Reduced Tumor Growth Research Articles

Customised design of antisense oligonucleotides targeting EGFR driver mutants for personalised treatment of non-small cell lung cancer

Tyrosine kinase inhibitors (TKIs) are currently the standard therapy for patients with non-small cell lung cancer (NSCLC) bearing mutations in epidermal growth factor receptor (EGFR). Unfortunately, drug-acquired resistance is inevitable due to the emergence of new mutations in EGFR. Moreover, the TKI treatment is associated with severe toxicities due to the unspecific inhibition of wild-type (WT) EGFR. Thus, treatment that is customised to an individual's genetic alterations in EGFR may offer greater therapeutic benefits for patients with NSCLC. In this study, we demonstrate a new therapeutic strategy utilising customised antisense oligonucleotides (ASOs) to selectively target activating mutations in the EGFR gene in an individualised manner that can overcome drug-resistant mutations. We use extracellular vesicles (EVs) as a vehicle to deliver ASOs to NSCLC cells. Specifically guided by the mutational profile identified in NSCLC patients, we have successfully developed ASOs that selectively inhibit point mutations in the EGFR gene, including L858R and T790M, while sparing the WT EGFR. Delivery of the EGFR-targeting ASOs by EVs significantly reduced tumour growth in xenograft models of EGFR-L858R/T790M-driven NSCLC. Importantly, we have also shown that EGFR-targeting ASOs exhibit more potent anti-cancer effect than TKIs in NSCLC with EGFR mutations, effectively suppressing a patient-derived TKI-resistant NSCLC tumour. Overall, by harnessing the specificity and efficacy of ASOs, we present an effective and adaptable therapeutic platform for NSCLC treatment. This study was funded by Singapore's Ministry of Health (NMRC/OFIRG/MOH-000643-00, OFIRG21nov-0068, NMRC/OFLCG/002-2018, OFYIRG22jul-0034), National Research Foundation (NRF-NRFI08-2022, NRF-CRP22-2019-0003, NRF-CRP23-2019-0004), A∗STAR, and Ministry of Education.

Indocyanine Green-Loaded Adhesive Proteinic Nanoparticles for Effective Locoregional and Prolonged Photothermal Anticancer Therapy.

Conventional anticancer therapies, including surgical resection, radiation, and chemotherapy, are the primary modalities for treating various forms of cancer. However, these treatments often bring significant side effects and risk of recurrence, underscoring the need for more targeted and less invasive therapeutic options. To address this challenge, we developed an adhesive nanoparticle (NP)-based effective anticancer photothermal therapy (PTT) system using bioengineered mussel adhesion protein (MAP). The unique underwater tissue adhesive properties of MAP NPs enabled targeted delivery and prolonged retention at the tumor site, thereby improving therapeutic efficacy. Our innovative indocyanine green (ICG)-loaded MAP NPs (MAP@ICG NPs) demonstrated strong photothermal capability and stability, and potent anticancer activity in vitro. In vivo intratumor injection of the MAP@ICG NPs showed remarkable anticancer PTT effects, effectively reducing tumor growth with minimal damage to surrounding tissues. The development and utilization of this adhesive proteinic NP-based PTT system represent a significant advancement in cancer therapy, offering a promising alternative that combines the precision of NP delivery with effective therapeutic efficacy.

IPLA2β regulates the dual effects of arachidonic acid in thyroid cancer.

Abnormal arachidonic acid metabolism in the tumor microenvironment is closely related to cancer progression; however, thyroid cancer was rarely researched. Through lipidomic analysis, we disclosed that dysregulated arachidonic acid metabolism plays dual effects on thyroid cancer. The promoting role of arachidonic acid in the progression of thyroid cancer cells was evaluated utilizing cell viability (CCK-8 assay) and transwell invasion assays, confirmed by corresponding inhibitors. Lipid peroxidation and the use of various cell death inhibitors confirmed that arachidonic acid confers vulnerability to ferroptosis in thyroid cancer. The roles of arachidonic acid and ferroptosis inducer in thyroid cancer were assessed in a xenograft mouse model. On one hand, arachidonic acid promotes the progression of thyroid cancer through the cyclooxygenase/prostaglandin pathway; on another hand, arachidonic acid confers vulnerability to ferroptosis through lipoxygenases. Moreover, iPLA2β drives converse roles of arachidonic acid between cancer-progression and ferroptosis vulnerability through releasing free arachidonic acid from the cell membrane. Finally, we confirmed high arachidonic acid diet promotes the development of thyroid cancer in vivo, whereas ferroptosis inducer sulfasalazine dramatically reduced tumor growth of mice with feeding arachidonic acid. Our research demonstrated the roles of iPLA2β in conversing dual effects of arachidonic acid in thyroid cancer and provides ferroptosis inducer as a potential therapeutic strategy.

