In vivo treatment of HT-29 xenografts with MV-CD46-muPA, Minnelide, or combination and NanoString nCounter analysis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE312436 | GEO | 2026/07/31
REPOSITORIES: GEO
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Project description:Background. Oncolytic viruses represent promising cancer biotherapies due to their ability to selectively lyse tumor cells and stimulate anti-tumor immune responses. However, their long-term efficacy as single agents is inconsistent, underscoring the need for virus-drug combinations to improve outcomes. This study evaluates the effects and mechanisms of triptolide and minnelide in enhancing measles virus oncolysis in human colorectal cancer (CRC) models. Methods. The in vitro effects of CD46 targeted (MV-GFP) and dual targeted (MV-CD46-muPA) oncolytic MV, alone and with triptolide were assessed in human CRC cell lines. Mechanistic studies included gene expression analysis, functional proteomics, and western blotting. In vivo efficacy of MV-CD46-muPA combined with minnelide was evaluated in HT-29 and HCT-116 xenografts. Biological effects were further characterized using transcriptomic profiling (RNA-seq), targeted gene expression (NanoString), and histological analysis . Results. Triptolide enhanced MV mediated oncolysis in vitro, particularly in BRAF mutant CRC cell lines, and modulated cancer pathways including AKT, autophagy, apoptosis and metabolism. In vivo, minnelide significantly improved the efficacy of systemically administered MV-CD46-muPA in human CRC xenografts, with greater effects in BRAF mutant (HT29) models. The combination modulated cell cycle, metabolism, and survival associated genes, promoted apoptosis, and improved intratumoral viral distribution. These molecular effects resulted in reduced tumor cell proliferation (Ki67), decreased angiogenesis (CD31) and increased apoptosis (TUNEL) relative to single agents. Conclusion. Triptolide and minnelide synergistically enhance the antitumor efficacy of oncolytic measles virus in colorectal cancer, particularly in BRAF mutant tumors through modulation of survival, metabolism and stromal pathways, together with improved viral distribution. These findings underscore the innovative potential of this virus-drug combination and support further translational development for CRC and other malignancies.
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Project description:HT-29 human colorectal cancer cells were treated in vitro with Vehicle control (Ctrl), MV-GFP (GFP), Triptolide (TRP), or MV-GFP + TRP (Combo). Three biological replicates were performed per treatment. RNA was extracted using NanoString protocols and analyzed with the nCounter Human Tumor Signaling 360 panel. RCC files for each replicate are provided as raw data. Data were processed using nSolver 4.0 Advanced Analysis module with standard normalization and Benjamini–Hochberg correction.
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Project description:CD46 is well known to be involved in diverse biological processes. Although several splice variants of CD46 have been identified, little is known about the contribution of alternative splicing to its tumorigenic functions. Here we found that exclusion of CD46 exon13 is significantly increased in bladder cancer samples. In bladder cancer cell lines, enforced expression of CD46-CYT2 (exon13-skipping isoform) induced cell growth and migration, and promoted tumorigenicity in a xenograft model. While enforced expression of CD46-CYT1 (exon13-containing isoform) attenuated tumorigenicity, representing an inverse phenotype of CD46-CYT2. We also used RNA sequencing to identify changes in gene expression after CD46-CYT1 or CD46-CYT2 overexpression and found KRT19 is a key CD46-CYT2 target gene. Furthermore, we applied interaction proteomics to identify exhaustively the complexes containing CYT1 or CYT2 domain in EJ-1 cells. 320 proteins were identified that interact with CYT1 or/and CYT2 domain, including some well-known CYT1 partners and most of them are new interactors. The new CYT2 partners’ translation machinery, RPL17 and EIF5A, were confirmed by coimmunoprecipitation experiments. We demonstrated that CD46-CYT2 enhances mRNA translation perhaps through an interaction with the translation machinery. Strikingly, the splicing factor SRSF1 is upregulated in bladder cancer and stimulates exclusion of exon13. Importantly, SRSF1 is highly correlated with CD46 exon13 exclusion in clinical bladder cancer samples. Taken together, our findings contribute to understanding the role of CD46 in bladder cancer development.
