Biology subjects

Nardini, E.

Publications and source records attributed to Nardini, E..

3 recordsLinked to original sources

bioRxiv2026

CMAS dampens anti-tumor immunity and associates with response to neoadjuvant immunotherapy in melanoma

Identifying immune-regulatory pathways to predict response is crucial for the efficacy of immune checkpoint blockade (ICB) immunotherapies. Sialylation is upregulated in tumor cells and modulates immune responses in cancer, yet its impact on patient clinical outcome and the spatial organization of the tumor microenvironment remain unclear. Here, using publicly available single-cell RNA sequencing data we show that expression of the sialylation master regulator CMAS in melanoma cells correlates with poorer patient survival. Using a murine melanoma model, we demonstrate that Cmas deletion in tumor cells severely impaired tumor growth and improved anti-tumor lymphoid and myeloid cell responses, increasing tumor cell-intrinsic susceptibility to interferon-gamma-, CD4+ T cell-, and macrophage-mediated killing. Single-cell spatial transcriptomics on neoadjuvant ICB-treated melanoma patient tumor biopsies revealed that CMAS expression in tumor cells inversely correlated with tumor cell proximity to and activation status of T cells and macrophages. Furthermore, expression of CMAS in tumor cells was increased in patients who did not respond to immunotherapy, compared to responders. Overall, our work identifies CMAS as a key modulator of tumor-immune dynamics associated with survival and response to neoadjuvant ICB immunotherapy in melanoma patients.

cancer biology↗

bioRxiv2025

Lysosomal RNA profiling reveals targeting of specific types of RNAs for degradation

Autophagy targets a wide variety of substrates for degradation within lysosomes1. While lysosomes are known to possess RNase activity2, the role of lysosomal RNA degradation in post-transcriptional gene regulation is not well understood. Here, we define RNASET2, PLD3, and both endogenous and exogenous RNase A family members as lysosomal RNases. Cells lacking these RNases accumulated large amounts of lysosomal RNA. Although all types of RNA can be found within lysosomes, SRP RNAs, Y RNAs, 5' TOP mRNAs, long-lived mRNAs, and mRNAs encoding membrane and secreted proteins were specifically enriched. All types of RNA depend on autophagy for lysosomal targeting, but the lysosomally-enriched RNAs are more sensitive to loss of autophagy, implying that selective mechanisms mediate their lysosomal entry. RNA stability measurements revealed that lysosomally-degraded transcripts also had autophagy-dependent changes in stability. In exploring how specific RNAs are targeted for lysosomal degradation, we found that the Alu domain of SRP RNAs is sufficient for targeting these RNAs to lysosomes in fashion that depends on its interactions with the SRP9 and SRP14 proteins. For mRNAs, 5' TOP motifs are sufficient to increase their targeting to lysosomes for degradation in a LARP1-dependent manner. Altogether, our results establish lysosomes as selective modulators of cellular RNA content.

molecular biology↗

bioRxiv2022

Ageing impairs the neuro-vascular interface in the heart

Aging is a major risk factor for impaired cardiovascular health. The aging myocardium is characterized by electrophysiological dysfunctions such as a reduced heart rate variability. These alterations can be intrinsic within cardiomyocytes, but might be modulated by the cardiac autonomic nervous system, as well1. It is known that nerves align with vessels during development2, but the impact of aging on the cardiac neuro-vascular interface is unknown. Here, we report that aging reduces nerve density specifically in the left ventricle and dysregulates vascular-derived neuro-regulatory genes. Aging leads further to a down-regulation of miR-145 and de-repression of the neuro-repulsive factor Semaphorin-3A. miR-145 deletion increased Sema3a expression and reduced axon density, thus mimicking the observed aged heart phenotype. Removal of senescent cells, which accumulated with chronological age while nerve density declined, rescued from age-induced dennervation, reduced Sema3a expression and preserved heart rate variability. These data suggest that senescence-associated regulation of neuro-regulatory genes contributes to a declined nerve density of the aging heart and thereby to a reduced heart rate variability.

physiology↗