From single-cell to spatial transcriptomics: decoding the glioma stem cell niche and its clinical implications.

Gliomas are aggressive brain tumors associated with a poor prognosis. Cancer stem cells (CSCs) play a significant role in tumor recurrence and resistance to therapy. This study aimed to identify and characterize glioma stem cells (GSCs), analyze their interactions with various cell types, and develop a prognostic signature. Single-cell RNA sequencing data from 44 primary glioma samples were analyzed to identify GSC populations. Spatial transcriptomics and gene regulatory network analyses were performed to investigate GSC localization and transcription factor activity. CellChat analysis was conducted to infer cell-cell communication patterns. A GSC signature (GSCS) was developed using machine learning algorithms applied to bulk RNA sequencing data from multiple cohorts. In vitro and in vivo experiments were conducted to validate the role of TUBA1C, a key gene within the signature. A distinct GSC population was identified, characterized by high proliferative potential and an enrichment of E2F1, E2F2, E2F7, and BRCA1 regulons. GSCs exhibited spatial proximity to myeloid-derived suppressor cells (MDSCs). CellChat analysis revealed an active MIF signaling pathway between GSCs and MDSCs. A 26-gene GSCS demonstrated superior performance compared to existing prognostic models. Knockdown of TUBA1C significantly inhibited glioma cell migration, and invasion in vitro, and reduced tumor growth in vivo. This study offers a comprehensive characterization of GSCs and their interactions with MDSCs, while presenting a robust GSCS. The findings offer new insights into glioma biology and identify potential therapeutic targets, particularly TUBA1C, aimed at improving patient outcomes.

Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer.

The effect of immune checkpoint inhibitors is extremely limited in patients with pancreatic ductal adenocarcinoma (PDAC) due to the suppressive tumor immune microenvironment (TIME). Autophagy, which has been shown to play a role in anti-tumor immunity, has been proposed as a therapeutic target for PDAC. Here, single-cell RNA-sequencing of autophagy-deficient murine PDAC tumors revealed that autophagy inhibition in cancer cells induced dendritic cell (DC) activation. Analysis of human PDAC tumors substantiated a negative correlation between autophagy and DC activation signatures. Mechanistically, autophagy inhibition increased intracellular accumulation of tumor antigens, which could activate DCs. Administration of chloroquine (CQ), an autophagy inhibitor, in combination with Flt3 ligand (Flt3L)-induced DC infiltration inhibited tumor growth and increased tumor-infiltrating T lymphocytes. However, autophagy inhibition in cancer cells also induced CD8+ T cell exhaustion with high expression of immune checkpoint LAG3. A triple therapy comprising CQ, Flt3L, and an anti-LAG3 antibody markedly reduced tumor growth in orthotopic syngeneic PDAC mouse models. Thus, targeting autophagy in cancer cells and activating DCs sensitizes PDAC tumors to immune checkpoint inhibitor therapy, warranting further development of this treatment approach to overcome immunosuppression in pancreatic cancer.