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Project description:Recent data indicate that intracellularly activated and autocrine-functioning complement activation fragments - in conjunction with an NLRP3 inflammasome - is critical for normal human Th1 induction and contraction. More specifically, engagement of of the C3aR and CD46 by autocrine generated C3a and C3b, respectively, drives the metabolic reprogramming needed for IFN-gamma secrtion by human CD4+ T cells. It was not clear whether autocrine complement and/or the NLRP3 inflammasome are also needed for normal human cytotoxic CD8+ T cell (CTL) responses. During this study, we used CTLs isolated from patients with either CD46 deficiency or with NLRP3 hyperactivity to determine that CD46 is also required for normal IFN-gamma secretion as well as killing activity in CTLs, whilst a canonical NLRP3 inflammasome is not required for these key functions. The CD46-deficient patient utilized in this study has a mutation in the CD46 gene that leads to reduced cell surface CD46 expression and a dysfunction in Th1 induction. The patient suffers from episodes of atypical hemolytic uremic syndrome (aHUS) and common variable immune deficiency (CVID) and recurrent infections.
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Project description:Adenoid B cells from anonymous human donors were isolated and nucleofected with RNP complexes targeting two loci within exon 2 of the CD46 gene, which encodes a cell surface protein. One hour after nucleofection, the same number of control cells (w/o-RNP) and CD46-RNP complex treated cells were infected with Epstein-Barr virus (strain 6008_B95-8) with a multiplicity of infection of 0.1. Newly transcribed RNAs were metabolically labeled with 4-thiouridine (4sU) for 60 min 23 hours after EBV infection. Twenty-four hours after the start of the experiment, 4sU-biotin-labeled, newly transcribed RNAs were thiol-specifically biotinylated and separated from unlabeled RNA using Streptavidin beads. RNA-seq experiments with the enriched RNA samples were performed to analyze the edited CD46 locus encompassing the RNP complex target sites. The experiment revealed that 24 hours after CRISPR-Cas9 mediated gene editing a substantial fraction of CD46 transcript contained indels and a larger deletion in between the two targets sites within exon 2 of CD46.
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Project description:CIC::DUX4 sarcoma (CDS) is a lethal cancer driven by a fusion between tumor suppressor Capicua (CIC) and pioneer transcription factor double homeobox 4 (DUX4). To develop an immunocompetent pre-clinical model of CDS, we previously generated three genetically engineered mouse models (GEMMs) of CDS with CIC::DUX4 regulated by loxP-STOP-loxP cassettes. However, all three models developed spontaneous tumors without Cre recombinase. Here, we established an innovative GEMM of CDS (dFLEx CDS) that employs a dual recombinase (Cre + FLPE) FLEx-switch design to activate CIC::DUX4 expression and initiate sarcomagenesis in a spatially and temporally-controlled manner. Because CIC::DUX4 drives sarcoma development by activating a distinct oncogenic transcriptional program, we performed a drug screen on human-derived CDS cell lines using a library of compounds that modulate transcriptional regulation. This screen identified Minnelide, an inhibitor of RNA polymerase II-mediated transcription, as a selective inhibitor of CDS. Mechanistically, Minnelide acted through xeroderma pigmentosum type B to alter phosphorylation of RPB1, the largest subunit of RNA polymerase II. Subsequently, RPB1 underwent degradation leading to apoptosis of CDS cells. Minnelide demonstrated in vivo efficacy in autochthonous dFLEx CDS GEMMs and in human CDS xenografts. As Minnelide has already been demonstrated to be safe in clinical trials with activity for adult cancers, these findings nominate Minnelide as a novel therapeutic option to test in CDS patients.
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Project description:CIC::DUX4 sarcoma (CDS) is a lethal cancer driven by a fusion between tumor suppressor Capicua (CIC) and pioneer transcription factor double homeobox 4 (DUX4). To develop an immunocompetent pre-clinical model of CDS, we previously generated three genetically engineered mouse models (GEMMs) of CDS with CIC::DUX4 regulated by loxP-STOP-loxP cassettes. However, all three models developed spontaneous tumors without Cre recombinase. Here, we established an innovative GEMM of CDS (dFLEx CDS) that employs a dual recombinase (Cre + FLPE) FLEx-switch design to activate CIC::DUX4 expression and initiate sarcomagenesis in a spatially and temporally-controlled manner. Because CIC::DUX4 drives sarcoma development by activating a distinct oncogenic transcriptional program, we performed a drug screen on human-derived CDS cell lines using a library of compounds that modulate transcriptional regulation. This screen identified Minnelide, an inhibitor of RNA polymerase II-mediated transcription, as a selective inhibitor of CDS. Mechanistically, Minnelide acted through xeroderma pigmentosum type B to alter phosphorylation of RPB1, the largest subunit of RNA polymerase II. Subsequently, RPB1 underwent degradation leading to apoptosis of CDS cells. Minnelide demonstrated in vivo efficacy in autochthonous dFLEx CDS GEMMs and in human CDS xenografts. As Minnelide has already been demonstrated to be safe in clinical trials with activity for adult cancers, these findings nominate Minnelide as a novel therapeutic option to test in CDS patients.
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