Biology subjects

Riedel, A.

Publications and source records attributed to Riedel, A..

16 recordsLinked to original sources

bioRxiv2026

Catabolism of extracellular glutathione is a driver of metastasis formation

Metastasizing cancer cells require metabolic plasticity to adapt to the microenvironment of the target organ. Analyzing metabolites in interstitial fluids, we found that the liver microenvironment is devoid of cystine but contains high concentrations of glutathione (GSH). Detailed mechanistic analysis revealed that cancer cells degrade extracellular GSH utilizing gamma-glutamyl-transferase (GGT) activity for provision of cysteine to support proliferation and prevent ferroptosis under cystine-free conditions. This was independent of system Xc- but required activity of glutamate-cysteine ligase (GCLC). GGT1 expression was associated with poor survival and upregulated in liver metastases of human breast cancer patients. Overexpression of Ggt1 in murine breast cancer cells enhanced their capacity for liver colonization and promoted lung metastases after orthotopic implantation. This identifies extracellular GSH catabolism as driver of metastasis that supports proliferation and oxidative stress resistance in metabolically challenging microenvironments.

cancer biology↗

bioRxiv2026

Next-generation insect digitization: combining phenomics and genomics by subsequent synchrotron X-ray imaging and DNA sequencing

Recent technological advances allow for the large-scale acquisition of genetic and morphological data: high-throughput sequencing has transformed the field of genomics while synchrotron X-ray microtomography enables rapid, noninvasive 3D imaging. However, integrating these approaches for the same specimens is challenging because X-rays can fragment DNA, and DNA extraction damages internal morphology, particularly relevant for small bodied organisms, such as insects. We systematically tested multiple extraction protocols and irradiation conditions across three model insect species. We irradiated more than 1,000 specimens under varying conditions and tested DNA quality through DNA barcoding and UCE sequencing. Our results demonstrate that high-quality DNA and high-resolution tomograms can be obtained from the same individuals, provided that the parameters are carefully optimized and rapid SR-CT scanning precedes DNA extraction. In this respect, our findings establish practical guidelines for combining genomics and phenomics, paving the way for comprehensive integrative digitization of biodiversity.

genetics↗

bioRxiv2026

Evolutionary diversification of the biological screw joint in weevils

Complex biomechanical innovations are often treated as discrete evolutionary breakthroughs, yet their diversification within large radiations remains poorly understood. Beetle leg joints provide a striking example: some weevils possess screw-like coxa-trochanteral articulations in which rotation and axial displacement are mechanically coupled, resembling engineered screw-and-nut mechanisms. Whether these joints represent isolated mechanical extremes, discrete adaptive types or part of a broader continuum of phenotypic variation has remained unknown. Here we combine synchrotron X-ray microtomography, landmark-free atlas-based morphometrics, quantitative functional morphology and phylogenetic comparative analyses to examine the mesocoxa-trochanteral joint in 68 specimens representing seven sampled family-level groups across early-diverging and derived weevil lineages. We show that screw joint evolution combines continuous variation in trochanteral shape with a restricted set of mechanically plausible joint-character combinations, rather than forming sharply separated morphological classes. True screw-and-nut joints are not confined to a distinct region of morphospace, indicating that overall form and mechanical configuration are not necessarily coupled. The occurrence of this configuration in the early diverging Caridae shows that it is not restricted to more derived families. Three-dimensional helix fitting revealed a mosaic geometry, with winding angle showing the clearest relationship with overall shape and joint architecture, whereas axial pitch varied largely independently of shape, size and lineage. Together, these patterns show that screw joint components diversified with different degrees of evolutionary integration. These results recast the weevil screw joint from a singular biomechanical curiosity into a diversified evolutionary system. They suggest that complex functional structures can evolve through the gradual recombination and differential persistence of structurally constrained and evolutionary flexible components, rather than through a single shift from simple to fully specialized designs.

zoology↗

bioRxiv2026

MYC/MIZ1 suppression of lysosomal protein degradation drives immune evasion in pancreatic ductal adenocarcinoma

