Biology subjects

Zamboni, M.

Publications and source records attributed to Zamboni, M..

4 recordsLinked to original sources

bioRxiv2023

Cytomegalovirus promotes proliferation and survival of prostate cancer cells and constitutes a therapeutic target

Metastatic prostate cancer is incurable and new therapeutic targets and drugs are needed. Viruses are associated with several cancer types, but their connection to prostate cancer is unclear. Here we show that human herpes virus cytomegalovirus (CMV) infection is common in the healthy prostate epithelium as well as in prostate cancer, with 85% of tumors being infected to varying degrees. The CMV gene locus UL122-UL123 upheld viral genome persistence in endogenously CMV infected prostate cancer cell lines. CMV promoted prostate cancer cell viability independently of androgen receptor status and anti-androgen resistance, partly through CMV UL97 and the androgen signaling pathway. DNA intercalation mitigated CMV infection and reduced CMV-dependent tumor size in xenotransplantation experiments. The anti-herpes drug aciclovir showed modest effects, but the well tolerated CMV UL97 kinase inhibitor maribavir partly mimicked CMV loss by inducing apoptosis and attenuating proliferation, resulting in reduced tumor growth in vivo. We conclude that CMV infects prostate cells in vivo and alters core prostate cancer cell properties, suggesting that it can be therapeutically targeted to improve prostate cancer outcomes.

cancer biology↗

bioRxiv2022

Chromatin accessibility profiling in tissue sections by spatial ATAC

Current methods for epigenomic profiling are limited in the ability to obtain genome wide information with spatial resolution. Here we introduce spatial ATAC, a method that integrates transposase-accessible chromatin profiling in tissue sections with barcoded solid-phase capture to perform spatially resolved epigenomics. We show that spatial ATAC enables the discovery of the regulatory programs underlying spatial gene expression during mouse organogenesis, lineage differentiation and in human pathological samples.

genomics↗

bioRxiv2020

Activation of a neural stem cell transcriptional program in parenchymal astrocytes

Neural stem cells, located in discrete niches in the adult brain, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions do not generate neurons under physiological conditions. After stroke, however, striatal astrocytes undergo neurogenesis in mice, triggered by decreased Notch signaling. We used single-cell RNA sequencing to characterize neurogenesis by Notch-depleted striatal astrocytes in vivo. Striatal astrocytes were located upstream of neural stem cells in the neuronal lineage. As astrocytes initiated neurogenesis, they became transcriptionally very similar to subventricular zone stem cells and progressed through a nearly identical neurogenic program. Surprisingly, in the non- neurogenic cortex, Notch-depleted astrocytes also initiated neurogenesis. Yet, the cortical astrocytes, and many striatal ones, stalled before entering transit- amplifying divisions. Infusion of epidermal growth factor enabled stalled striatal astrocytes to resume neurogenesis. We conclude that parenchymal astrocytes are latent neural stem cells and that targeted interventions can guide them through their neuronal differentiation.

neuroscience↗

bioRxiv2019

Clonally distinct differentiation trajectories shape CD8+ memory T cell heterogeneity after acute viral infections in humans

CD8+ T cells play essential roles in immunity to viral and bacterial infections, and to guard against malignant cells. The CD8+ T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogenous repertoire of phenotypically and functionally distinct effector and memory cells1, 2. How individual T cell clones contribute to this heterogeneity during an immune response is key to understand immunity but remains largely unknown. Here, we longitudinally tracked CD8+ T cell clones expanding in response to yellow fever virus vaccination at the single cell level in humans. We show that only a fraction of the clones detected in the acute response persists as circulating memory T cells, indicative of clonal selection. Clones persisting in the memory phase displayed biased differentiation trajectories along a gradient of stem cell memory (SCM) towards terminally differentiated effector memory (EMRA) fates. Reactivation of single memory CD8+ T cells revealed that they were poised to recapitulate skewed differentiation trajectories in secondary responses, and this was generalizable across individuals for both yellow fever and influenza virus. Together, we show that the sum of distinct clonal differentiation repertoires results in the multifaceted T cell response to acute viral infections in humans.

immunology↗