportunities in Cancer Targeted Therapy.

Rspos (R-spondins) belong to a family of secreted proteins that causes various cancers via interacting the corresponding receptors. However, targeted therapeutic approaches against Rspos are largely lacking. In this study, a chimeric protein Rspo-targeting anticancer chimeric protein (RTAC) is originally designed, engineered, and characterized. RTAC shows satisfactory anticancer effects through inhibition of pan-Rspo-mediated Wnt/ß-catenin signaling activation both in vitro and in vivo. Furthermore, a conceptually novel antitumor strategy distinct from traditional drug delivery systems that release drugs inside tumor cells is proposed. A special "firewall" nano-system is designed to enrich on tumor cell surface and cover the plasma membrane, rather than undergoing endocytosis, to block oncogenic Rspos from binding to receptors. Cyclic RGD (Arg-Gly-Asp) peptide-linked globular cluster serum albumin nanoparticles (SANP) are integrated as a vehicle for conjugating RTAC (SANP-RTAC/RGD) for tumor tissue targeting. These nanoparticles can adhere to the tumor cell surface and enable RTAC to locally capture free Rspos with high spatial efficiency and selectivity to antagonize cancer progression. Therefore, this approach offers a new nanomedical anticancer route and obtains the "dual-targeting" capability for effective tumor clearance and low potential toxicity. This study presents a proof-of-concept for anti-pan-Rspo therapy and a nanoparticle-integrated paradigm for targeted cancer treatment.