The MYC oncoprotein promotes immune evasion of pancreatic ductal adenocarcinoma (PDAC), but the underlying molecular mechanisms are not fully understood. Here we show that MYC protects PDAC tumors from CD4+ T cell-dependent elimination. Single cell sequencing shows that MYC suppression in tumor cells increases amino acid availability and broadly activates amino acid-responsive gene expression programs in immune cell populations. This occurs because MYC-driven uptake depletes free amino acids from tumor interstitial fluid and plasma, while MYC compromises macropinocytosis and autophagy, both of which depend on lysosomal protein degradation. MYC engages the POZ/BTB transcription factor MIZ1 to suppress lysosomal genes regulated by the TFE3/TFEB/MITF network or by free MIZ1, thereby inhibiting lysosomal protein degradation. An orthogonal genetic model enabling transient, selective inhibition of amino acid uptake in tumor cells recapitulates the effects of MYC depletion on amino acid levels in the tumor microenvironment and induces complete, CD4+ T cell-dependent tumor eradication with long-term survival. We propose that MYC-mediated, cell-autonomous disruption of lysosome function coupled to non-cell-autonomous protection from immune clearance allows MYC-low cells to benefit from MYC-high neighbors, such that intratumoral heterogeneity in MYC expression confers a selective advantage to the entire tumor. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/740267v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@140d2ccorg.highwire.dtl.DTLVardef@cf5f1borg.highwire.dtl.DTLVardef@6d132aorg.highwire.dtl.DTLVardef@10535e6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Profound CD4+ T-Cell Reprogramming by Melphalan-Driven Oxidative Stress in High-Risk Multiple Myeloma

T cell-based immunotherapies have become central to the treatment of multiple myeloma (MM), yet their efficacy depends on the functionality of endogenous T cells. How cumulative treatment exposure, particularly high-dose melphalan, together with disease-intrinsic high-risk features shapes T-cell composition and immune competence remains incompletely understood. Here, we analyzed T cell composition and function in bone marrow (BM) and peripheral blood (PB) samples from MM patients across different stages of their treatment journey using flow cytometry (BM, n=162; PB, n=1,733), single-cell RNA sequencing (n=19), and cytotoxicity assays (n=20). We reveal reduced overall T cell frequencies and CD4+/CD8+ T cell ratio, associated with lines of therapy and driven in part by depletion of naive CD4+ T cells in gene-expression defined high risk (HR) disease. Among therapeutic agents, melphalan exerted the strongest effects on T cell populations and induced pronounced redox stress in both T cells and myeloma cell lines. This oxidative stress signature was enriched in HR patients and was reversible with N-acetyl-L-cysteine treatment. Together, these findings identify immune dysregulation as a defining feature of HR MM that extends beyond tumor-intrinsic genomic alterations and is further shaped by treatment-induced remodeling of the BM microenvironment. Given the association between higher CD4+ T cell numbers and improved CAR-T cell outcomes, our data highlight the translational importance of treatment sequencing, particularly in HR MM. One Sentence SummaryMelphalan-induced redox stress depletes CD4+ naive T cells, particularly in patients with high-risk multiple myeloma.

Cancer Biology↗

bioRxiv2025

Secondary lymphoid organ endothelial cells prime alloreactive CD4+ T cells to trigger acute graft-versus-host disease

Donor CD4 T cell priming is a pivotal determinant of acute graft-versus-host disease (aGvHD) after allogeneic hematopoietic cell transplantation (allo-HCT). While professional hematopoietic antigen-presenting cells (APCs) have long been implicated in the pathogenesis of aGvHD, the contribution of non-hematopoietic APCs has remained unclear. Here, we show that naive alloreactive CD4 T cells initially localize and activate specifically within secondary lymphoid organs (SLOs) before infiltrating target tissues. Using genetic models to selectively ablate MHC class II on endothelial cells (ECs) or hematopoietic cells, we demonstrate that blood endothelial cells (BECs) in SLOs function as APCs, efficiently processing and presenting antigen to prime donor CD4 T cells. Deletion of MHC class II (MHCII) specifically in ECs substantially attenuates T cell activation and protects mice from lethal aGvHD, whereas selective deletion of MHCII in lymphatic ECs has no effect. Likewise, selective deletion of MHCII in hematopoietic cells also protects mice against aGvHD, suggesting that both cell types contribute to pathogenic allogeneic T cells activation after allo-HCT. Mechanistically, IL-12/IFN{gamma} signaling upregulates MHC class II expression on BECs. These findings identify BECs in SLOs as initiators of alloreactive CD4 T cell responses and highlight a potential target for preventing aGvHD. HighlightsO_LIBlood endothelial cells in secondary lymphoid organs prime naive CD4 T cells to trigger acute GvHD. C_LIO_LIT cell activation occurs exclusively in secondary lymphoid organs before tissue infiltration. C_LIO_LIExpression of MHC class II only on endothelial cells is sufficient to drive lethal GvHD, independent of other antigen presenting cells. C_LIO_LIRegulation of MHC class II expression in blood endothelial cells by IL-12/IFN{gamma} offers the potential for new therapeutic targets and corroborates findings for existing therapeutics. C_LI

immunology↗

bioRxiv2024

Acute Myeloid Leukemia with deletion 5q is an epigenetically distinct subgroup defined by heterozygous loss of KDM3B

