Biology subjects

Verhaegen, M.

Publications and source records attributed to Verhaegen, M..

3 recordsLinked to original sources

bioRxiv2026

An immunocompetent Merkel cell carcinoma model for preclinical studies

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that frequently carries integrated Merkel cell polyomavirus DNA and expresses oncogenic viral small T antigen (sTAg) and truncated large T antigen (tLTAg). We previously reported a mouse model of MCC with skin-targeted expression of sTAg, tLTAg, and the Merkel cell transcription factor ATOH1, combined with deletion of Trp53. Here, we optimized this model to achieve 100% tumor penetrance with lymph node metastases, established four mouse MCC cell lines, and selected one line, mMCC2, for pilot preclinical trials. In immunocompetent C57BL/6J mice, mMCC2 cells reliably produce MCCs and lymph node metastases following subcutaneous or intradermal (orthotopic) injection, and liver and lung metastases after tail vein injection. Mouse MCC allografts resemble parental tumors histologically and express a full complement of MCC differentiation markers. Treatment of allografted mice with anti-PD-1 resulted in variable inhibition of tumor growth. In contrast, treatment with lysine-specific histone Wdemethylase 1 (LSD1) inhibitors, with or without anti-PD-1, led to consistently lower tumor volumes by 5.7-fold in both groups (P < 0.0001) and smaller or undetectable lymph node metastases. Growth-inhibited tumors in all groups showed a marked reduction in proliferating tumor cells and increased infiltration by F4/80+ macrophages and CD8+ T cells. These findings support a role for immune-cell recruitment in treatment response and underscore the importance of immunocompetent preclinical models, even in studies using targeted therapies. This unique virus-positive MCC allograft model, which produces local tumors as well as regional and distant metastases in immunocompetent hosts, provides a critical platform for preclinical evaluation of new therapeutic strategies and sets the stage for much-needed translational studies to inform future clinical trials.

Cancer Biology↗

bioRxiv2025

Sec61 translocon inhibitor Flavitransin blocks selectively dengue virus polyprotein insertion into the ER membrane with pan-flavivirus antiviral potency

Flavivirus infections by Dengue and Zika virus impose a significant healthcare threat worldwide. At present no FDA-approved specific antiviral treatment is available, and the safety of a vaccine against Dengue virus is still under debate. Here, we report the identification of the CADA derivative flavitransin (FT), with potent activity against DENV serotype 2 in various cell types. Moreover, FT showed consistent anti-flaviviral activity against all four DENV serotypes, and also against Zika and Yellow fever virus. Viral polyprotein biogenesis was completely abolished by FT treatment of DENV-infected cells. Drug profiling by a-time-of-drug-addition assay revealed a post-entry antiviral effect of FT, in line with its anticipated Sec61 inhibitory effect. Subsequent analysis of the individual viral proteins in transfected HEK293T cells indicated that FT suppresses the expression of the structural proteins (pre-membrane and envelope) only. Furthermore, cell free in vitro protein translation analysis demonstrated a direct inhibitory effect of FT on the co-translational translocation of the DENV polyprotein across the ER membrane. More specifically, FT inhibited the initiation of protein translocation into the ER that relies on the N-terminal transmembrane region of the capsid subunit of the DENV polyprotein, resulting in rerouting of the viral pre-protein to the cytosol for proteasomal degradation. Finally, selection and genotyping of FT-resistant HCT116 cells revealed a unique A70V mutation in the Sec61 subunit that conferred resistance to FT in infected cells. Long-term exposure of DENV to FT demonstrated a high barrier to resistance development. In conclusion, our data demonstrate that FT selectively interferes with the initiation of ER co-translational translocation of the DENV polyprotein and confirm the critical role of this translocation process in the flavivirus replication cycle.

microbiology↗

bioRxiv2020

The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieves a durable remission. SIRT5 is a member of the sirtuin family of protein deacylases that regulate metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we show that SIRT5 is required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye and is incurable once metastatic. Likewise, SIRT5 is required for efficient tumor formation by melanoma xenografts and in an autochthonous mouse Braf;Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we find that SIRT5 is required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably include MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a novel, druggable genotype-independent addiction in melanoma.

cancer biology↗