Biology subjects

Fabian, C.

Publications and source records attributed to Fabian, C..

3 recordsLinked to original sources

bioRxiv2026

Cellular stemness identifies high-risk ductal carcinoma in situ and offers a therapeutic interception opportunity

Ductal carcinoma in situ (DCIS) exhibits substantial heterogeneity in its risk of progression to invasive breast cancer, yet the cellular and molecular determinants of high-risk lesions remain incompletely defined. Using spatially resolved single-cell transcriptomic and epigenomic profiling of 43 patient-derived DCIS and DCIS/invasive ductal carcinoma (IDC) samples, we delineate cellular programs, spatial organization, and epigenetic regulatory mechanisms associated with invasive potential. We identify an epithelial population with stemness features within luminal hormone-responsive (LumHR) cells that progressively expands from benign tissue to DCIS and IDC, and is strongly associated with invasive progression and recurrence-linked transcriptional programs. Spatial mapping reveals discrete DCIS niches enriched for stem-like LumHR cells, characterized by elevated CEACAM6 expression and enhanced ligand-receptor interactions, including CEACAM6-EGFR signaling between epithelial and stromal compartments, including cancer-associated fibroblasts, macrophages (APOC1-positive) and perivascular cells. These niches define a microenvironmental context that supports stemness and invasive potential. Epigenomic analyses implicate FOXA1 as a key regulator of these stem-like transcriptional states. Pharmacologic disruption of FOXA1-regulatory network using LSD1 inhibition suppresses stemness-associated transcriptional programs in vitro and significantly restrains tumor growth in vivo. Collectively, these findings define high-risk DCIS as a stemness-driven disease embedded within specialized microenvironments, and identify associated regulatory networks as candidate biomarkers and therapeutic vulnerabilities.

cancer biology↗

bioRxiv2026

Spatial Single-Cell Proteomics Reveals Molecular Trajectories Of Tangle-Bearing Neurons In Alzheimer's Disease

Neurofibrillary tangles composed of hyperphosphorylated tau are a defining pathological hallmark of Alzheimers disease (AD); however, the pathways and mechanisms associated with the transition from physiological tau to tangle pathology remain unclear. Here, we integrate laser microdissection of post-mortem, fixed human AD brain tissue labelled with an antibody recognizing tangle-associated phospho-tau (AT8) with mass spectrometry-based proteomics, applied to individual neurons and to small neuronal pools. This approach identified [~]2,000 and [~]5,000 proteins, respectively, and enabled direct detection of disease-associated tau phosphorylation sites without prior enrichment. A layered analysis of the proteome of tangle-positive and tangle-negative neurons revealed heterogeneous disease-associated states. Pseudotime analysis, combined with an AI-driven analytical framework, indicates that neurons do not segregate into discrete classes but instead organize along a continuum of proteomic changes that correlate with tau abundance. This organization enabled the construction of a trajectory of pathological neuronal responses that can be resolved within an individual brain. Early stages of this trajectory are characterized by coordinated remodeling of proteostasis networks, including reduced proteasome component abundance and increased lysosomal acidification machinery, followed by disruption of synaptic pathways. Notably, despite extensive proteomic remodeling, neurons bearing tangles show little evidence of activated cell-death programs, suggesting prolonged molecular adaptation rather than acute degeneration. Together, these findings establish a framework for single-cell-resolved proteome analysis of human brain disease in situ and define a continuum of neuronal states underlying tau pathogenesis, revealing early vulnerabilities and adaptive responses during AD progression.

neuroscience↗

bioRxiv2025

EGFL7 promotes immune evasion in glioma through its interaction with integrin β2

Glioblastoma is the most aggressive form of malignant brain cancer, characterized by an immunosuppressive microenvironment and immune evasion. Despite the success of immune checkpoint inhibitors in other cancers, immunotherapies such as anti-PD1 have shown limited efficacy in glioblastoma, underscoring the need to identify tumor-intrinsic mechanisms that sustain this immunosuppressive microenvironment and to develop more effective therapeutic strategies targeting them. Previously, the secreted factor epidermal growth factor-like protein 7 (EGFL7) has been shown to promote brain tumor growth by affecting the glioblastoma microenvironment (GME). However, its impact on the immune system remained enigmatic. Here, we studied the role of EGFL7 in shaping the immune landscape in glioblastoma and identified the underlying molecular mechanisms it engages to drive glioma immune evasion. Single-cell transcriptomic profiling of immune cells derived of glioblastoma revealed that EGFL7 promotes an immunosuppressive GME, characterized by enhanced T cell exhaustion and polarization of macrophages towards a protumorigenic state. Proteomic profiling of EGFL7s interactome in glioma revealed its interaction with integrin {beta}2 (ITGB2), an immune cell surface receptor involved in cell adhesion and migration. Mechanistic studies uncovered the central role of this interaction for immune evasion, which promoted T cell exhaustion and the polarization of macrophages towards a pro-tumorigenic state. Genetic perturbation of the EGFL7-ITGB2 axis attenuated immunosuppression and prolonged the survival of glioblastoma-bearing mice. Remarkably, a combinatorial regimen of anti-EGFL7 and the checkpoint inhibitor anti-PD1 improved the efficacy of this drug, which by itself did not improve glioma patient survival so far. In conclusion, our study provides unequivocal evidence that EGFL7 mediates immune evasion in glioma and has great potential to serve as an add-on drug target to improve immunotherapies not functional in glioblastoma patients so far.

cancer biology↗