Enhancing anti-angiogenic immunotherapy for melanoma through injectable metal-organic framework hydrogel co-delivery of combretastatin A4 and poly(I:C).

The interplay between vascularization and macrophage-induced immune suppression plays a crucial role in melanoma treatment. In this study, we propose a novel combination approach to combat melanoma by simultaneously inhibiting tumor vascularization and enhancing macrophage-mediated anti-tumor responses. We investigate the potential of combining combretastatin A4 (CA4), a vascular-disrupting agent, with poly(I:C) (PIC), an immunostimulatory adjuvant. This combination approach effectively suppresses melanoma cell proliferation, disrupts vascularization, and promotes macrophage polarization towards the M1 phenotype for melanoma suppression. To facilitate efficient co-delivery of CA4 and PIC for enhanced anti-angiogenic immunotherapy, we develop an injectable metal-organic framework hydrogel using Zeolitic Imidazolate Framework-8 (ZIF-8) and hyaluronic acid (HA) (ZIF-8/HA). Our findings demonstrate that ZIF-8 enables efficient loading of CA4 and enhances the stability of PIC against RNAase degradation in vitro. Furthermore, the developed co-delivery hydrogel system, PIC/CA4@ZIF-8/HA, exhibits improved rheological properties, good injectability and prolonged drug retention. Importantly, in vivo experiments demonstrate that the PIC/CA4@ZIF-8/HA formulation significantly reduces the dosage and administration frequency while achieving a more pronounced therapeutic effect. It effectively inhibits melanoma growth by suppressing angiogenesis, destroying blood vessels, promoting M1 macrophage infiltration, and demonstrating excellent biocompatibility. In conclusion, our study advances anti-angiogenic immunotherapy for melanoma through the potent combination of PIC/CA4, particularly when administered using the PIC/CA4@ZIF-8/HA formulation. These findings provide a new perspective on clinical anti-angiogenic immunotherapy for melanoma, emphasizing the importance of targeting tumor vascularization and macrophage-mediated immune suppression simultaneously.

Decitabine suppresses MDSC-induced immunosuppression through dual functional mechanism and inhibits melanoma metastasis.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting melanoma metastasis. Reprogramming MDSCs into mature M1 macrophages has emerged as a strategy to inhibit metastasis. Decitabine (Dec) is known to eradicate MDSCs and suppress tumor growth. In this study, we provide evidence that Dec not only reduces the MDSC population by inducing apoptosis, arresting cell cycle, and impairing recruitment, but also suppresses their immunosuppressive function by downregulating related genes and facilitating differentiation into M1 macrophages. Transcriptomic analysis of Dec-treated MDSCs revealed a marked downregulation of immunosuppressive genes including S100a9, S100a8, Vegf, Cxcr2, and Nos2. Meanwhile, M1 macrophage-associated genes involved in immune activation were upregulated, such as Ddx58, Isg15, Tap1, Ccl5, Cxcl9, and Cxcl10. Further bioinformatic analysis indicated that Dec promotes MDSC-to-M1 macrophage differentiation and activates innate immune pathways including NOD-like signaling to enhance anti-tumor immunity. Time-course studies implied that Dec upregulates myeloid transcription factor Irf7 to initiate MDSC differentiation and orchestrate the anti-tumor immune response. Collectively, our study unveils a novel dual-functional mechanism of Dec as both a cytotoxic agent reducing MDSCs and an inducer of their differentiation into M1 macrophages, thereby alleviating immunosuppression. This highlights Dec's potential for clinical melanoma metastasis suppression.

Capturing Protein-Protein Interactions with Acidic Amino Acids Reactive Cross-Linkers.

