Biology subjects

Rognoni, E.

Publications and source records attributed to Rognoni, E..

5 recordsLinked to original sources

bioRxiv2026

Plasticity of squamous differentiation drives drug resistance in HNSCC

A critical hallmark of carcinogenesis is the ability of cancer cells to evade the loss of self-renewal normally imposed by terminal differentiation. However, therapies directly attempting to promote differentiation have shown limited efficacy in solid tumours and the cellular mechanisms behind cancer cell persistence are poorly understood. Here we established a patient-derived orthotopic head and neck squamous cell carcinoma (HNSCC) model in vivo that recapitulates the genetic, cellular and histopathological heterogeneity of HNSCC. Experimental induction of differentiation and clonal lineage tracing by fluorescent barcoding revealed a heterogeneous response to terminal differentiation stimuli, enabling subsets of cancer cells to escape differentiation-associated loss of self-renewal. While pharmacological inhibition of ErbB-MEK1/2-ERK1/2 pathway by afatinib could induce the differentiation of patient-derived cancer cells, some highly clonogenic cells remained refractory to differentiation signals even though they were capable of differentiating. Differentiation reporter IVLmCherry further confirmed that differentiation and loss of self-renewal ability were partially uncoupled in patient-derived HNSCC cells. These findings identify differentiation-resistant clonogenic populations as a key barrier to therapeutic efficacy and provide a framework for improving differentiation-based strategies in HNSCC.

cancer biology↗

bioRxiv2024

A single cell and spatial genomics atlas of human skin fibroblasts in health and disease

Fibroblasts are critical cells that shape the architecture and cellular ecosystems in multiple tissues. Understanding fibroblast heterogeneity and their spatial context in health and disease has enormous clinical relevance. In this study, we constructed a spatially-resolved atlas of human skin fibroblasts from healthy skin and 23 skin disorders. We define 6 major skin fibroblast populations in health and a further three skin disease-specific fibroblast subtypes, and demonstrate the fibroblast composition in different types of skin disease. We characterise a human-specific fibroblastic reticular cell (FRC)-like subtype in the skin perivascular niche and postulate their origin from prenatal skin lymphoid tissue organiser (LTo)-like cells. We also show that inflammatory myofibroblasts (IL11+MMP1+CXCL5+IL7R+) are a conserved fibroblast subtype in inflammatory disorders and cancers across multiple human tissues. We provide a harmonised nomenclature for skin fibroblasts that integrates previous findings from human skin and other tissues.

cell biology↗

bioRxiv2024

Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma

Disruption of processes involved in tissue development and homeostatic self-renewal is increasingly implicated in cancer initiation, progression, and recurrence. The adrenal cortex is a dynamic tissue that undergoes life-long turnover. Here, using genetic fate mapping and murine adrenocortical carcinoma (ACC) models, we have identified a population of adrenocortical stem cells that express delta-like non-canonical Notch ligand 1 (DLK1). These cells are active during development, near dormant postnatally but are re-expressed in ACC. In a study of over 200 human ACC samples, we have shown DLK1 expression is ubiquitous and is an independent prognostic marker of recurrence-free survival. Paradoxically, despite its progenitor role, spatial transcriptomic analysis has identified DLK1 expressing cell populations to have increased steroidogenic potential in human ACC, a finding also observed in four human and one murine ACC cell lines. Finally, the cleavable DLK1 ectodomain is measurable in patients serum and can discriminate between ACC and other adrenal pathologies with high sensitivity and specificity to aid in diagnosis and follow-up of ACC patients. These data demonstrate a prognostic role for DLK1 in ACC, detail its hierarchical expression in homeostasis and oncogenic transformation and propose a role for its use as a biomarker in this malignancy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/609117v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@12aba74org.highwire.dtl.DTLVardef@374daaorg.highwire.dtl.DTLVardef@cbdc37org.highwire.dtl.DTLVardef@1e6aeac_HPS_FORMAT_FIGEXP M_FIG C_FIG Statement of significanceThis study presents DLK1 as a novel biomarker in ACC with opportunities for use in the diagnosis, prognosis and longitudinal follow up of patients. DLK1, a marker of adrenocortical stem cells, is re-expressed in ACC, is measurable in patients serum and is associated with increased malignancy.

cancer biology↗

bioRxiv2021

Role of distinct fibroblast lineages and immune cells in dermal repair following UV radiation induced tissue damage

Solar ultraviolet radiation (UVR) is a major source of skin damage, resulting in inflammation, premature ageing and cancer. While several UVR-induced changes, including extracellular matrix reorganisation and epidermal DNA damage, have been documented, the role of different fibroblast lineages and their communication with immune cells has not been explored. We show that acute and chronic UVR exposure led to selective loss of fibroblasts from the upper dermis in human and mouse skin. Lineage tracing and in vivo live imaging revealed that repair following acute UVR is predominantly mediated by papillary fibroblast proliferation and migration. In contrast, chronic UVR exposure led to a permanent loss of papillary fibroblasts, with expansion of fibroblast membrane protrusions partially compensating for the reduction in cell number. Although UVR strongly activated Wnt-signalling in skin, stimulation of fibroblast proliferation by epidermal {beta}-catenin stabilisation did not support papillary dermis repair. Acute UVR triggered an infiltrate of neutrophils and T cell subpopulations and increased pro-inflammatory prostaglandin signalling in skin. Depletion of CD4 and CD8 positive cells resulted in increased papillary fibroblast depletion, which correlated with an increase in DNA damage and reduction in fibroblast proliferation. Conversely, topical COX-2 inhibition prevented fibroblast depletion and neutrophil infiltration after UVR. We conclude that loss of papillary fibroblasts is primarily induced by a deregulated inflammatory response, with infiltrating T cells supporting fibroblast survival upon UVR-induced environmental stress. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC="FIGDIR/small/447606v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@d246bborg.highwire.dtl.DTLVardef@121b5faorg.highwire.dtl.DTLVardef@324114org.highwire.dtl.DTLVardef@14e9eb7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2017

Fibroblast state switching orchestrates dermal maturation and wound healing

Murine dermis contains functionally and spatially distinct fibroblast lineages that cease to proliferate in early postnatal life. Here we propose a model in which a negative feedback loop between extracellular matrix (ECM) deposition and fibroblast proliferation determines dermal architecture. Virtual-tissue simulations of our model faithfully recapitulate dermal maturation, predicting a loss of spatial segregation of fibroblast lineages and dictating that fibroblast migration is only required for wound healing. To test this, we performed in vivo live imaging of dermal fibroblasts, which revealed that homeostatic tissue architecture is achieved without active cell migration. In contrast, both fibroblast proliferation and migration are key determinants of tissue repair following wounding. The results show that tissue-scale coordination is driven by the interdependence of cell proliferation and ECM deposition, paving the way for identifying new therapeutic strategies to enhance skin regeneration.\n\nStandfirst textWe show that fibroblast behaviour switching between two distinct states - proliferating and depositing ECM - is necessary and sufficient to define dermal architecture. Understanding this interdependence is critical for identifying new therapeutic strategies to enhance skin regeneration.\n\nHighlightsO_LITissue-scale coordination in murine dermis is driven by the interdependence of cell proliferation and ECM deposition\nC_LIO_LIThe tissue architecture is set by a negative feedback loop between ECM deposition/remodelling and proliferation\nC_LIO_LIFibroblast lineages lose segregation with age\nC_LIO_LIFibroblast migration is the critical discriminator between dermal development and wound healing\nC_LI

systems biology↗