Abstract B047: Antigenic properties determine the outcome of B cell driven anti-tumor immunity

Abstract B cells have the capacity to elicit both anti- and pro-tumorigenic effects; yet the determinants of productive B cell responses in cancer remain elusive. Using a system where a B cell neoantigen is either soluble or tethered to the surface of pancreatic cancer cells, we demonstrate that membrane-tethered antigen is sufficient to elicit activation of anti-tumor immunity and reduce tumor growth in an NK cell-dependent manner. We also show that decreased antigen affinity to the BCR promotes regulatory B cell function which can be overcome by increased avidity of membrane-tethered antigen. Furthermore, soluble and membrane-tethered antigens drive qualitatively distinct germinal center, plasma cell, memory B cell, and Treg responses. Finally, we describe two classes of membrane-associated antigens that correlate with GC B cell signature and improved survival in pancreatic cancer patients. Thus, antigen localization impacts basic mechanisms governing B cell differentiation and the resulting immune response to solid malignancy with implications for vaccine engineering. Citation Format: Colleen Sturdevant, Nancy Kren, Harrison Silva, Ismael Gomez, Austin Hepperla, Yuliya Pylayeva-Gupta. Antigenic properties determine the outcome of B cell driven anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B047.

Long-term exposure to polystyrene microplastics reduces macrophages and affects the microbiota–gut–brain axis in mice

The remarkably increase in plastic use has led to worldwide pollution involving microplastics (MPs), which have been shown to be potentially hazardous substances. Although several studies have focused on the effects of small MPs on the brain and behavior of aquatic species, their effects on the mouse brain and the underlying mechanisms remain unclear. Our study’s aim was to investigate the effects of long-term oral ingestion of different sizes of MPs (0.1, 5, and 50 μm) on mouse colon tissue. Of these sizes, the smallest (0.1 μm) had the greatest effect. Pre-administration of MP promotes colitis but reduces tumor growth in a colitis-associated colorectal cancer (CAC) mouse mode. MPs can increase inflammation in mice via activation of the very late antigen 4–vascular cell adhesion molecule 1 (VLA4-VCAM1) signaling pathway in macrophages, while also inducing macrophage reduction in the late phase of inflammation. In the microbiota–gut–brain axis, polystyrene MP treatment altered bile acid and carbohydrate metabolism in the intestine, inhibited intestinal motility, reduced water reabsorption, and led to a certain degree of depression in mice. These findings suggest that small MPs can induce macrophage reduction, thereby affecting the physical and mental health by modulating the microbiota–gut–brain axis.

Preparation of a Plasma‐Induced Dendritic Cell Vaccine and its Anti‐Tumor Immunity in a Murine Model of Melanoma

AbstractDendritic cell (DC) vaccines play an important role in anti‐tumor immunotherapy. Tumor‐associated cells or cytokines in the tumor microenvironment (TME) can inhibit the antigen‐presenting function of DC. Immunogenic cell death (ICD) can enhance the uptake and presentation of tumor antigens by DC. This study investigates the maturation mechanism of DC induced by low‐temperature plasma (LTP), as well as the therapeutic and protective effects of LTP‐induced DC vaccine in a tumor model. DC2.4 that is co‐cultured with LTP‐treated B16F10 (LTP‐B16) or with these supernatants exhibited decreased phagocytic activity, increased production of cytokines (IL‐12, IL‐6, TNF‐α, and IL‐1β), and increased expression of cell surface activation markers (CD80, CD86, and MHC II). The expression of CD80+/CD86+ is decreased after pre‐treatment with TLR4 and NF‐κB (p65) inhibitors, respectively. In vivo, trials indicated that the LTP‐induced DC vaccine‐induced anti‐tumor immunity and, when combined with cisplatin, synergistically reduced tumor growth.

Casticin suppresses self-renewal related stemness via miR-342-3p-mediated FoxM1 downregulation in cervical cancer cells

