Biology subjects

Hofman, P.

Publications and source records attributed to Hofman, P..

7 recordsLinked to original sources

bioRxiv2025

Glucocorticoids Modulate mRNA Translation Fate Through P-Body Dynamics

Processing bodies (P-bodies) are cytoplasmic, membraneless organelles that play a key role in regulating RNA translation. To identify new pathways controlling their formation, we conducted a Food and Drug Administration (FDA)-approved drug screen. We found that glucocorticoids, among the most prescribed medicines, significantly increase P-body numbers across diverse epithelial cell types. This effect was fully reversible after glucocorticoid withdrawal, illustrating the adaptive dynamics of P-bodies. Using genetic invalidation and rescue approaches, we demonstrated that this accumulation requires the Glucocorticoid Receptor alpha isoform. P-body accumulation was associated with the sequestration of P-body-specific-targeted mRNAs, altering their translation yield. Notably, this translational regulation depends on transcript sequence features rather than abundance, with AU-rich mRNA transcripts being sequestered and GC-rich mRNAs preferentially translated under glucocorticoid treatment. Furthermore, we linked the decrease of LSM14B, a negative regulator of P-bodies, under glucocorticoid treatment to P-body reshaping. Our results reveal that, beyond their known transcriptional activity, prolonged exposure to glucocorticoids influences mRNA post-transcription and translation through a nucleotide composition-based mechanism.

cell biology↗

bioRxiv2025

Comprehensive mapping of identical epitopes across human proteins reveals implications for immune recognition and therapeutic design

Shared epitopes create safety and efficacy issues for T-cell immunotherapy. In order to facilitate the monitoring of immune responses and the engineering required to solve this problem, we performed a computational proteome-wide epitope screening to establish the complete atlas of shared epitopes in the human and murine proteomes. Unlike bacterial or viral antigens, self-antigens like tumor-associated antigens (TAAs) frequently contained a high level of shared MHC-II epitopes identical to unintended other self-proteins. Therefore, shared epitopes should be a mandatory and systematic concern in studies using TAA. Noticeably, a subset of TAAs identified in this atlas is free of this drawback. Therefore, this dataset will be essential for immunologists designing cancer vaccines, but also to interpret immunomonitoring studies against self-antigens in oncology and autoimmunity. To facilitate the detection of common epitopes, a web server has been made available at https://epitopscanner.ircan.org/.

bioinformatics↗

bioRxiv2023

Lung injury shifts pulmonary capillary endothelial cells towards regeneration-associated Lrg1+ subpopulations with delayed dynamics in aged mice

Aging increases the risk of developing fibrotic diseases by hampering tissue regeneration after injury. Using longitudinal single-cell RNA-seq and spatial transcriptomics, here we compare the transcriptome of bleomycin-induced fibrotic lungs of young and aged mice, at 3 time points corresponding to the peak of fibrosis, regeneration and resolution. We find that lung injury shifts the transcriptomic profiles of three pulmonary capillary endothelial cells (PCEC) subpopulations. The associated signatures are linked to pro-angiogenic signaling with strong Lrg1 expression and do not progress similarly throughout the resolution process between young and old animals. Moreover, part of this set of resolution-associated markers is also detected in PCEC from samples of patients with idiopathic pulmonary fibrosis. Finally, we find that aging also alters the transcriptome of PCEC which display typical pro-fibrotic and pro-inflammatory features. We propose that age-associated alterations in specific PCEC subpopulations may interfere with the process of lung progenitor differentiation, thus contributing to the persistent fibrotic process typical of human pathology.

pathology↗

bioRxiv2021

Processing body dynamics drive non-genetic MEK inhibitors tolerance by fine-tuning KRAS and NRAS translation