Acidic residues (Asp and Glu) have a high prevalence on protein surfaces, but cross-linking reactions targeting these residues are limited. Existing methods either require high-concentration coupling reagents or have low structural compatibility. Here a previously reported "plant-and-cast" strategy is extended to develop heterobifunctional cross-linkers. These cross-linkers first react rapidly with Lys sidechains and then react with Asp and Glu sidechains, in a proximity-enhanced fashion. The cross-linking reaction proceeds at neutral pH and room temperature without coupling reagents. The efficiency and robustness of cross-linking using model proteins, ranging from small monomeric proteins to large protein complexes are demonstrated. Importantly, it is shown that this type of cross-linkers are efficient at identifying protein-protein interactions involving acidic domains. The Cross-linking mass spectrometry (XL-MS) study with p53 identified 87 putative binders of the C-terminal domain of p53. Among them, SARNP, ZRAB2, and WBP11 are shown to regulate the expression and alternative splicing of p53 target genes. Thus, these carboxylate-reactive cross-linkers will further expand the power of XL-MS in the analysis of protein structures and protein-protein interactions.

Genome-wide CRISPR screens define determinants of epithelial-mesenchymal transition mediated immune evasion by pancreatic cancer cells.

The genetic circuits that allow cancer cells to evade immune killing via epithelial mesenchymal plasticity remain poorly understood. Here, we showed that mesenchymal-like (Mes) KPC3 pancreatic cancer cells were more resistant to cytotoxic T lymphocyte (CTL)-mediated killing than the parental epithelial-like (Epi) cells and used parallel genome-wide CRISPR screens to assess the molecular underpinnings of this difference. Core CTL-evasion genes (such as IFN-γ pathway components) were clearly evident in both types. Moreover, we identified and validated multiple Mes-specific regulators of cytotoxicity, such as Egfr and Mfge8. Both genes were significantly higher expressed in Mes cancer cells, and their depletion sensitized Mes cancer cells to CTL-mediated killing. Notably, Mes cancer cells secreted more Mfge8 to inhibit proliferation of CD8+ T cells and production of IFN-γ and TNFα. Clinically, increased Egfr and Mfge8 expression was correlated with a worse prognosis. Thus, Mes cancer cells use Egfr-mediated intrinsic and Mfge8-mediated extrinsic mechanisms to facilitate immune escape from CD8+ T cells.

Immunologically active ferumoxytol-poly(I : C) nanomaterials inhibit metastatic melanoma by regulating myeloid-derived suppressor cell differentiation.

Nanomaterials have been identified as a potential therapeutic option for targeting myeloid-derived suppressor cells (MDSCs), which are known to play a crucial role in tumor metastasis and treatment resistance. Here, we report a unique immunologically active nanomaterial composed of ferumoxytol and poly(I : C) (FP-NPs) and investigate its immunoregulatory activities on MDSCs in metastatic melanoma. In vivo assays demonstrated that FP-NPs had the ability to significantly impede the progression of metastatic melanoma and decrease the MDSC population in the lungs, spleen, and bone marrow of mice. Both in vivo and in vitro experiments revealed that FP-NPs reduced the number of granulocytic MDSCs and promoted the differentiation of monocytic MDSCs into anti-tumor M1 macrophages. Transcriptome sequencing indicated that FP-NPs significantly altered the expression of several genes involved in immunity. Analysis of Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and quantitative real-time PCR revealed that FP-NPs significantly increased the expression of the myeloid cell differentiation-related gene interferon regulatory factor 7 and activated interferon beta-related signaling pathways, which stimulated the differentiation of MDSCs into M1 macrophages. These findings suggest that FP-NPs, a unique nanomaterial with immunological properties, can induce MDSCs to differentiate into M1 macrophages, potentially offering new treatment prospects for metastatic melanoma in the future.

Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy.

Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, most patients fail to respond or achieve durable responses due to primary or acquired ICB resistance. Recently, tumor epithelial-to-mesenchymal plasticity (EMP) was identified as a critical determinant in regulating immune escape and immunotherapy resistance in cancer. In this review, we summarize the emerging role of tumor EMP in ICB resistance and the tumor-intrinsic or extrinsic mechanisms by which tumors exploit EMP to achieve immunosuppression and immune escape. We discuss strategies to modulate tumor EMP to alleviate immune resistance and to enhance the efficiency of ICB therapy. Our discussion provides new prospects to enhance the ICB response for therapeutic gain in cancer patients.

