Biology subjects

Schmidt-Supprian, M.

Publications and source records attributed to Schmidt-Supprian, M..

7 recordsLinked to original sources

bioRxiv2026

Cross-species single-cell atlases chart progression, therapy-driven remodelling and immune evasion in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at advanced stages, yet single-cell datasets that capture late-stage and treated disease remain sparse, hindering progress in understanding tumour heterogeneity and therapy resistance. Here, we have generated integrated single-cell transcriptomic atlases of human and mouse PDAC to define the cellular and molecular landscape of the disease, from early to advanced and metastatic stages, including post-treatment disease, and to enable direct cross-species comparison. Using scANVI to harmonize 16 human studies comprising 257 donors and representative mouse models (101 tumours), we compiled over 1.6 million cells and established a four-level hierarchical taxonomy of more than 60 distinct cell states spanning malignant, stromal, immune, endothelial, adipose, exocrine and endocrine compartments. We resolve ten malignant programmes linked to progression and uncover rare immune phenotypes, including CD4CD8 double-positive T cells that remain poorly characterized in PDAC. Notably, we show that radiotherapy (RT) exposure is associated with enrichment of an EMT-persistent malignant state and an immunosuppressive microenvironment characterized by expansion of tumour-associated endothelium, depletion of intratumoral T cells and heightened laminin-CD44 signalling, with RT-associated genes linked to adverse prognosis in independent cohorts. Cross-species mapping reveals that orthotopic syngeneic allografts more faithfully recapitulate the cellular diversity and EMT-enriched states of advanced human PDAC, underrepresented in autochthonous genetically engineered models, with differences driven primarily by cell-type composition rather than pathway divergence. Together, these atlases and pretrained models provide a broadly accessible reference for benchmarking PDAC model fidelity and for interrogating mechanisms of tumour progression, microenvironmental remodelling and therapy response and resistance.

cancer biology↗

bioRxiv2025

Angström Resolution with Flow Immunofluorescence Localization Microscopy (FILM)

We present flow immunofluorescence localization microscopy (FILM) as a novel paradigm for single-molecule localization microscopy (SMLM). FILM is based on continuous flow of standard fluorescent binders, including conventional antibodies or nanoscale probes, over a fixed sample along with gentle imaging-to-photobleaching of the stochastically bound probes with an LED on a widefield microscope setup. Gentle illumination yields 104-106 photons per fluorophore corresponding to localization precision at the few nanometer to [A]ngstrom scales. We employ FILM to localize diverse markers in cultured cells and immunological synapses down to 9 [A] resolution, and for sequential localization of multiple targets in tissue slices. Requiring only minimal hardware and off-the-shelf probes, FILM offers an accessible and versatile route for serial SMLM at molecular resolution.

cell biology↗

bioRxiv2023

ARID1A Mutations Protect Follicular Lymphoma from FAS-dependent Immune Surveillance by Reducing RUNX3/ETS1-Driven FAS-Expression

The cell death receptor FAS and its ligand (FASLG) play crucial roles in the selection of B cells during the germinal center (GC) reaction. Failure to eliminate potentially harmful B cells via FAS can lead to lymphoproliferation and the development B cell malignancies. The classic form of follicular lymphoma (FL) is a prototypic GC-derived B cell malignancy, characterized by the t(14;18) (q32;q21)IGH::BCL2 translocation and overexpression of antiapoptotic BCL2. Additional alterations were shown to be clinically relevant, including mutations in ARID1A. ARID1A is part of the SWI/SNF nucleosome remodeling complex that regulates DNA accessibility ("openness"). However, the mechanism how ARID1A mutations contribute to FL pathogenesis remains unclear. We analyzed 151 FL biopsies of patients with advanced stage disease at initial diagnosis and found that ARID1A mutations were recurrent and mainly disruptive, with an overall frequency of 18%. Additionally, we observed that ARID1A mutant FL showed significantly lower FAS protein expression in the FL tumor cell population. Functional experiments in BCL2-translocated lymphoma cells demonstrated that ARID1A is directly involved in the regulation of FAS, and ARID1A loss leads to decreased FAS protein and gene expression. However, ARID1A loss did not affect FAS promotor openness. Instead, we identified and experimentally validated a previously unknown co-transcriptional complex consisting of RUNX3 and ETS1 that regulates FAS expression, and ARID1A loss leads to reduced RUNX3 promotor openness and gene expression. The reduced FAS levels induced by ARID1A loss rendered lymphoma cells resistant to both soluble and T cell membrane-anchored FASLG-induced apoptosis. In summary, we have identified a functionally and clinically relevant mechanism how FL cells can escape FAS-dependent immune surveillance, which may also impact the efficacy of T cell-based therapies, including bispecific antibodies and CAR T cells.

cancer biology↗

bioRxiv2022

The lncRNA landscape of cardiac resident macrophages and identification of Schlafenlnc as a regulator of macrophage migratory function