BackgroundCasticin (CAS), a natural flavonoid found in Viticis Fructus, Viticis Cannabifoliae Fructus, and Semen Euphorbiae, shows anti-inflammatory activity and efficacy against various cancers. However, its effect on stemness associated with self-renewal in cervical cancer (CC) cells remains unclear, as well as the underlying mechanism. PurposeThe primary objective of this study was to examine the effect of CAS on CC stemness and to explore the underpinning regulatory mechanism. MethodsHeLa cells underwent treatment with varying concentrations of CAS (0, 10, 30, 100 nM). To evaluate the impacts of CAS on CC stemness and tumorigenicity, sphere- and colony-formation assays and a xenograft model were employed. The study involved screening for changes in miRNAs and their target genes. The miRNA array identified an upregulation in miRNAs, whereas the mRNA array detected a downregulation of specific target genes. The latter genes were found to regulate stem cell-related genes through miR-342-3p in HeLa cells administered CAS. Next, whether miR-342-3p directly targets FOXM1 when upregulated by CAS was assessed by the luciferase reporter assay. qRT-PCR was performed to analyze miR-342-3p expression. Additionally, immunoblotting was conducted to assess the protein amounts of FoxM1 and stemness-related factors (CD133, CD49f, Nanog, and Sox2). Function rescue experiments were conducted to determine the mechanism of CAS in stemness regulation. These experiments involved utilizing a miR-342-3p inhibitor and overexpressing FOXM1 in HeLa cells. ResultsCAS decreased in vitro stemness, suppressing sphere- and colony-formation capabilities of CC. It also dose-dependently downregulated the expression of stemness-associated proteins, including CD133, CD49f, Nanog, and Sox2. Moreover, CAS inhibited in vivo carcinogenesis, remarkably reducing tumor growth in mice bearing HeLa cell xenografts. Analysis revealed downregulated FOXM1 expression in HeLa cells treated with CAS. In the luciferase reporter assay, miR-342-3p was found to directly target FOXM1 in CAS-treated HeLa cells. Additionally, miR-342-3p inhibitor transfection successfully rescued CAS’ suppressive impact on stemness. Furthermore, overexpression of FOXM1 did not induce changes in miR-342-3p expression. However, it effectively rescued CAS’ suppressive effects on stemness. Moreover, CAS also inhibited stemness, upregulated miR-342-3p, and lowered FOXM1 expression in the SiHa cell line. ConclusionCAS suppresses self-renewal-associated stemness by targeting FOXM1 via miR-342-3p upregulation. These findings suggest CAS is promising as a novel therapeutic candidate in CC.

PFKFB3 deprivation attenuates the cisplatin resistance via blocking its autophagic elimination in colorectal cancer cells.

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3) is highly expressed in several cancers and plays important roles during the whole pathological process of cancer. It is also involved in chemoresistance, while the intrinsic mechanism needs to be further revealed. The different responses to cisplatin (DDP) between wild type (WT) and DDP-resistant (DDR) colorectal cancer (CRC) cells were analyzed by several assays. Coumarin conjugated DDP (CP-DDP) was utilized to trace the distribution of DDP. Pharmacological and genetic methods were used to deprive autophagy and PFKFB3, and the effects were investigated. The mouse xenograft model was performed to confirm the effect of the PFKFB3 inhibitor on reversing DDP resistance. DDR cells showed a lower capacity for apoptosis upon DDP treatment, but exhibited higher levels of autophagy and PFKFB3. CP-DDP partly co-localized with LC3, and its content lessened faster in DDR cells. Deprivation of both autophagy and PFKFB3 attenuated CP-DDP elimination, and reversed the DDP resistance. Moreover, PFKFB3 inhibition reduced DDP-induced autophagy. PFKFB3 inhibitor in combination with DDP led to a remarkable reduction in tumor growth in vivo. Inhibition of PFKFB3 reduced the autophagy induced by DDP, and therefore extended the retention time of CP-DDP. Meanwhile, PFKFB3 deprivation reversed the DDP resistance and made it a potent therapeutic target for CRC.

A novel mertansine conjugate for acid-reversible targeted drug delivery validated through the Avidin-Nucleic-Acid-NanoASsembly platform

In targeted cancer therapy, antibody-drug-conjugates using mertansine (DM1)-based cytotoxic compounds rely on covalent bonds for drug conjugation. Consequently, the cytotoxic DM1 derivative released upon their proteolytic digestion is up to 1000-fold less potent than DM1 and lacks a bystander effect. To overcome these limitations, we developed a DM1 derivative (keto-DM1) suitable for bioconjugation through an acid-reversible hydrazone bond. Its acid-reversible hydrazone conjugate with biotin (B-Hz-DM1) was generated and tested for efficacy using the cetuximab-targeted Avidin-Nucleic-Acid-NanoASsembly (ANANAS) nanoparticle (NP) platform.NP-tethered B-Hz-DM1 is stable at neutral pH and releases its active moiety only in endosome/lysosome mimicking acidic pH. In vitro, the NP/Cetux/B-Hz-DM1 assembly showed high potency on MDA-MB231 breast cancer cells. In vivo both B-Hz-DM1 and NP/Cetux/B-Hz-DM1 reduced tumor growth. A significantly major effect was exerted by the nanoformulation, associated with an increased in situ tumor cell death. Keto-DM1 is a promising acid-reversible mertansine derivative for targeted delivery in cancer therapy.