Acute myeloid leukemia (AML) is a hematological malignancy characterized by a block in differentiation and accelerated proliferation of myeloid progenitor cells. Genes encoding for epigenetic regulators are among the most frequent targets for mutations and structural variations in AML, giving rise to profound epigenetic heterogeneity between and within tumors. Deletions of chromosome 5q [del(5q)] are among the most common copy number alterations in AML and are associated with extremely poor clinical outcome and therapy resistance, however the mechanisms linking del(5q) to leukemic progression are not understood. Analyzing DNA methylation profiles from 477 elderly AML patients using DNA methylome deconvolution, we discovered that del(5q) AML is an epigenetically distinct subgroup characterized by a signature of DNA hypermethylation, which we propose may be linked to dysregulation of H3K9me1/2 and overexpression of the leukemic stem cell marker, DNMT3B. Interrogation of the minimally deleted 5q region highlighted the H3K9me1/2 demethylase KDM3B as a likely target for haploinsufficiency in this subgroup. Our data suggest that del(5q) AML should be reconsidered as an epigenetically dysregulated subgroup, driven by heterozygous loss of KDM3B, and that the resulting imbalance of H3K9me1/2 may contribute to the progression of these aggressive leukemias.

cancer biology↗

bioRxiv2024

Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q

Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML. Statement of significanceThis study examines the consequences of structural alterations and demonstrates that proto-oncogene activation by enhancer hijacking is an overlooked pathomechanism in AML. MNX1 overexpression demonstrates that deletions on chromosome 7q can not only lead to haploinsufficiency, but also to activation of oncogenes by enhancer hijacking, providing a novel leukemogenic mechanism.

cancer biology↗

bioRxiv2023

Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between breakpoint partners (MNX1 and ETV6) has only been reported in a subset of cases. However, a universal feature is the strong transcript and protein expression of MNX1, a homeobox transcription factor that is normally not expressed in hematopoietic cells. Here, we map the translocation breakpoints on chromosomes 7 and 12 in affected patients to a region proximal to MNX1 and either introns 1 or 2 of ETV6. The frequency of MNX1 overexpression in pediatric AML (n=1556, own and published data) is 2.4% and occurs predominantly in t(7;12)(q36;p13) AML. Chromatin interaction assays in a t(7;12)(q36;p13) iPSC cell line model unravel an enhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Our data suggest that enhancer-hijacking is a more common and overlooked mechanism for structural rearrangement-mediated gene activation in AML. Key pointsO_LIExpression analysis of over 1500 pediatric AML samples demonstrates MNX1 expression as a universal feature of t(7;12)(q36;p13) AML as well as in rare cases without t(7;12)(q36;p13) C_LIO_LIMNX1 is activated by an enhancer-hijacking event in t(7;12)(q36;p13) AML and not, as previously postulated, by the creation of a MNX1::ETV6 oncofusion gene. C_LI

cancer biology↗

bioRxiv2023

Deficiency for scavenger receptors Stabilin-1 and Stabilin-2 leads to age-dependent renal and hepatic depositions of fasciclin domain proteins TGFBI and Periostin in mice

BackgroundStabilin-1 and Stabilin-2 are two major scavenger receptors of liver sinusoidal endothelial cells that mediate removal of diverse molecules from the plasma. Double-knockout mice (Stab-DKO) develop impaired kidney function and a decreased lifespan, while single Stabilin deficiency or therapeutic inhibition ameliorates atherosclerosis and Stab1-inhibition is subject of clinical trials in immuno-oncology. Although POSTN and TFGBI have recently been described as novel Stabilin ligands, the dynamics and functional implications of these ligands have not been comprehensively studied. MethodsImmunofluorescence, Western Blotting and Simple Western as well as in situ hybridization (RNAScope) und qRT-PCR were used to analyze transcription levels and tissue distribution of POSTN and TGFBI in Stab-KO mice. Stab-POSTN-Triple deficient mice were generated to assess kidney and liver fibrosis and function in young and aged mice. ResultsTGFBI and POSTN protein accumulated in kidney and liver tissue in Stab-DKO mice during aging despite unchanged transcriptional levels. Stab-POSTN-Triple KO mice showed glomerulofibrosis and a reduced lifespan comparable to Stab-DKO mice. However, alterations of the glomerular diameter and vascular density were partially normalized in Stab-POSTN-Triple KO. ConclusionTGFBI and POSTN are Stabilin-ligands that are deposited in an age-dependent manner in the kidneys and liver due to insufficient scavenging in the liver. Functionally, POSTN appears to partially contribute to the observed renal phenotype in Stab-DKO mice. This study provides details on downstream effects how how Stabilin dysfunction affects distant organs on a molecular and functional level.

