Biology subjects

Veiga-Villauriz, C.

Publications and source records attributed to Veiga-Villauriz, C..

5 recordsLinked to original sources

bioRxiv2026

Mast Cell Specific Cyp11a1 Deficiency Promotes T Cell Mediated Immunity and Suppresses Tumour Metastasis in a Mouse Model of Melanoma

Mast cells are emerging players in malignant conditions, but the underlying molecular mechanisms remain poorly defined. Based on previous studies showing that steroids can impact on tumour progression in various settings, we here investigated whether mast cell-derived steroid synthesis can have an impact on tumour metastasis in a melanoma model. To this end, we used mice with mast cell-specific ablation of Cyp11a1, a key enzyme in steroid synthesis. We show that lung colonization of melanoma nodules was markedly diminished in mice with mast cell-specific ablation of Cyp11a1, accompanied by reduced infiltration of mast cells into the lungs. Cyp11a1 gene expression was significantly decreased in lungs of mice with mast cell-specific ablation of Cyp11a1, indicating that mast cells account for a substantial fraction of the total Cyp11a1 expression. Our results also revealed that the mast cell-specific deletion of Cyp11a1 led to an overall increase in CD107a/LAMP1 staining intensity of the lung tissue, suggesting that mast cell-derived steroids can suppress immune cell activation and degranulation. A further dissection of this finding by flow cytometry analysis of individual immune cell populations revealed that CD8+ T cells, NK cells and basophils were activated to a higher extent in lungs from mice with mast cell-specific Cyp11a1 ablation. We also demonstrate that both CD8+ and CD4+ T cells in lungs of mice with mast cell-specific deletion of Cyp11a1 expressed elevated levels of IFN-{gamma} in comparison with controls. Altogether, these findings introduce a hitherto unrecognized role of a mast cell-derived steroid axis in regulating tumour metastasis.

immunology↗

bioRxiv2025

Local glucocorticoid signalling promotes pancreatic cancer

Pancreatic cancer (PC) represents one of the biggest challenges in terms of cancer treatment, mainly due to its continuously rising incidence, advanced stage at time of diagnosis, and dismal 5-year overall survival, which has not improved in recent decades despite the major advances made in oncological therapies. The limited progress in developing more effective therapies is, in part, attributable to the vast desmoplastic stroma present in PC. Additionally, immunosuppressive steroid-signalling has recently been shown to aid the development and metastasis of various tumour types. Therefore, we sought to explore whether local steroidogenesis and steroid signalling within the tumour microenvironment (TME) play a role in pancreatic cancer development. Reanalysis of publicly available datasets, including single cell RNA sequencing, as well as in vivo metastatic pancreatic ductal adenocarcinoma (PDAC) mouse models, allowed us to identify Hsd11b1 as the key enzyme responsible for locally elevated levels of the immunosuppressive glucocorticoid hormone, corticosterone. We identified fibroblasts as the major Hsd11b1-expressing populations in the pancreatic TME. Specifically, in mice, Hsd11b1 expression is primarily observed in iCAFs. Additionally, we found that patients with higher HSD11B1 expression present an increased mortality rate as well as an enriched fibrotic signature and inhibited immune activity. Collectively, these findings suggest that Hsd11b1 upregulation in iCAFs could be aiding PDAC development by promoting the activation of glucocorticoids directly in the TME. The presence of glucocorticoids inhibits inflammation and could also be enhancing local fibrosis by autocrine signalling in the fibroblast population. Given the urgent need for effective treatments in this fatal disease, targeting HSD11B1 represents a promising therapeutic strategy to overcome the immunosuppressive desmoplastic barrier and improve patient outcomes in pancreatic cancer.

cancer biology↗

bioRxiv2025

Immune cell de novo steroidogenesis regulates inflammation resolution and recovery in acute lung injury

Effective resolution of inflammation following acute lung infection or injury is critical for restoring immune and tissue homeostasis to ensure functional recovery. Prolonged or unresolved inflammation can impair lung repair, promote fibrosis, and contribute to pulmonary dysfunction. While systemic steroid signalling is known to modulate general immune responses, the specific role of immune cell-mediated steroidogenesis in regulating lung inflammation and repair remains unknown. Here, we show that immune cell de novo steroidogenesis is essential for resolving inflammation and promoting recovery in a murine model of acute lung injury. During the resolution phase, steroid-synthesizing immune cells, predominantly basophils, are enriched in the lung. Mice with immune cell-specific ablation of de novo steroidogenesis exhibit exacerbated lung injury, impaired resolution of inflammation, and defective tissue repair. These findings reveal a previously unrecognized immunoregulatory function of immune cell-derived steroids and identify immune cell steroidogenesis as a potential therapeutic target for promoting resolution and recovery in inflammatory lung diseases.

immunology↗

bioRxiv2025

Glucocorticoid receptor and RUNX transcription factors cooperatively drive CD8 T cells dysfunction in human cancer

Glucocorticoids (GCs) are potent modulators of immune responses; however, the mechanisms by which GCs regulate gene expression in human CD8 T cells remain incompletely defined. Here, we delineate how physiological cortisol signalling shapes the transcriptional and chromatin landscapes of primary human CD8 T cells. We identify a substantial cohort of GC-responsive genes that are co-regulated through the cooperative activity of the glucocorticoid receptor (GR) and RUNX transcription factors. Integrative RNA sequencing and ChIP sequencing analyses identified genome-wide cortisol-responsive immunoregulatory genes. Genetic deletion of the GR (encoded by NR3C1) abolished cortisol-induced gene expression changes, confirming GR-dependency. Notably, GR chromatin occupancy in cortisol-treated CD8 T cells was strongly enriched at RUNX transcription factor (TF) motif rather than canonical GC response elements (GREs). Co-immunoprecipitation assays validated a ligand-dependent physical interaction between GR and RUNX and revealed the interacting domains. Single-cell transcriptomic analyses of tumour infiltrating CD8 T cells revealed significant enrichment of cortisol-responsive genes, indicating an active GC signalling (response) within the tumour microenvironment. GR-RUNX dual controlled genes were enriched in tumour-infiltrating CD8 T cells across multiple cancer types, including lung adenocarcinoma, head and neck squamous carcinoma, pancreatic cancer, and breast cancer. We found GR-RUNX co-regulated genes are predominantly expressed in the predysfunctional state of CD8 T cell population of different solid tumours. These results suggest that local cortisol signalling within tumour microenvironments drives CD8 T cell dysfunction through GR-RUNX TF cooperation. Collectively, our findings identify RUNX3 TF as a critical mediator of GR signalling in human CD8 T cells and reveal a novel mechanism by which endogenous GCs influence antitumour immunity, which could be therapeutically targetable.

immunology↗

bioRxiv2022

Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells

The network of thymic stromal cells provides essential niches with unique molecular cues controlling T-cell development and selection. Recent single-cell RNA-sequencing studies uncovered a large transcriptional heterogeneity among thymic epithelial cells (TEC) demonstrating a previously unappreciated complexity. However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here we deconvoluted by massively parallel flow cytometry and machine learning known and novel TEC phenotypes into novel subpopulations and related these by CITEseq to the corresponding TEC subtypes defined by the cells individual RNA profiles. This approach phenotypically identified perinatal cTEC, physically located these cells within the cortical stromal scaffold, displayed their dynamic change during the life course and revealed their exceptional efficiency in positively selecting immature thymocytes. Collectively, we have identified novel markers that allow for an unprecedented dissection of the thymus stromal complexity, the cells physical isolation and assignment of specific functions to individual TEC subpopulations.

immunology↗