Antitumor Activity of Dehydroxymethylepoxyquinomicin (DHMEQ) in Monotherapy and Combination with Cisplatin in the SKOV-3 Ovarian Cancer Model

The objective of this study was to evaluate the antitumor activity of DHMEQ as monotherapy and in combination with cisplatin in a human ovarian cancer xenograft model. Cisplatin was used as a comparator. To create the xenograft model, human ovarian cancer cells (SKOV-3 line) were subcutaneously implanted into immunodeficient mice. The study was conducted on female SCID Beige C.B-17 Cg-Prkdcscid Lystbg/Crl mice. Antitumor activity was determined by comparing tumor growth inhibition (TGI) in the treatment groups to that in the control group. Results showed that daily intraperitoneal administration of DHMEQ at a dose of 14 mg/kg following a single intraperitoneal dose of cisplatin at 4 mg/kg reduced tumor growth in the SKOV-3 cell line xenograft model.

An Oxidative Stress Nano-Amplifier for Improved Tumor Elimination and Combined Immunotherapy.

Amplifying oxidative stress to disrupt intracellular redox homeostasis can accelerate tumor cell death. In this work, an oxidative stress amplifier (PP@T) is prepared for enhanced tumor oxidation therapy to reduce tumor growth and metastases. The nano-amplifier has been successfully constructed by embedding MTH1 inhibitor (TH588) in the PDA-coated porphyrin metal-organic framework PCN-224. The controllable-released TH588 is demonstrated from pores can hinder MTH1-mediated damage-repairing process by preventing the hydrolysis of 8-oxo-dG, thereby amplifying oxidative stress and exacerbating the oxidative DNA damage induced by the sonodynamic therapy of PP@T under ultrasound irradiation. Furthermore, PP@T can effectively induce immunogenic cell death to trigger systemic anti-tumor immune response. When administered in combination with immune checkpoint blockade, PP@T not only impedes the progression of the primary tumor but also achieves obvious antimetastasis in breast cancer murine models, including orthotopic and artificial whole-body metastasis models. Furthermore, the nanoplatform also provides photoacoustic imaging for in vivo treatment guidance. In conclusion, by amplifying oxidative stress and reactive oxygen species sensitized immunotherapy, this image-guided nanosystem shows potential for highly specific, effective combined therapy against tumor cells with negligible side-effects to normal cells which will provide a new insight for precise tumor treatment.

Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy

BackgroundCombining interleukin-2 (IL-2) with radiotherapy (RT) and immune checkpoint blockade (ICB) has emerged as a promising approach to address ICB resistance. However, conventional IL-2 cytokine therapy faces constraints owing to its brief half-life and adverse effects. RDB 1462, the mouse ortholog of Nemvaleukin alfa, is an engineered IL-2 with an intermediate affinity that selectively stimulates antitumor CD8 T and NK cells while limiting regulatory T cell expansion. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462, RT, and anti-PD1 in mouse tumor models.MethodsTwo bilateral lung adenocarcinoma murine models were established using 344SQ-Parental and 344SQ anti-PD1-resistant cell lines. Primary tumors were treated with RT, and secondary tumors were observed for evidence of abscopal effects. We performed immune phenotyping by flow cytometry, analyzed 770 immune-related genes using NanoString, and performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit.ResultsCompared to native IL-2 (RDB 1475), RDB 1462 demonstrated superior systemic antitumoral responses, attributable, at least in part, to augmented levels of CD4 and CD8 T cells with the latter. Our findings reveal substantial reductions in primary and secondary tumor volumes compared to monotherapy controls, with some variability observed among different dosing schedules of RDB 1462 combined with RT. Blood and tumor tissue-based flow cytometric phenotyping reveals an increase in effector memory CD8 and CD4 T cells and a decrease in immunosuppressive cells accompanied by a significant increase in IL-2, IFN-γ, and GM-CSF levels in the combination group. Transcriptomic profiling and TCR sequencing reveal favorable gene expression and T cell repertoire patterns with the dual combination. Furthermore, integrating anti-PD1 therapy with RT and RDB 1462 further reduced primary and secondary tumor volumes, prolonged survival, and decreased lung metastasis. Observations of immune cell profiles indicated that RT with escalating doses of RDB 1462 significantly reduced tumor growth and increased tumor-specific immune cell populations.ConclusionThe addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD1.Graphical

