Biology subjects

Kancheva, D.

Publications and source records attributed to Kancheva, D..

7 recordsLinked to original sources

bioRxiv2026

Lung cancer-fueled emergency myelopoiesis is characterized by an increase of S100A9+ and LCN2+ hematopoietic stem and progenitor cells

The pivotal role of tumor infiltrating myeloid cells in lung cancer composition and response to therapy is universally recognized. Nevertheless, their main cradle being the bone marrow (BM), remains vastly understudied owing to the spatiotemporal complexity of hematopoiesis and its hard to access anatomical location. Therefore, the BM niche of lung cancer subjects remains understudied which is why we integrated transcriptional and translational single-cell profiling, ELISA and two-photon microscopy to characterize the medullary hematopoietic compartment in orthotopic lung cancer-bearing mice with validation in human non-small cell lung cancer (NSCLC) samples. In brief we found that lung cancer remotely alters the entire hematopoietic process resulting in higher levels of hematopoietic stem cells (HSCs), myeloid and lymphoid multipotent progenitors (MPPs) and downstream predominance of Granulocyte Monocyte Progenitors (GMP), early Granulocyte Progenitors (GP) and Common Monocyte Progenitors (cMoP) at the expense of mature neutrophils and B cells. Furthermore, a significant increase in the expression and secretion of S100A9 and Lipocalin-2 (LCN2), was characteristic across the entire hematopoietic trajectory in lung cancer-bearing mice and patients. In vivo inhibition of S100A9 with Tasquinimod reduced tumor growth, irrespective of its combination with immunotherapy. In addition, it altered the secretion profile of S100A9 but also LCN2 in the BM, suggesting that S100A9 serves as an upstream regulator of LCN2 and holds therapeutic premise to treat immunotherapy refractory lung cancer.

immunology↗

bioRxiv2024

VSIG4-Expressing Macrophages Contribute To Anti-Parasitic And Anti-Metastatic Responses In The Peritoneal Cavity

Peritoneal tissue-resident macrophages, also referred to as large peritoneal macrophages (LPMs), play an important role as gatekeepers of peritoneal homeostasis by providing a first line of defense against pathogenic threats. About a third of the LPMs express the surface receptor V-set and Immunoglobulin domain containing 4 (VSIG4), but it is unclear to what extent these cells differ from their VSIG4-negative counterparts and perform dedicated functions. Here, we demonstrate that VSIG4+ LPMs, in contrast to VSIG4- LPMs, are in majority derived from embryonal precursors and their occurrence is to a large extent independent from sex and microbiota. Although their transcriptome and surface proteome are indistinguishable from VSIG4- LPMs at steady-state, VSIG4+ LPMs are superior in phagocytosing Gram-positive bacteria and colorectal carcinoma (CRC) cells. In-house generated anti-VSIG4 nanobody constructs that are antibody-dependent cell-mediated cytotoxicity (ADCC)-enabled allowed a selective elimination of the VSIG4+ LPM subset without affecting the overall LPM content of the peritoneal cavity. This strategy uncovered a role for VSIG4+ LPMs in lowering the first peak of parasitemia in a Trypanosoma brucei brucei infection model and in reducing the outgrowth of CRC cells in the peritoneal cavity, a prime metastatic site in CRC patients. Altogether, our data uncover a protective role for VSIG4+ LPMs in infectious and oncological diseases in the peritoneal cavity.

immunology↗

bioRxiv2024

ER stress relief drives beta cell proliferation

Regenerating endogenous pancreatic {beta}-cells is a potentially curative yet currently elusive strategy for diabetes therapy. Mimicking the microenvironment of the developing pancreas and leveraging vascular signals that support pancreatic endocrinogenesis may promote {beta}-cell regeneration. We aimed to investigate whether recovery from experimental hypovascularization of the endocrine pancreas, achieved by modulating the transgenic production of a VEGF-A blocker in {beta}-cells, could trigger mouse {beta}-cell proliferation. Serendipitously, we found that transgene overexpression in {beta}-cells induces endoplasmic reticulum (ER) stress and that subsequent relief from this stress stimulates {beta}-cell proliferation independent of vessel recovery. Transient GFP overexpression in vivo and chemical induction of ER stress in vitro replicated this {beta}-cell cycling response. Our findings highlight the potential side effects of ER stress due to transgene overexpression in {beta}-cells and assert that ER stress relief serves as a potent regenerative stimulus.