The combinational nano-immunotherapy of ferumoxytol and poly(I:C) inhibits melanoma via boosting anti-angiogenic immunity.

Angiogenesis plays a key role in the progression and metastasis of melanoma, and the pro-angiogenic effect of macrophages is one major reason for the failure of current anti-angiogenic therapies. Here, a nano-immunotherapy combining ferumoxytol and poly(I:C) (ferumoxytol/poly(I:C)) has been developed to boost the anti-angiogenic activities of macrophages to inhibit melanoma. Our findings demonstrated that ferumoxytol/poly(I:C) was a highly efficacious anti-tumor therapy with limited toxicity. Both in vivo and in vitro experiments indicated that this combination was successful in impeding angiogenesis. Ferumoxytol/poly(I:C) was demonstrated to reduce the viability of endothelial cells, thus hindering tube formation. Particularly, ferumoxytol/poly(I:C) was able to polarize macrophages to the M1 phenotype and decrease the expression of vascular endothelial growth factor, which in turn amplified the anti-angiogenic properties of ferumoxytol/poly(I:C). This combination of ferumoxytol/poly(I:C) nano-immunotherapy enriches the anti-angiogenic therapeutic nature of ferumoxytol and will shed new light on the treatment of melanoma.

Exosomal miR-485-3p derived from pancreatic ductal epithelial cells inhibits pancreatic cancer metastasis through targeting PAK1.

BACKGROUND: Cell competition is an important feature in pancreatic cancer (PC) progression, but the underlying mechanism remains elusive. This study aims to explore the role of exosomes derived from normal pancreatic ductal epithelial cells involved in PC progression. METHODS: PC cells and pancreatic stellate cells (PSCs) were treated with exosomes isolated from pancreatic ductal epithelial cells. Cell proliferation was assessed by CCK8 assays. Cell migration and invasion were assessed by Transwell assays. PC and matched adjacent non-tumor tissue specimens were obtained from 46 patients pathologically diagnosed with PC at Peking University First Hospital from 2013 to 2017. Tissue miR-485-3p and p21-activated kinase-1 (PAK1) expression was examined by real-time polymerase chain reaction (RT-PCR), and the relationship of the two was analyzed using Pearman's product-moment correlation. The clinical significance of miR-485-3p was analyzed using the Chi-square test, Wilcoxon rank-sum test, and Fisher exact probability, respectively. The binding of miR-485-3p to PAK1 5'-untranslated region (5'-UTR) was examined by luciferase assay. PC cells were xenografted into nude mice as a PC metastasis model. RESULTS: Exosomes from pancreatic ductal epithelial cells suppressed PC cell migration and invasion as well as the secretion and migration of PSCs. MiR-485-3p was enriched in the exosomes of pancreatic ductal epithelial cells but deficient in those of PC cells and PSCs, in accordance with the lower level in PSCs and PC cells than that in pancreatic ductal cells. And the mature miR-485-3p could be delivered into these cells by the exosomes secreted by normal pancreatic duct cells, to inhibit PC cell migration and invasion. Clinical data analysis showed that miR-485-3p was significantly decreased in PC tissues (P < 0.05) and was negatively associated with lymphovascular invasion (P = 0.044). As a direct target of miR-485-3p, PAK1 was found to exert an inhibitory effect on PC cells, and there was a significantly negative correlation between the expression levels of miR-485-3p and PAK1 (r = -0.6525, P < 0.0001) in PC tissues. Moreover, miR-485-3p could suppress PC metastasis in vivo by targeting p21-activated kinase-1. CONCLUSIONS: Exosomal miR-485-3p delivered by normal pancreatic ductal epithelial cells into PC cells inhibits PC metastasis by directly targeting PAK1. The restoration of miR-485-3p by exosomes or some other vehicle might be a novel approach for PC treatment.

USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-ß receptor TßRII.

TGF-ß signaling is a key player in tumor progression and immune evasion, and is associated with poor response to cancer immunotherapies. Here, we identified ubiquitin-specific peptidase 8 (USP8) as a metastasis enhancer and a highly active deubiquitinase in aggressive breast tumors. USP8 acts both as a cancer stemness-promoting factor and an activator of the TGF-ß/SMAD signaling pathway. USP8 directly deubiquitinates and stabilizes the type II TGF-ß receptor TßRII, leading to its increased expression in the plasma membrane and in tumor-derived extracellular vesicles (TEVs). Increased USP8 activity was observed in patients resistant to neoadjuvant chemotherapies. USP8 promotes TGF-ß/SMAD-induced epithelial-mesenchymal transition (EMT), invasion, and metastasis in tumor cells. USP8 expression also enables TßRII+ circulating extracellular vesicles (crEVs) to induce T cell exhaustion and chemoimmunotherapy resistance. Pharmacological inhibition of USP8 antagonizes TGF-ß/SMAD signaling, and reduces TßRII stability and the number of TßRII+ crEVs to prevent CD8+ T cell exhaustion and to reactivate anti-tumor immunity. Our findings not only reveal a novel mechanism whereby USP8 regulates the cancer microenvironment but also demonstrate the therapeutic advantages of engineering USP8 inhibitors to simultaneously suppress metastasis and improve the efficacy of cancer immunotherapy.

RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells.

Tumor escape mechanisms for immunotherapy include deficiencies in antigen presentation, diminishing adaptive CD8+ T cell antitumor activity. Although innate natural killer (NK) cells are triggered by loss of MHC class I, their response is often inadequate. To increase tumor susceptibility to both innate and adaptive immune elimination, we performed parallel genome-wide CRISPR-Cas9 knockout screens under NK and CD8+ T cell pressure. We identify all components, RNF31, RBCK1, and SHARPIN, of the linear ubiquitination chain assembly complex (LUBAC). Genetic and pharmacologic ablation of RNF31, an E3 ubiquitin ligase, strongly sensitizes cancer cells to NK and CD8+ T cell killing. This occurs in a tumor necrosis factor (TNF)-dependent manner, causing loss of A20 and non-canonical IKK complexes from TNF receptor complex I. A small-molecule RNF31 inhibitor sensitizes colon carcinoma organoids to TNF and greatly enhances bystander killing of MHC antigen-deficient tumor cells. These results merit exploration of RNF31 inhibition as a clinical pharmacological opportunity for immunotherapy-refractory cancers.

Inhibition of bone morphogenetic protein receptor 2 suppresses pancreatic ductal adenocarcinoma growth by regulating GRB2/PI3K/AKT axis.

BACKGROUND: Bone morphogenetic protein receptor 2 (BMPR2) is an important transmembrane serine/threonine kinase that involves oncogenic processes in multiple cancers. However, the role of BMPR2 and its regulatory mechanism in pancreatic ductal adenocarcinoma (PDAC) remain unknown. METHODS: We performed a tissue array to explore the expression of BMPR2 in PDAC tissues. The Cell Counting Kit-8 (CCK-8) and colony formation assays were used to measure PDAC cells' proliferation. Proteomics and mass spectrometry technology was applied to analyze the BMPR2-regulating proteins. Flow cytometry was used to analyze the cell cycle distribution of PDAC cells. Orthotopic pancreatic cancer (PC) and patient-derived xenograft (PDX) models were used for in vivo experiments. RESULTS: This study revealed the over-expression of BMPR2 in PDAC tissues and its proliferation-promoting role in PDAC cells. By carrying out protein mass spectrometry technique as well as bioinformatics analysis, we identified that BMPR2 regulated the growth factor receptor-bound protein 2/phosphatidylinositol 3-kinase/protein kinase B (GRB2/PI3K/AKT) signaling pathway, and further in vitro experiments showed that inhibition of BMPR2 resulted in suppressing proliferation and G2/M arrest by inhibiting the GRB2/PI3K/AKT signaling pathway in PDAC cells. The inhibition of BMPR2 by LDN193189 showed similar results in PDAC cells, orthotopic PC, and PDX models, which revealed that inhibition of BMPR2 significantly suppressed tumor growth by suppressing the GRB2/PI3K/AKT axis. CONCLUSIONS: Inhibition of BMPR2 suppresses PDAC growth by regulating the GRB2/PI3K/AKT axis and is a promising PDAC treatment strategy.

