Biology subjects

Neff, T.

Publications and source records attributed to Neff, T..

3 recordsLinked to original sources

bioRxiv2025

Clinical and molecular features of primary gliosarcoma with digital spatial whole-transcriptome analysis of glial and mesenchymal components

Gliosarcoma is a rare subtype of IDH-wildtype glioblastoma defined by mixed malignant glial and high-grade sarcomatous histological elements. Gliosarcoma is clinically managed similarly to glioblastoma and has a poor clinical outcome. The sarcoma-like regions of gliosarcoma are thought to represent extreme mesenchymal metaplasia of neoplastic glial cells. Factors contributing to this phenomenon are not completely understood. Here we report a single-institution series of 37 gliosarcomas including next-generation sequencing data on 25 cases and digital spatial whole-transcriptome analysis on 4 cases to characterize differential gene expression between glial and mesenchymal components. Gliosarcoma demographic and genetic features were compared to a cohort of 75 primary adult hemispheric IDH-wildtype non-sarcomatous glioblastomas. Patient age, tumor location, sex, and overall survival in gliosarcoma were similar to glioblastoma. Gliosarcomas showed a significantly lower rate of EGFR amplification and a higher rate of NF1 mutation compared to glioblastomas in next-generation sequencing analysis. Digital spatial whole-transcriptome analysis showed a distinct transcriptomic profile in sarcomatous regions with over-expression of genes involved in extracellular matrix development and remodeling. Selected differentially expressed transcripts were examined further by immunohistochemistry. The glial elements of gliosarcomas showed higher immunoreactivity for Chitinase-3-like protein 1 (CHI3L1) than glioblastomas, but low to absent expression within the sarcomatous elements. Lymphoid Enhancer-Binding Factor 1 (LEF1) immunoreactivity was identified within sarcomatous regions of gliosarcoma without detectable nuclear {beta}-catenin, suggesting a role for {beta}-catenin independent wingless (WNT) effector signaling in sarcomatous transformation. This study adds to the growing literature demonstrating differences in the genetic underpinning of gliosarcoma and glioblastoma, establishes feasibility of spatial transcriptomic approaches in gliosarcoma, and validates digital spatial profiling-based results as a discovery platform to identify pathways and immunohistochemical markers for further study.

pathology↗

bioRxiv2025

Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline

Aging-associated decline in brown adipose tissue (BAT) function and mass contributes to energy and metabolic homeostasis disruption. Alcohol dehydrogenase 5 (ADH5) is a major denitrosylase that prevents cellular nitro-thiol redox imbalance, an essential feature of aging. However, the functional significance of BAT ADH5 in the context of aging is largely unknown. Here, we aimed to investigate the role of BAT ADH5 in protecting against age-related metabolic dysfunction. We show that aging elevates BAT protein S-nitrosylation modification and downregulates ADH5 in mice. Furthermore, BAT ADH5-deletion accelerates BAT senescence and aging-associated declines in metabolic homeostasis and cognition. Mechanistically, we found that aging inactivates BAT Adh5 by suppressing heat shock factor 1 (HSF1), a well-recognized proteostasis regulator. Moreover, pharmacologically enhancing HSF1 improved age-related BAT senescence, metabolic decline, and cognitive dysfunction. Together, these findings suggest that the BAT HSF1-ADH5 signaling cascade plays a key role in protecting against age-related systemic functional decline. Ultimately, unraveling the role of thermogenic adipose nitrosative signaling will provide novel insights into the interplay between BAT nitric oxide bioactivity and metabolism in the context of aging. HighlightsO_LIAging elevates general protein S-nitrosylation while downregulating ADH5 expression in BAT. C_LIO_LILoss of thermogenic adipose tissue ADH5 accelerates BAT senescence and exacerbates aging-associated metabolic and cognitive dysfunctions. C_LIO_LIDisruption of HSF1-activated Adh5 in BAT contributes to aging-associated metabolic and cognitive impairments. C_LIO_LIPharmacological targeting of BAT HSF1 alleviates aging-related BAT senescent and systemic declines. C_LI

physiology↗

bioRxiv2019

Epigenetic regulation of protein translation in KMT2A-rearranged AML

Inhibition of the histone methyl-transferase DOT1L (KMT4) has shown encouraging activity in preclinical models of KMT2A (MLL)-rearranged leukemia. The DOT1L inhibitor pinometostat (EPZ5676) was well tolerated in early phase clinical trials and showed modest clinical activity, including occasional complete responses (CRs) as single agent. These studies support the development of combinatorial therapies for KMT2A-rearranged leukemias. Here, we investigated two novel combinations: dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination of a DOT1L inhibitor with the protein synthesis inhibitor homoharringtonine (HHR).\n\nEZH2 is the catalytic histone methyltransferase in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has reported preclinical activity in KMT2A-rearranged leukemia. We found that the H3K79 and H3K27 methyl marks are not dependent on each other, and that DOT1L and EZH2 inhibition affect largely distinct gene expression programs. In particular, the KMT2A/DOT1L target HOXA9, which is commonly de-repressed as a consequence of PRC2 loss or inhibition in other contexts, was not re-activated upon dual DOT1L/EZH2 knockout or inhibition. Despite encouraging data in murine KMT2A-MLLT3 transformed cells suggesting synergy between DOT1L and EZH2 inhibition, we found both synergistic and antagonistic effects on a panel of human KMT2A rearranged cell lines. Combinatorial inhibition of DOT1L and EZH2 is thus not a promising strategy. We identified opposing effects on ribosomal gene transcription and protein translation by DOT1L and EZH2 as a mechanism that is partially responsible for observed antagonistic effects. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (HHR), supporting further preclinical/clinical development of this combination.

cancer biology↗