Biology subjects

Antonova, A. U.

Publications and source records attributed to Antonova, A. U..

3 recordsLinked to original sources

bioRxiv2025

Myofibroblastic CAFs arising from bone-resident osteoblast precursors retain an osteolineage signature and support breast cancer progression via Osterix-mediated signaling.

Cancer-associated fibroblasts (CAFs) are a major component of the breast cancer (BC) microenvironment, involved in tumor progression and resistance to therapy. Despite the recent identification of multiple CAF subtypes with unique functions, it remains unclear whether each subtype arises from a distinct precursor or a shared common progenitor. Here, we identified a unique subpopulation of myofibroblast CAFs (myCAFs) arising from committed Osterix (Osx)+ osteoblast progenitors in the bone, recruited to primary tumors in both murine BC models and BC patients. Osx+myCAFs exhibit strong protumorigenic features and retain osteoblastic gene expression, which distinguishes them from OsxnegCAF subsets. Osx drives the expression of extracellular matrix remodeling genes and promotes tumor growth via the secretion of MMP13, a key Osx target gene. Finally, we find that increased Osx+myCAFs and a stromal osteolineage gene signature correlate with poor therapeutic response and reduced BC patient survival.

cancer biology↗

bioRxiv2025

The metabolic program of inflammatory eosinophils accounts for chronic parasite-induced skin-disease

Eosinophils exert antimicrobial, cytotoxic and immunoregulatory effects, but their function in cutaneous tissue still remains poorly understood. Here, we used a mouse model of chronic cutaneous leishmaniasis caused by the protozoan parasite Leishmania (L.) mexicana to investigate the function and transcriptomic signature of eosinophils in the skin. In C57BL/6 wild-type mice, L. mexicana infection induced local and systemic eosinophilia that was dependent on type 2 innate lymphoid cells and interleukin-5. Genetic and pharmacological depletion of eosinophils led to complete clinical resolution of disease, which was accompanied by a more pronounced Th1 and M1-like macrophage response. Bioinformatic analyses revealed a novel inflammatory and tissue-specific transcriptional trajectory in skin-infiltrating eosinophils. Skin-imprinted eosinophils strongly expressed the high-affinity glucose transporter 3 (Slc2a3), deprived the environment of glucose and directly impeded the function of Th1 cells. Together, our results demonstrate that disease progression and chronicity of L. mexicana infection is caused by inflammatory eosinophils and linked to their metabolic program. Short SummaryThe authors describe that depletion of eosinophils prevents chronic cutaneous disease caused by Leishmania mexicana. They identify a novel, tissue-specific transcriptomic profile of inflammatory skin eosinophils and demonstrate that skin-imprinted eosinophils show strong glucose uptake and directly repress Th1 responses. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/640104v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@3ecd3org.highwire.dtl.DTLVardef@1b1283forg.highwire.dtl.DTLVardef@1c941fdorg.highwire.dtl.DTLVardef@b7c39_HPS_FORMAT_FIGEXP M_FIG C_FIG KEY POINTSO_LIEosinophil accumulation precedes the development of chronic cutaneous leishmaniasis C_LIO_LIEosinophil depletion or IL-5 neutralization lead to clinical cure of the disease C_LIO_LIL. mexicana infection elicits a unique transcriptomic signature of skin eosinophils C_LIO_LISkin eosinophils show a marked uptake of glucose and directly repress Th1 responses C_LI

immunology↗

bioRxiv2024

Cross-species analyses reveal RORγt-expressing dendritic cells are a lineage of antigen presenting cells conserved across tissues

Conventional dendritic cells (cDCs) are potent antigen presenting cells (APCs) that exhibit tissue and age-specific diversity allowing them to direct situation-adapted immunity. Thereby they harbor great potential for being targeted in vaccination and cancer. Here, we resolve conflicting data about expression of retinoic acid receptor-related orphan receptor-{gamma}t (ROR{psi}t) in cDCs. We show that ROR{psi}t+ DCs exist in murine lymphoid and non-lymphoid tissues across age. Fate mapping, functional assays and single cell multiomic profiling reveal these cells as ontogenetically and transcriptionally distinct from other well characterized cDC subtypes, as well as from ROR{psi}t+ type 3 innate lymphocytes (ILC3s). We show that ROR{psi}t+ DCs can migrate to lymph nodes and activate naive CD4+ T cells in response to inflammatory triggers. Comparative and cross-species transcriptomics revealed homologous populations in human spleen, lymph nodes and intestines. Further, integrated meta-analyses aligned ROR{psi}t+ DCs identified here with other emerging populations of ROR{psi}t+APCs, including R-DC-like cells, Janus cells/extrathymic Aire expressing cells (eTACs) and subtypes of Thetis cells. While ROR{psi}t+APCs have primarily been linked to T cell tolerance, our work establishes ROR{psi}t+ DCs as unique lineage of immune sentinel cells conserved across tissues and species that expands the functional repertoire of ROR{psi}t+ APCs beyond promoting tolerance. One sentence summaryROR{gamma}t+ DC exhibit versatile APC functions and are a distinct immune lineage conserved across age, tissues and species that entails Thetis cells, Janus cells/ROR{gamma}t+ eTACs and R-DC-like cells.

immunology↗