Biology subjects

Ferran, M.

Publications and source records attributed to Ferran, M..

3 recordsLinked to original sources

bioRxiv2026

Multi-omics Profiling Reveals an NF-κB-Driven Anti-apoptotic Network Underlying Resistance to Oncolytic VSV in Prostate Cancer Cells

The therapeutic efficacy of oncolytic viruses is often limited by the presence of tumor cells that resist virus-mediated killing. Here, we investigated the molecular mechanisms underlying resistance to Vesicular Stomatitis Virus (VSV) in PC3 cells, an aggressive metastatic prostate cancer (PrCa) cell line, using the VSV-sensitive LNCaP cell line as a comparator. RNA sequencing revealed that, relative to untreated cells, VSV-infected PC3 cells upregulated both pro-apoptotic genes, including BIM, PUMA, and NOXA, and anti-apoptotic and antiviral genes, including A20 and RIG-I. In addition, genes associated with antiviral and pro-survival pathways, including NF{kappa}B and PI3K-Akt signaling, were more highly expressed in PC3 cells than in LNCaP cells. At baseline, PC3 cells also exhibited elevated expression of multiple pro-survival genes, including BCL-xL, MCL1, and CK2, compared with LNCaP cells. Complementary proteomic analyses identified enhanced activation of NF{kappa}B, PI3K-Akt, and MSK1 signaling in VSV-infected PC3 cells relative to infected LNCaP cells. Furthermore, pharmacological inhibition of BCL-2 family proteins or NF{kappa}B signaling restored sensitivity to VSV-induced cell death in PC3 cells. Collectively, these findings identify NF{kappa}B-centered pro-survival signaling networks as key contributors to the resistant phenotype of PC3 cells and suggest that combining oncolytic virotherapy with targeted inhibitors may improve therapeutic efficacy in resistant prostate cancers.

Cancer Biology↗

bioRxiv2025

Constitutive NF-kB Activation is Amplified by VSV in Aggressive PC3 Prostate Cancer Cells that Resist Viral Oncolysis

Cancer cells often have defects in antiviral pathways, making them susceptible to oncolytic viruses like vesicular stomatitis virus (VSV). However, some cancer cells resist viral infection through the constitutive expression of interferon-stimulated genes. This study examined whether NF-{kappa}B activation and NF-{kappa}B-dependent antiviral signaling contributes to resistance to VSV infection in the PC3 cell line, derived from an aggressive metastatic prostate cancer (PrCa) tumor. We found that NF-{kappa}B localized to the nucleus in VSV-infected PC3 cells, but not in the VSV-susceptible LNCaP PrCa cell line. Analysis of the upstream NF-{kappa}B inhibitor I{kappa}B- revealed higher levels of both total and phosphorylated I{kappa}B- in PC3 cells compared to LNCaP cells, indicating constitutive activation of the NF-{kappa}B pathway via an I{kappa}B--dependent mechanism. Notably, VSV infection did not alter I{kappa}B- phosphorylation in PC3 cells, suggesting that VSV may amplify NF-{kappa}B signaling through an I{kappa}B--independent pathway. Furthermore, PC3 cells displayed elevated levels of the NF-{kappa}B p65 protein subunit compared to LNCaP cells, with its phosphorylated form significantly increased upon VSV infection. These results from phosphorylation assays confirm that multiple steps in the NF-{kappa}B pathway are differentially activated in PC3 and LNCaP cells. Additionally, the expression of several NF-{kappa}B-dependent cytokine and proinflammatory genes, including IL12 and IL6, were upregulated following VSV infection in PC3 cells, as compared to LNCaP cells. Blocking the NF-{kappa}B pathway using a pharmaceutical inhibitor resulted in increased PC3 cell death with VSV infection. Collectively, these findings suggest that enhanced NF-{kappa}B signaling may underlie the resistance of PC3 cells to VSV oncolysis, potentially offering new insights into therapeutic strategies targeting NF-{kappa}B in resistant prostate cancers.

cancer biology↗

bioRxiv2025

Methionine matters: a common mechanism of viral inhibition of host defense identified via AI-assisted molecular dynamics

Diverse groups of viruses infecting higher eukaryotes inhibit mRNA export via physical blockage of the Rae1-Nup98 complex within the host cells nucleopore. This is thought to most often involve the critical placement of hydrophilic flanked single methionine residues along polypeptide extensions that reach into the nucleopore. However, it is unknown how this presumably conserved mechanism might function across diverse viral taxa. Here we employ a comparative molecular dynamics (MD) approach comparing motions of wild-type and mutant viral proteins in Rae-Nup98 bound vs. unbound states. Our comparisons of MD simulations are enhanced by kernel-based denoising allowing the isolation of non-random functional dynamics from random thermal noise. We demonstrate that despite large structural differences, three evolutionarily distinct viral systems (i.e. VSV M protein, SARS-CoV2 ORF 6, and KSHV ORF 10) share nearly identical single methionine-dependent functional dynamics related to the host cell inhibition of nuclear transport. This finding strongly supports a convergently-evolved common functional mechanism across viruses involving specific structural placement of non-polar residues like methionine and potentially providing a common therapeutic target for broad spectrum anti-viral treatment.

microbiology↗