Biology subjects

Hendrikse, L. D.

Publications and source records attributed to Hendrikse, L. D..

4 recordsLinked to original sources

bioRxiv2026

Ependymomas are cancers of the pre-neural crest/roof plate lineage

Distinct molecular variants of the brain cancer ependymoma are distributed along the rostral-caudal extent of the central nervous system (CNS). Historically proposed to arise from ventricular ependyma, recent studies have suggested conflicting cellular origins, including the neural radial glia and the roof plate lineages. Using single-cell transcriptomics, immunohistochemistry, and lineage tracing, we demonstrate that ependymomas across all CNS compartments transcriptionally mirror MSX1+ve pre-neural crest/roof plate (Pre-NC/RP) lineage derivatives. Ependymoma subgroups recapitulate the spatial and molecular diversity of regional Pre-NC/RP populations, while retaining conserved MSX1 expression. Expression of the oncogenic fusion ZFTA-RELA within the murine Pre-NC/RP lineage generated tumors that faithfully resembled human ependymoma. These findings identify a common embryonic cellular origin for ependymomas and reconcile previously conflicting models of tumorigenesis.

developmental biology↗

bioRxiv2025

Synergistic RAS-MAPK and AKT Activation in MYC-Driven Tumors via Adjacent PVT1 Rearrangements

MYC-driven (MYC+) cancers are aggressive and often fatal. MYC dysregulation is a key event in these cancers, but overexpression of MYC alone is not always enough to cause cancer. Plasmocytoma Variant Translocation 1 (PVT1), a long non-coding RNA (lncRNA) adjacent to MYC on chromosome 8 is a rearrangement hotspot in many MYC+ cancers. In addition to being co-amplified with MYC, the genomic rearrangement at PVT1 involves translocation, which has had obscure functional consequences. We report that translocation at the PVT1 locus cause asymmetric enrichment of 5-PVT1 and loss of 3-PVT1. Despite being classified as a non-coding RNA, the retained 5 region of PVT1 generates a circular RNA (CircPVT1) that codes for the novel peptide we call Firefox (FFX). FFX augments AKT signaling and synergistically activates MYC and mTORC1 in these cells. Further, the 3 end of PVT1, which is lost during the translocation, codes for a tumor-suppressing micropeptide we named as Honeybadger (HNB). We demonstrate that HNB interacts with KRAS and disrupts the activation of KRAS effectors. Loss of HNB leads to activation of RAS/MAPK signaling pathway, and enhances MYC stability by promoting phosphorylation of MYC at Ser62. These findings identify PVT1 as a critical node that synchronizes MYC, AKT, and RAS-MAPK activities in cancer. Our study thus identifies a key mechanism by which rearrangements at the PVT1 locus activate additional oncogenic pathways that synergize with MYC to exacerbate the aggressiveness of MYC+ cancers. This newfound understanding explains the poor prognosis associated with MYC+ cancers and offers potential therapeutic targets that could be leveraged in treatment strategies for these cancers.

cancer biology↗

bioRxiv2022

Enhancement of mitochondrial function fosters B cell immune memory

Differentiation of T and B cells to effector and memory cell fates are associated with extensive metabolic changes which are accompanied by altered mitochondrial dynamics. However, whether alterations in mitochondrial structure and function plays an active role in regulating effector versus memory cell fate decisions during immune responses remains unclear. Our studies here characterize changes in mitochondrial dynamics in activated B cells and show that increased mitochondrial mass and activity is a distinct feature of memory B cell lineage commitment in vivo. Using a directed screen of mitochondrial modulators, we identify mitochondrial fission inhibitor, Mdivi-1 as an agent that could enhance mitochondrial mass and function leading to augmented memory B cell differentiation. The enhanced memory B cell responses mediated by Mdivi-1, translated to more robust recall responses upon secondary antigen exposures. Moreover, Mdivi-1 when used in combination with subunit (SARS-CoV2) and inactivated (H1N1 influenza) vaccines led to remarkably improved vaccine efficacies and protection from lethal viral (H1N1) challenge. Single-cell transcriptomics revealed enhanced commitment to memory lineage differentiation in B cells following Mdivi-1 treatment. We propose that mitochondrial modulators such as Mdivi-1 are a novel class of "immune enhancers" that specifically reinforces immunological memory and could be broadly applied to improve the fidelity of immune responses and vaccine efficacies.

immunology↗

bioRxiv2019

Identification of a novel gammaherpesvirus in Canada lynx (Lynx canadensis)

Gammaherpesviruses (GHVs) infect many animal species and are associated with lymphoproliferative disorders in some. Previously, we identified several novel GHVs in North American felids, however a GHV had never been identified in Canada lynx (Lynx canadensis). We therefore hypothesized the existence of an unidentified GHV in lynx. Using degenerate nested and subsequently virus-specific PCR, we amplified and sequenced 3.4 kb of DNA from a novel GHV in lynx, which we named Lynx canadensis gammaherpesvirus 1 (LcaGHV1). We then estimated the prevalence of LcaGHV1 in lynx by developing a PCR-based assay and detected LcaGHV1 DNA in 36% (95% CI: 22-53%) of lynx spleen DNA samples from Maine, USA and 17% (95% CI: 8-31%) from Newfoundland, Canada. Phylogenetic analysis determined that LcaGHV1 is a distinct GHV species belonging to the genus Percavirus. The potential ecologic and pathologic consequences of this novel virus for Canada lynx populations warrant further study.

microbiology↗