molecular biology↗

bioRxiv2024

Epigenomic programming of peripheral monocytes determines their transcriptional response to the tumor microenvironment

Classical monocytes are recruited to tumors and undergo transcriptional reprogramming resulting in tumor-promoting functions. Epigenomic features, such as post-translational modification of histones and chromatin accessibility, are key determinants of transcription factor binding and thereby play an important role in determining transcriptional responses to the tissue environment. It is unknown to what extent the epigenetic landscape of peripheral monocytes is rewired by cancer and how this could shape their transcriptional response upon recruitment to the tumor microenvironment. Here we used a combination of genome-wide assays for mRNA expression, chromatin accessibility and multiple histone modifications (H3K4me1, H3K4me3, H3K27ac) in a mouse model to investigate changes in the epigenomic landscape of peripheral monocytes. We then linked these epigenetic alterations to gene expression changes in monocytes occurring in the periphery or during tumor infiltration. We found that the distal tumor caused extensive remodeling of both H3K4me3+ promoters and H3K4me1+ enhancers in peripheral monocytes. Specifically, this involved the repression of interferon-responsive promoters and enhancers as well as the establishment of enhancers harboring binding motifs for transcription factors downstream of inflammatory and cytokine signaling pathways. The enhancers altered in the periphery could be linked to sustained gene expression changes which were less likely to be reversed in the tumor microenvironment. In addition, genes activated upon tumor infiltration showed prior epigenetic priming in peripheral monocytes. Overall, these results indicate that the epigenomic landscape of peripheral monocytes is altered in response to a distal tumor, and this could shape the transcriptional response of monocytes when they encounter microenvironmental signals upon infiltrating the tumor.

immunology↗

bioRxiv2023

Murine classical monocyte subsets display distinct functions and fates

Monocytes are short-lived myeloid immune cells that arise from adult hematopoiesis and circulate for a short time in the blood. They comprise two main subsets, in mice defined as classical Ly6Chigh and non-classical Ly6Clow monocytes (CM, NCM). Recent fate mapping and transcriptomic analyses revealed that CM themselves are heterogeneous. Here, we report surface markers that allow segregation of murine GMP- and MDP-derived CM in the BM and blood. Functional characterization, including fate definition following adoptive cell transfer, established that GMP-Mo and MDP-Mo could equal rise to homeostatic CM progeny, such as NCM in blood and gut macrophages, but differentially seeded selected other tissues. Specifically, GMP-Mo and MDP-Mo gave rise to distinct interstitial lung macrophages, thus linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide comprehensive evidence for the existence of two functionally distinct CM subsets in the mouse, which differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge. Our findings are indicative of impact of monocyte ontogeny on in situ differentiation.

immunology↗

bioRxiv2022

Global hypo-methylation in a subgroup of glioblastoma enriched for an astrocytic signature is associated with increased invasion and altered immune landscape

We describe a new molecular subgroup of glioblastoma, the most prevalent malignant adult brain tumour, harbouring a bias towards hypomethylation at defined differentially methylated regions. This epigenetic signature correlates with an enrichment for an astrocytic gene signature, which together with the identification of enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, point to a shared ontogeny between this glioblastoma subgroup and astroglial progenitors. At functional level, increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration characterise this glioblastoma subgroup.

cancer biology↗

bioRxiv2021

Distinct cDC subsets co-operate in CD40 agonist response while suppressive microenvironments and lack of antigens subvert efficacy

Agonistic CD40 therapy has shown to inhibit cancer progression, but only in a fraction of patients. Hence, understanding the cancer cell-intrinsic and microenvironmental determinants of CD40 therapy response is crucial to identify responsive patient populations and design efficient combination treatments. Here, we showed that the therapeutic efficacy of CD40 in responder melanoma tumours, relied on pre-existing cDC1-primed CD8+ T cells, however cDC1s were dispensable after CD40 administration. Surprisingly, in response to CD40 the abundance of activated cDCs, potentially derived from cDC2s increased, thereby further activating antitumour CD8+ T cells. Hence, distinct cDC subsets are required to induce CD40 responses. By contrast, lung tumours, characterised by a high abundance of macrophages, were resistant to CD40 therapy. Combining CD40 therapy with macrophage depletion led to tumour growth inhibition only in the presence of strong neoantigens. Accordingly, treatment with immunogenic cell-death inducing chemotherapy sensitised non-immunogenic tumours to CD40 therapy.

cancer biology↗