The Functional Deubiquitinating Enzymes in Control of Innate Antiviral Immunity.

Innate antiviral immunity is the first line of host defense against invading viral pathogens. Immunity activation primarily relies on the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). Viral proteins or nucleic acids mainly engage three classes of PRRs: Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). These receptors initiate a series of signaling cascades that lead to the production of proinflammatory cytokines and type I interferon (IFN-I) in response to viral infection. This system requires precise regulation to avoid aberrant activation. Emerging evidence has unveiled the crucial roles that the ubiquitin system, especially deubiquitinating enzymes (DUBs), play in controlling immune responses. In this review, an overview of the most current findings on the function of DUBs in the innate antiviral immune pathways is provided. Insights into the role of viral DUBs in counteracting host immune responses are also provided. Furthermore, the prospects and challenges of utilizing DUBs as therapeutic targets for infectious diseases are discussed.

Molecular characterization of circulating tumor cells in pancreatic ductal adenocarcinoma: potential diagnostic and prognostic significance in clinical practice.

BACKGROUND: The clinical value of heterogeneous sub-populations of circulating tumor cells (CTCs) in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: Peripheral blood samples were obtained from 67 PDAC patients. CTCs were isolated by employing CD45 negative enrichment technique and further characterized for epithelial to mesenchymal transition (EMT) or human equilibrative nucleoside transporter-1 (hENT-1). The relationships between CTCs sub-phenotypes with clinicopathological factors or post-operative recurrence in PDAC patients were analyzed. RESULTS: EMT related CTCs could be isolated and identified from the 81% of patients (54/67), and both the total count (median: 5 vs. 17/mL, P<0.0001) and M-CTC percentage (median: 0.2 vs. 0.345, P=0.0244) of CTCs could differentiate local/regional with metastatic disease. Multivariate analysis showed that both AJCC stage (P=0.025) and M-CTC percentage (P=0.001) were independent prognostic indicators of recurrence free survival (RFS) in resected patients. Moreover, Kaplan-Meier survival analysis showed that M-CTC after 2 courses of chemotherapy was significantly associated with inferior RFS (49.5 weeks vs. undefined, P=0.0288). No significant correlation in hENT-1 expression was found between CTCs and matched tumor tissues, and further multivariate analysis suggested hENT-1 expression in CTCs as independent prognostic factor for RFS (P=0.016). Patients with low hENT-1 expression in CTCs had decreased RFS (32 weeks vs. undefined, P=0.0337). CONCLUSIONS: CTCs could be the promising diagnostic biomarkers in PDAC patients, and phenotypic profiling of CTCs based on EMT or hENT-1 could help establish novel prognostic biomarkers in resected patients undergoing adjuvant gemcitabine-based chemotherapy. KEYWORDS: Circulating tumor cells (CTCs); Pancreatic ductal adenocarcinoma (PDAC); Epithelial to mesenchymal transition (EMT); human equilibrative nucleoside transporter-1 (hENT-1).

Acetylation-Dependent Deubiquitinase OTUD3 Controls MAVS Activation in Innate Antiviral Immunity.