Hsa_circ_ROBO1 competes with miR-324-3p and upregulates NME1 to promote tumor metastasis in nasopharyngeal carcinoma

BackgroundThis work aims to explore circ_ROBO1’s function in nasopharyngeal carcinoma (NPC).Methodscirc_ROBO1 expression in NPC tissues and cell lines was measured. The regulation of circ_ROBO1 and/or miR-324-3p on the proliferation, migration, invasion, and apoptosis of NPC cells was investigated by functional experiments. The interplay between circ_ROBO1, miR-324-3p, and NME1 was explored. Tumor growth and metastasis were studied in mice.Resultscirc_ROBO1 was overexpressed in NPC. Knockdown of circ_ROBO1 repressed proliferation, migration, and invasion and induced apoptosis of NPC cells. Loss of circ_ROBO1 reduced tumor growth and metastasis in mice. circ_ROBO1 competed with miR-324-3p to upregulate NME1. Lowering miR-324-3p expression impaired the effect of knockdown of circ_ROBO1on NPC cells.ConclusionOverexpressed circ_ROBO1 promotes NPC development by modifying the miR-324-3p/NME1 axis.

In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor–microenvironment interactions

Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR–Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo. MEN1 knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, MEN1 knockout redistributes MLL1 chromatin occupancy, increasing H3K4me3 at repetitive genomic regions, activating double-stranded RNA expression and increasing neutrophil and CD8+ T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin–MLL interaction reduces tumor growth in a CD8+ T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1 and provide a rationale for targeting MEN1 in solid cancers.

Lymphocyte antigen 6 family member E suppresses apoptosis and promotes pancreatic cancer growth and migration via Wnt/β-catenin pathway activation

Pancreatic cancer (PC) is the primary cause of cancer-related mortality. Due to the absence of reliable biomarkers for predicting prognosis or guiding treatment, there is an urgent need for molecular studies on PC. Lymphocyte antigen 6 family member E (LY6E) is implicated in uncontrolled cell growth across various cancers. However, the precise mechanism of LY6E in PC remains unclear. Here, we conducted comprehensive bioinformatic analyses using online tools and R- × 64–4.1.1, complemented by experimental validation through Western blotting, immunohistochemistry, immunosorbent assays, flow cytometry, cell assays, and animal models. Our findings reveal significantly elevated expression of LY6E in PC, correlating with poor prognosis. LY6E knockdown inhibited proliferation, invasion, and migration of PC cells, while enhancing apoptosis evidenced by increased cleaved caspase 3 levels and alterations in the Bcl-2/Bax ratio. Conversely, LY6E overexpression promoted PC cell proliferation and migration, and inhibited apoptosis. Mechanistically, LY6E downregulation suppressed the Wnt/β-catenin signaling pathway. In vivo studies demonstrated that LY6E suppression attenuated tumor growth in murine models. Additionally, LY6E suppression resulted in reduced tumor growth in mice. In conclusion, our study confirms the significant role of LY6E in the progression of PC. LY6E, serving as an independent prognostic indicator, has the potential to serve as a valuable biomarker for PC to inform treatment strategies.

