Biology subjects

Munoz, D. G.

Publications and source records attributed to Munoz, D. G..

3 recordsLinked to original sources

bioRxiv2026

Spatially resolved gene expression and tumour-microenvironment interactions across malignant transformation in IDH-mutant glioma

Isocitrate dehydrogenase (IDH)-mutant gliomas represent most lower-grade diffuse gliomas in young adults. Although IDH-mutant gliomas initially behave indolently relative to IDH-wildtype counterparts, they undergo inevitable malignant transformation. The mechanisms driving this progression remain poorly defined. We analyzed a unique longitudinal cohort of two patients with IDH-mutant diffuse gliomas, each with matched WHO grade 2, 3, and 4 tumours. Spatial transcriptomics (NanoString GeoMx and 10X Visium), combined with differential expression, spatially variable gene analysis, and gene ontology enrichment, were used to define transcriptional programs underlying progression. Unexpectedly, across both patients, higher-grade tumours demonstrated reduced proliferation at the infiltrative margin as measured by Ki67. Spatial transcriptomic analysis identified an enrichment of invasion-associated genes associated with increasing tumour grade. In an independent bulk RNA-seq cohort, expression of this spatially derived program did not outperform grade-only PFS or OS analysis. These observations underscore the need to develop new metrics that account for spatial evolution that occurs across progression, but escapes detection in bulk analyses and provide the rationale for prioritizing migration-, cytoskeletal- and stress-associated programs for further investigation.

cancer biology↗

bioRxiv2025

Reinke crystals are immunoreactive for purine-synthesizing metabolic enzymes

Reinke crystals are a defining histological feature of human adult Leydig cells, the testosterone producing cells of the testis. These structures are present in the cytoplasm and the nucleus and display quantitative alterations in a variety of physiological and pathological contexts. The functional significance and protein composition of Reinke crystals have remained elusive for over a century. Here, we demonstrate that Reinke crystals are intensely immunoreactive for inosine monophosphate dehydrogenase (IMPDH), and phosphoribosyl pyrophosphate synthetase (PRPS), two key rate-limiting enzymes in the de novo synthesis of purine nucleotides. IMPDH and PRPS are two of several metabolic enzymes that are capable of forming mesoscale filamentous aggregates as a mechanism to regulate enzyme activity. IMPDH is also able to form crystals in cellulo. Our observations link Reinke crystal formation to purine nucleotide metabolism in Leydig cells. We discuss how this novel finding may relate to the unique dependence of Leydig cells on guanyl-based purine nucleotides for testosterone synthesis. The results of this study may have important implications for understanding metabolic contributions to male reproductive disorders as well as offering a novel diagnostic and theranostic tool applicable to Leydig cell neoplasms.

pathology↗

bioRxiv2024

Transglutaminase 2 function in glioblastoma tumor efferocytosis

Glioblastoma is an aggressive and incurable type of brain cancer. Regions of tissue necrosis are a distinctive pathological feature of this cancer. These arise through thrombosis of tumor vasculature, driven by tumor-derived pro-coagulation factors. In studies of transglutaminase 2 (TGM2), we observed that TGM2 mRNA expression in glioblastoma was primarily in a subset of tumor-infiltrating myeloid cells with hypoxia gene expression signatures. Analysis of xenograft and human glioblastoma samples by immunohistochemistry showed that macrophages in the vicinity of necrotic regions expressed very high levels of TGM2. These macrophages were engaged in the phagocytosis of apoptotic cells, a process known as efferocytosis. In cell culture, incubation of macrophages with apoptotic cells induced TGM2 expression in macrophages, and TGM2 inhibitors blocked efferocytosis. In patient-derived glioblastoma organoids cultured in 5% O2, a basal level of apoptosis was observed, and endogenous macrophages were observed in the process of clearing apoptotic cells. Clearance of apoptotic cells was reduced in organoids treated with a TGM2 inhibitor. Apoptotic cells and efferocytosis were both markedly lower in organoids grown in 20% O2. These data, together with previous work, define a model in which necrotic regions in glioblastoma induce hypoxia-driven apoptosis, which in turn promotes efferocytosis by macrophages. TGM2 is both a marker of efferocytosis and a target for efferocytosis inhibition in this process. Efferocytosis is a potent immunosuppressive mechanism, so this process provides an additional mechanism by which large glioblastoma tumors can evade immune responses.

cancer biology↗