Biology subjects

Van de Velde, L.-A.

Publications and source records attributed to Van de Velde, L.-A..

4 recordsLinked to original sources

bioRxiv2025

IL4i1-sourced oncometabolites promote neuroblastoma cell survival

High-risk neuroblastoma (NB) is driven by the amplification of MYCN in conjunction with additional oncogenic mutations in kinases such as ALK. NB cells require antioxidant responses to maintain redox balance and are highly sensitive to ferroptosis. Here, we show that metabolites derived from infiltrating immune cells expressing IL4i1, a secreted oxidoreductase, are potent suppressors of NB ferroptosis. IL4i1 metabolites (indole-3-pyruvate and 4-hydroxyphenylpyruvate) blocked ferroptosis in all human NB cell lines via a mechanism that depended on free radical scavenging and NRF2 activation but did not require the aryl hydrocarbon receptor. Supernatant transfer experiments confirmed that IL4i1 creates a milieu that protects NB cells from oxidative cell death. Importantly, mice lacking IL4i1 were protected from NB in a high-penetrance MYCN and mutant ALK-driven autochthonous cancer model. Therefore, we propose that immune IL4i1 is permissive for NB growth and survival. IL4i1 produces context-dependent oncometabolites and, as a secreted enzyme, represents a target for cell death manipulation in cancers sensitive to oxidative stress-driven cell death. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/669062v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@6e79baorg.highwire.dtl.DTLVardef@f9a9bcorg.highwire.dtl.DTLVardef@f6b2aaorg.highwire.dtl.DTLVardef@4bb764_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown and how to eradicate neuroblastoma regardless of their cell states is a clinical challenge. To better understand the lineage switch of neuroblastoma in chemoresistance, we comprehensively defined the transcriptomic and epigenetic map of ADRN and MES types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We showed that cancer cells not only undergo a bidirectional switch between ADRN and MES states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. The lineage alterations are coupled with epigenetic reprogramming and dependency switch of lineage-specific transcription factors, epigenetic modifiers and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.

cancer biology↗

bioRxiv2022

Improved metabolic syndrome and timing of weight loss is crucial for influenza vaccine-induced immunity in obese mice

Persons with obesity are at higher risk for developing severe complications upon influenza virus infection making vaccination a priority. Yet, studies demonstrate vaccine responses are less effective in obese hosts. In these studies, we examined how the timing of weight loss influenced influenza vaccine efficacy in male and female diet- induced obese mice. Here, we show weight loss post-vaccination is insufficient to rescue poor vaccine efficacy; however, weight loss occurring pre-vaccination successfully improves outcomes at viral challenge. Pre-vaccination weight loss improved vaccine immunogenicity and restored a functional recall response at challenge. Through tracking sera metabolic biomarkers, we propose the metabolic state at the time of vaccination is predictive of vaccine immunogenicity. Altogether, these findings highlight how timing of host-directed interventions is vital when seeking to improve influenza vaccine immunogenicity in obese hosts.

microbiology↗

bioRxiv2021

Neuroblastoma formation requires unconventional CD4 T cells and myeloid amino acid metabolism

By mirroring their function as tissue repair organizers in normal tissues, immune cells regulate tumor growth. To understand the different facets of immune-tumor collaboration through genetics, spatial transcriptomics, and immunological manipulation with non-invasive, longitudinal imaging, we generated a penetrant double oncogene-driven autochthonous model of neuroblastoma. Using spatial transcriptomic analysis, we co-localized CD4+ and myeloid populations within the tumor parenchyma, while CD8+ T cells and B cells were peripherally dispersed. Depletion of CD4+ T cells or CCR2+ macrophages, but not B cells, CD8+, or NK cells, prevented tumor formation. Tumor CD4+ T cells displayed unconventional phenotypes, were clonotypically diverse, and antigen-independent. Within the myeloid fraction, tumor growth required myeloid cells expressing Arginase-1. Overall, our results suggest that arginine-metabolizing myeloid cells conspire with pathogenic CD4+ T cells to create permissive conditions for tumor formation, and therefore suggest that these pro-tumorigenic pathways can be disabled by targeting myeloid amino acid metabolism.

cancer biology↗