Combination of microRNA and suicide gene for targeting Glioblastoma: Inducing apoptosis and significantly suppressing tumor growth in vivo

Glioblastoma (GBM), a grade IV brain tumor, presents a severe challenge in treatment and eradication due to its high genetic variability and the existence of stem-like cells with self-renewal potential. Conventional therapies fall short of preventing recurrence and fail to extend the median survival of patients significantly. However, the emergence of gene therapy, which has recently obtained significant clinical outcomes, brings hope. It has the potential to be a suitable strategy for the treatment of GBM. Notably, microRNAs (miRNAs) have been noticed as critical players in the development and progress of GBM. The combined usage of hsa-miR-34a and Cytosine Deaminase (CD) suicide gene and 5-fluorocytosine (5FC) prodrug caused cytotoxicity against U87MG Glioma cells in vitro. The apoptosis and cell cycle arrest rates were measured by flow cytometry. The lentiviral vector generated overexpression of CD/miR-34a in the presence of 5FC significantly promoted apoptosis and caused cell cycle arrest in U87MG cells. The expression level of the BCL2, SOX2, and P53 genes, target genes of hsa-miR-34a, was examined by quantitative real-time PCR. The treatment led to a substantial downregulation of Bcl2 and SOX2 genes while elevating the expression levels of Caspase7 and P53 genes compared to the scrambled control. The hsa-miR-34a hindered the proliferation of GBM cancer cells and elevated apoptosis through the P53–miR-34a–Bcl2 axis. The CD suicide gene with 5FC treatment demonstrated similar results to miR-34a in the apoptosis, cell cycle, and real-time assays. The combination of CD and miR-34a produced a synergistic effect. In vivo, anti-GBM efficacy evaluation in rats bearing intracranial C6 Glioma cells revealed a remarkable induction of apoptosis and a significant inhibition of tumor growth compared with the scrambled control. The simultaneous use of CD/miR-34a with 5FC almost entirely suppressed tumor growth in rat models. The combined application of hsa-miR-34a and CD suicide gene against GBM tumors led to significant induction of apoptosis in U87MG cells and a considerable reduction in tumor growth in vivo.

Tuning Immune-Cold Tumor by Suppressing USP10/B7-H4 Proteolytic Axis Reinvigorates Therapeutic Efficacy of ADCs.

Tuning immune-cold tumor hot has largely attracted attention to improve cancer treatment, including immunotherapy and antibody-drug conjugates (ADCs). Utilizing multiomic analyses and experimental validation, this work identifies a pivotal role for the USP10/B7-H4 proteolytic axis in mediating the interplay between tumor immune responses and ADC efficacy, particularly for sacituzumab govitecan (SG) in treating triple negative breast cancers (TNBCs). Mechanistically, the inhibition of autocrine motility factor receptor (AMFR)-mediated ubiquitylation of B7-H4 by the deubiquitinase USP10 leads to the stabilization of B7-H4, which suppresses tumor immune activity and reduces SG treatment effectiveness. Pharmacological inhibition of USP10 promotes the degradation of B7-H4, enhancing tumor immunogenicity and consequently improving the tumor-killing efficacy of SG. In preclinical TNBC models, suppression of USP10/B7-H4 proteolytic axis is effective in increasing SG killing efficacy and reducing tumor growth, especially for the tumors with the USP10high/B7-H7high signature. Collectively, these findings uncover a novel strategy for targeting the immunosuppressive molecule B7-H4 for cancer therapy.

Selenium Nanoparticles Synergize with a KRAS Nanovaccine against Breast Cancer.

Selenium (Se) is an element crucial for human health, known for its anticancer properties. Although selenium nanoparticles (SeNPs) have shown lower toxicity and higher biocompatibility than other Se compounds, bare SeNPs are unstable in aqueous solutions. In this study, several materials, including bovine serum albumin (BSA), chitosan, polymethyl vinyl ether-alt-maleic anhydride, and tocopherol polyethylene glycol succinate, are explored to develop stable SeNPs and further evaluate their potential as candidates for cancer treatment. All optimized SeNP are spherical, <100nm, and with a narrow size distribution. BSA-stabilized SeNPs produced under acidic conditions present the highest stability in medium, plasma, and at physiological pH, maintaining their size ≈50-60nm for an extended period. SeNPs demonstrate enhanced toxicity in cancer cell lines while sparing primary human dermal fibroblasts, underscoring their potential as effective anticancer agents. Moreover, the combination of BSA-SeNPs with a nanovaccine results in a strong tumor growth reduction in an EO771 breast cancer mouse model, demonstrating a three-fold decrease in tumor size. This synergistic anticancer effect not only highlights the role of SeNPs as effective anticancer agents but also offers valuable insights for developing innovative combinatorial approaches using SeNPs to improve the outcomes of cancer immunotherapy.