Biology subjects

Declercq, J.

Publications and source records attributed to Declercq, J..

3 recordsLinked to original sources

bioRxiv2026

IL-1 instructs para-bronchial cuff fibroblasts to organize lung antibody secreting cell niches during continued antigen exposure

Secondary lymphoid organs (SLO) are prototypic sites of antibody production, yet mucosal sites also generate and maintain mucosal antibodies during continued inflammation. Using a murine model of house dust mite-induced airway inflammation, we show that prolonged allergen exposure induces tertiary lymphoid organs (TLO) within para-bronchial adventitial cuffs. Within these regions, IL-1 signaling instructs fibroblasts to form niches that recruit, retain, and sustain lung antibody-secreting cells (ASCs) through chemokine induction. These mucosal ASCs share immunoglobulin repertoires with TLO-derived germinal center B cells. Thus, continued allergen exposure reshapes the lung microenvironment by converting para-bronchial fibroblasts into IL-1-dependent supportive niches for non-IgE antibody production, revealing a fibroblast-mediated mechanism for local immune regulation in chronic inflammation. One sentence summaryContinued allergen exposure drives lung TLO to generate ASCs that home to IL1-instructed para-bronchial cuffs.

immunology↗

bioRxiv2024

Transcriptional Dosage of Oncogenic KRAS Drives Lung Adenocarcinoma Cell States, Progression and Metastasis

Cancer cells display distinct, recurrent phenotypic cell states. Metastatic spreading correlates with tumor cell state evolution. However, the molecular mechanisms underlying metastasis remain elusive. Here, we demonstrate that the quantitative dosage of oncogenic KRAS drives lung adenocarcinoma progression and metastasis via the integration of external signaling and pioneer transcription factor dynamics into qualitative cell states. Combining mouse models, in vivo CRISPR activation screens, and fate mapping, we show that even mild transcriptional amplification of KRAS significantly fuels tumor progression and metastasis. Chromatin profiling and transcriptomics reveal that high and low KRAS dosages supersede and integrate inflammatory and TGF{beta} signaling to dictate mouse cancer cell states. Patient data show that KRAS dosages correlate with distinct survival outcomes, transcription factor activity, and cell states. Direct KRAS inhibition in xenografts limits the KRAS-high "proliferative" cell state but spares a minimal residual state mimicking the KRAS-low "ciliated-like" state. Thus, oncogenic KRAS dosage fuels tumor heterogeneity at the cell state level and drives a bimodal tumor evolution during metastasis, with implications for prognosis and treatment.

cancer biology↗

bioRxiv2020

Furin controls β cell function via mTORC1 signaling

Furin is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, yet its specific role in pancreatic {beta} cells is largely unknown. The aim of this study was to determine the role of furin in glucose homeostasis. We show that furin is highly expressed in human islets, while PCs that potentially could provide redundancy are expressed at considerably lower levels. {beta} cell-specific furin knockout ({beta}furKO) mice are glucose intolerant, due to smaller islets with lower insulin content and abnormal dense core secretory granule morphology. RNA expression analysis and differential proteomics on {beta}furKO islets revealed activation of Activating Transcription Factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). {beta}furKO cells show impaired cleavage of the essential V-ATPase subunit Ac45, and by blocking this pump in {beta} cells the mTORC1 pathway is activated. Furthermore, {beta}furKO cells show lack of insulin receptor cleavage and impaired response to insulin. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation in {beta} cells lacking furin, which causes {beta} cell dysfunction.

physiology↗