Overactivation of the Mitogen-activated protein kinase (MAPK) pathway is a critical driver of many human cancers. However, therapies targeting this pathway have proven effective in only a few cancers, as cancers inevitably develop resistance. Puzzling observations suggest that MAPK targeting fails in tumors due to early compensatory RAS overexpression, albeit by unexplained mechanisms. We identified a novel mechanism of drug tolerance to MEK inhibitors (MEKi) that involves Processing Bodies (PBs), a membraneless organelle (MLO). MEKi promoted translation of the oncogenes KRAS and NRAS, which in turn triggered BRAF phosphorylation. This overexpression, which occurred in the absence of neotranscription, depended on PB dissolution as the source of the RAS mRNA. Moreover, in response to MEKi removal, the process was dynamic as PBs rapidly reformed and reduced MAPK signaling. These results highlight a dynamic spatiotemporal negative feedback loop of MAPK signaling via RAS mRNA sequestration. Furthermore, we observed a phenotype with a low number of PBs along with strong KRAS and NRAS induction capacities. Overall, we describe a new intricate mechanism involving PBs in the translational regulation of essential cellular signaling pathways like MAPKs, paving the way for future therapies altering MLO and thereby improving targeted cancer therapies.

cancer biology↗

bioRxiv2021

Disentangling heterogeneity of Malignant Pleural Mesothelioma through deep integrative omics analyses

Malignant Pleural Mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Using the largest series of whole-genome sequencing data integrated with transcriptomic and epigenomic data using multi-omic factor analysis, we demonstrate that MPM heterogeneity arises from four sources of variation: tumor cell morphology, ploidy, adaptive immune response, and CpG island methylator phenotype. Previous genomic studies focused on describing only the tumor cell morphology factor, although we robustly find the three other sources in all publicly available cohorts. We prove how these sources of variation explain the biological functions performed by the cancer cells, and how genomic events shape MPM molecular profiles. We show how these new sources of variation help understand the heterogeneity of the clinical behavior of MPM and drug responses measured in cell lines. These findings unearth the interplay between MPM functional biology and its genomic history, and ultimately, inform classification, prognostication and treatment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/461908v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@b6c43corg.highwire.dtl.DTLVardef@10d45a9org.highwire.dtl.DTLVardef@58746eorg.highwire.dtl.DTLVardef@143f880_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

A ganglioside-based senescence-associated immune checkpoint

Senescent cells accumulate in aging tissues, and their elimination can favor healthy aging1-4. Therefore, therapeutic interventions targeting cellular senescence may be promising strategies for delaying or reversing a vast range of age-related diseases5. As cells of the immune system are responsible for senescent cell elimination6-11, a possible anti-aging and pro-healthspan treatment is the specific activation of the immune system to induce senescent cell clearance. However, whether this elimination is limited by an immune checkpoint leading to tolerance of senescence cells is currently unknown. Here, we show that cellular senescence, elicited by various stressors other than oncogenic activation, triggers immune escape toward natural killer (NK) cells, which may thus limit the use of anti-senescence immunotherapies. Moreover, using mass spectrometry, we reveal that senescent cells reshuffle their glycosphingosine composition, toward a marked increase in the ganglioside content, including the appearance of disialylated ganglioside GD3. This senescence associated GD3 overexpression results from transcriptional upregulation of the gene encoding the enzyme ST8SIA1, which is responsible for GD3 synthesis. The high level of GD3 leads to a strong immunosuppressive signal affecting NK cell-mediated immunosurveillance. In a mouse model of lung fibrosis, senescent cell-dependent NK cell immunosuppression is blunted by in vivo administration of anti-GD3 monoclonal antibodies leading to a clear anti-fibrotic effect. These results demonstrate that GD3 upregulation in senescent cells drives a switch from immune clearance toward immune tolerance of senescent cells. Therefore, we propose that GD3 level acts as a senescence-associated immune checkpoint (SIC) that regulates NK cell functions toward senescent cells. Thus, targeting GD3 with specific antibodies may be a promising strategy for the development of effective anti-senescence immunotherapies.

immunology↗

bioRxiv2020

Small-molecule P2RX7 activator sensitizes tumor to immunotherapy and vaccinates mouse against tumor re-challenge

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop new therapeutic strategies to improve patient outcome. We developed a new chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates PD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7 expressing cells to generate IL-18 which leads to the production of IFN-{gamma} by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a promising novel strategy that may be active against NSCLC.

cancer biology↗