Accurate regulation of innate immunity is necessary for the host to efficiently respond to invading pathogens and avoid excessive harmful immune pathology. Here we identified OTUD3 as an acetylation-dependent deubiquitinase that restricts innate antiviral immune signaling. OTUD3 deficiency in mice results in enhanced innate immunity, a diminished viral load, and morbidity. OTUD3 directly hydrolyzes lysine 63 (Lys63)-linked polyubiquitination of MAVS and thus shuts off innate antiviral immune response. Notably, the catalytic activity of OTUD3 relies on acetylation of its Lys129 residue. In response to virus infection, the acetylated Lys129 is removed by SIRT1, which promptly inactivates OTUD3 and thus allows timely induction of innate antiviral immunity. Importantly, acetyl-OTUD3 levels are inversely correlated with IFN-ß expression in influenza patients. These findings establish OTUD3 as a repressor of MAVS and uncover a previously unknown regulatory mechanism by which the catalytic activity of OTUD3 is tightly controlled to ensure timely activation of antiviral defense.

LncRNA H19-Derived miR-675-3p Promotes Epithelial-Mesenchymal Transition and Stemness in Human Pancreatic Cancer Cells by targeting the STAT3 Pathway.

Objective: The functional role and mechanism of the long noncoding RNA (lncRNA) H19 in regulating human pancreatic cancer (PC) cell stemness and invasion have not been completely elucidated. This study aimed to evaluate the role of H19 in regulating the stemness, epithelial-mesenchymal transition (EMT), invasion and chemosensitivity of PC cells. Methods: The sphere-forming ability was assessed using serum-free floating-culture systems. Chemosensitivity was evaluated via CCK-8 and flow cytometry assays in vitro. Migration and invasion were evaluated by transwell assays. The expression of stemness and EMT markers was detected by flow cytometry, qRT-PCR and western blot analyses. Xenograft initiation, growth and sensitivity were examined; Ki-67 nuclear staining intensity was evaluated by immunohistochemistry; and in situ apoptosis was evaluated by a TUNEL assay. Results: H19 played an important role in maintaining PC cell stemness. Upregulated H19 expression in CAPAN-1 cells promoted tumor cell migration, invasion, EMT and chemoresistance. In contrast, downregulated H19 expression in PANC-1 cells yielded the opposite results. These effects were mediated by positively modulating the STAT3 pathway. Furthermore, SOCS5, an endogenous inhibitor of the STAT3 pathway, was a direct target of miR-675-3p, which was positively regulated by H19 in PC cells. Conclusions: The H19/miR-675-3p signaling axis plays a critical role in maintaining the EMT process and stemness of PC cells by directly targeting SOCS5 to activate the STAT3 pathway. These data provide new insights into the oncogenic function of H19 in human PC and reveal potential targets for the development of optimal treatment approaches for this disease.

The interactions between cGAS-STING pathway and pathogens.

Cytosolic DNA is an indicator of pathogen invasion or DNA damage. The cytosolic DNA sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) detects DNA and then mediates downstream immune responses through the molecule stimulator of interferon genes (STING, also known as MITA, MPYS, ERIS and TMEM173). Recent studies focusing on the roles of the cGAS-STING pathway in evolutionary distant species have partly sketched how the mammalian cGAS-STING pathways are shaped and have revealed its evolutionarily conserved mechanism in combating pathogens. Both this pathway and pathogens have developed sophisticated strategies to counteract each other for their survival. Here, we summarise current knowledge on the interactions between the cGAS-STING pathway and pathogens from both evolutionary and mechanistic perspectives. Deeper insight into these interactions might enable us to clarify the pathogenesis of certain infectious diseases and better harness the cGAS-STING pathway for antimicrobial methods.

High mobility group AT-hook 2 promotes tumorigenicity of pancreatic cancer cells via upregulating ANLN.