Cardiac resident macrophages (crMPs) were recently shown to exert pivotal functions in cardiac homeostasis and disease, but the underlying molecular mechanisms are largely unclear. Long non-coding RNAs (lncRNAs) are increasingly recognized as important regulatory molecules in a number of cell types, but neither the identity nor the molecular mechanisms of lncRNAs in crMPs are known. Here, we have employed deep RNA-seq and single cell RNA sequencing to resolve the crMP lncRNA landscape from healthy and diseased murine myocardium. CrMPs express previously unknown and highly cell type-specific lncRNAs, among which one lncRNA, termed Schlafenlnc, was particularly abundant and enriched in crMPs. We found Schlafenlnc to be necessary for migration-associated gene expression in macrophages in vitro and in vivo and essential for their adhesion and migration. Collectively, our data provide a basis to the systematic characterization of lncRNAs in crMPs and establish Schlafenlnc as a critical regulator of macrophage migratory functions.

cell biology↗

bioRxiv2022

Slow integrin-dependent migration organizes networks of tissue-resident mast cells

Many leukocytes use fast and flexible amoeboid migration strategies to move autonomously throughout tissues. Here, we show that the movement of mast cells (MCs), leukocytes with important roles during allergies and anaphylaxis, fundamentally differs from this rapid adhesion-free leukocyte migration. We identify a crucial role for integrin-dependent adhesion in controlling slow MC movement, which shapes the positioning and network-like tissue distribution of this long-lived immune cell type. In contrast to other immune and non-immune cells, MCs cannot compensate for the lack of integrin function by switching to another migration mode. Single-cell RNA-sequencing revealed a special role for integrins in defining a mature MC phenotype in the periarteriolar tissue space where several stromal cell types provide an anatomical niche rich in Kit ligand, the major MC growth and survival factor. Collectively, this study highlights substrate-dependent haptokinesis as an important mechanism for MC network formation and the tissue organization of resident immune cells.

cell biology↗

bioRxiv2020

In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets

High-throughput sequencing describes multiple alterations in each tumor (1), but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient (2). Here, we established a Cre-ERT2-loxP based inducible RNAi-mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition was initiated in mice harboring orthotopic tumors. Fluorochrome guided, competitive in vivo trials identified a major tumor-maintaining potency of the MLL-AF4 fusion protein and validated MCL1 as vulnerability in some, but not all patients tumors. We could prove DUX4 to play an essential role in patients leukemias carrying the recently described DUX4-IGH translocation. By individualizing functional genomics in established tumors in vivo, our technique decisively complements the value chain of precision oncology. Being broadly applicable to tumors of all kinds, it will considerably reinforce personalizing anti-cancer treatment in the future.

cancer biology↗

bioRxiv2020

Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability

NF-{kappa}B and MYC are found co-deregulated in human B and plasma-cell cancers. In physiology, NF-{kappa}B is necessary for terminal B-to-plasma cell differentiation, whereas MYC repression is required. It is thus unclear if NF-{kappa}B/MYC co-deregulation is developmentally compatible in carcinogenesis and/or impacts cancer cell differentiation state, possibly uncovering unique sensitivities. Using a mouse system to trace cell lineage and oncogene activation we found that NF-{kappa}B/MYC co-deregulation originated cancers with a plasmablast-like phenotype, alike human plasmablastic-lymphoma and was linked to t(8;14)[MYC-IGH] multiple myeloma. Notably, in contrast to NF-{kappa}B or MYC activation alone, co-deregulation rendered cells addicted to IL6 for survival and phenotypic stability. We propose that conflicting oncogene-driven differentiation pressures can be accommodated at a cost in poorly-differentiated cancers. SignificanceOur studies improve the understanding of cancer pathogenesis by demonstrating that co-deregulation of NF-{kappa}B and MYC synergize in forming a cancer with a poorly-differentiated state. The cancers in the mouse system share features with human Plasmablastic lymphoma that has a dismal prognosis and no standard of care, and with t(8;14)[MYC-IGH] Multiple myeloma, which is in overall resistant to standard therapy. Notably, we found that NF-{kappa}B and MYC co-deregulation uniquely render cells sensitive to IL6 deprivation, providing a road-map for patient selection. Because of the similarity of the cancers arising in the compound mutant mouse model with that of human Plasmablastic lymphoma and t(8;14)[MYC-IGH] Multiple myeloma, this model could serve in preclinical testing to investigate novel therapies for these hard-to-treat diseases. HighlightsO_LINF-{kappa}B and MYC co-activation originates (pre)plasmablast-like cancer C_LIO_LINF-{kappa}B/MYC+ renders cancer cells addicted to IL6 for survival and phenotypic stability C_LIO_LINF-{kappa}B/MYC+ cancers are alike a fraction of human plasmablastic lymphoma C_LIO_LIt(8;14)[MYC-IGH] multiple myeloma is linked to a NF-{kappa}B/MYC co-activation signature C_LI

cancer biology↗