HMGA2 is associated with the regulation of cellular biological processes in various human disorders and cancer progression, yet little is known about how HMGA2 controls tumorigenesis. This study uncovered the mechanism of HMGA2-mediated regulation of tumorigenicity in pancreatic cancer. We showed that HMGA2 was highly expressed in pancreatic cancer cells and correlated with poor prognosis. HMGA2 expression knockdown inhibited the tumorigenicity of pancreatic cancer cells. Conversely, overexpression of HMGA2 promoted tumorigenicity. Combination of ChIP-Seq, RNA-Seq and dual-luciferase reporter assays revealed HMGA2 could directly regulate ANLN expression. Furthermore, we found ANLN could mediate the HMGA2-induced effects on pancreatic cancer cells. The identification of the regulatory mechanism of HMGA2 and ANLN will provide insights into the progression for human pancreatic cancer.

Length effects of cylindrical polymer brushes on their in vitro and in vivo properties.

Understanding the relationship between the morphology and biological performance of nanomaterials is very important for their biomedical applications. However, most of the published research focused on spherical systems. The biological properties of the anisotropic nanomaterials have not been studied enough. In this study, we synthesized three sets of cylindrical polymer brushes (CPBs) with different lengths (∼34, 60 and 119 nm) by taking advantage of controlled radical polymerization and Cu(i)-catalyzed alkyne-azide click chemistry. These CPBs had one-dimensional wormlike morphology, the same chemical structure and diameter, desirable water solubility, abundant amino groups and narrowly distributed lengths. These characteristics encouraged us to study length effects on their in vitro and in vivo properties. We demonstrated that longer CPBs had higher cellular uptake, lower tissue permeability, shorter blood circulation time, lower tumor accumulation and rapider body clearance than their shorter counterparts. This work might provide important guidance for the design of biomedical nanomaterials.

Shape Effects of Cylindrical versus Spherical Unimolecular Polymer Nanomaterials on in Vitro and in Vivo Behaviors.

To date, how the shape of nanomaterials influences their biological properties is poorly understood, due to the insufficient controllability of current preparative methods, especially in the shape and size of nanomaterials. In this paper, we achieved the precise syntheses of nanoscale unimolecular cylindrical polymer brushes (CPBs) and spherical polymer nanoparticles (SPNPs) with the same volume and surface chemistry, which ensured that shape was essentially the only variable when their biological performance was compared. Accurate shape effects were obtained. Impressively, the CPBs had remarkable advantage in tissue penetration over the SPNPs. The CPBs also exhibited higher cellular uptake and rapider body clearance than the SPNPs, whereas the SPNPs had longer blood circulation time, rapider tumor vascular extravasation, and higher tumor accumulation than the CPBs. Additionally, this work also provided a controllable synthesis strategy for nanoscale unimolecular SPNPs by integrating 21 CPBs to a ß-cyclodextrin core, whose diameter in dry state could be up to 45 nm.

BRM transcriptionally regulates miR-302a-3p to target SOCS5/STAT3 signaling axis to potentiate pancreatic cancer metastasis.

Brahma (BRM) has recently been documented as a significant predictor of pancreatic cancer (PC) metastasis. This study aimed to further elucidate molecular mechanism by which BRM promotes PC metastasis. We found that silencing BRM reduced PC cell migration and invasion both in vivo and in vitro, accompanied by reduced level of miR-302a-3p. BRM positively regulated the transcription of miR-302a-3p, which acted as a metastasis-promoting miRNA in PC cells. miR-302a-3p directly targeted SOCS5 to boost STAT3 phosphorylation and induce the transcription of STAT3 target genes. Furthermore, miR-302a-3p level was higher in tissue and plasma samples derived from PC patients, and was significantly associated with worse clinical pathological features. In xenograft models, inhibiting miR-302a-3p was synergistically lethal in BRM-silenced PC cells. In conclusion, our results suggest that transcriptional regulation of miR-302a-3p by BRM potentiates PC metastasis by epigenetically suppressing SOCS5 expression and activating STAT3 signaling. These new findings provide potential therapeutic avenues for preventing PC-associated death.