molecular biology↗

bioRxiv2021

Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs

When cancers progress to metastasis, disseminated cancer cells frequently lodge near vasculature in secondary organs. However, our understanding of the cellular crosstalk evoked at perivascular sites is still rudimentary. In this study, we identify intercellular machinery governing formation of a pro-metastatic vascular niche during breast cancer colonization in lungs. We show that four secreted factors, INHBB, SCGB3A1, OPG and LAMA1, induced in metastasis-associated endothelial cells (ECs), are essential components of the vascular niche and promote metastasis in mice by enhancing stem cell properties and survival ability of cancer cells. Notably, blocking VEGF, a key regulator of EC behavior, dramatically suppressed EC proliferation, whereas no impact was observed on the expression of the four vascular niche factors in lung ECs. However, perivascular macrophages, activated via the TNC-TLR4 axis, were shown to be crucial for EC-mediated production of niche components. Together, our findings provide mechanistic insights into the formation of vascular niches in metastasis.

cancer biology↗

bioRxiv2021

A beta-glucosidase of an insect herbivore determines both toxicity and deterrence of a dandelion defense metabolite

Gut enzymes can metabolize plant defense metabolites and thereby affect the growth and fitness of insect herbivores. Whether these enzymes also influence herbivore behavior and feeding preference is largely unknown. We studied the metabolization of taraxinic acid {beta}-D-glucopyranosyl ester (TA-G), a sesquiterpene lactone of the common dandelion (Taraxacum officinale) that deters its major root herbivore, the common cockchafer larva (Melolontha melolontha). We demonstrate that TA-G is rapidly deglycosylated and conjugated to glutathione in the insect gut. A broad-spectrum M. melolontha {beta}-glucosidase, Mm_bGlc17, is sufficient and necessary for TA-G deglycosylation. Using plants and insect RNA interference, we show that Mm_bGlc17 reduces TA-G toxicity. Furthermore, Mm_bGlc17 is required for the preference of M. melolontha larvae for TA-G deficient plants. Thus, herbivore metabolism modulates both the toxicity and deterrence of a plant defense metabolite. Our work illustrates the multifacteted roles of insect digestive enzymes as mediators of plant-herbivore interactions.

ecology↗

bioRxiv2018

Tumors induce de novo steroid biosynthesis in T cells to evade immunity

Tumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a novel transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway was sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.

immunology↗

bioRxiv2018

Single-cell RNA sequencing reveals a dynamic stromal niche within the evolving tumour microenvironment

Non-cancerous stromal cells represent a highly diverse compartment of the tumour, yet their role across tumour evolution remains unclear. We employed single-cell RNA sequencing to determine stromal adaptations in murine melanoma at different points of tumour development. Naive lymphocytes recruited from lymph nodes underwent activation and clonal expansion within the tumour, prior to PD1 and Lag3 expression, while tumour-associated myeloid cells promoted the formation of a suppressive niche through cytokine secretion and inhibitory T cell interactions. We identified three temporally distinct cancer-associated fibroblast (CAF) populations displaying unique signatures, and verified these in human datasets. In early tumours, immune CXCL12/CSF1 and complement-expressing CAFs supported recruitment of macrophages, whereas contractile CAFs became more prevalent in later tumours. This study highlights the complex interplay and increasing diversity among cells that co-evolve with the tumour, indicating that from early stages of development, stromal cells acquire the capacity to modulate the immune landscape towards suppression.

cancer biology↗

bioRxiv2018

Tumor pre-conditioning of draining lymph node stroma by lactic acid

Communication between tumors and the stroma of tumor draining lymph nodes (TDLNs) exists before metastasis arises, altering structure and function of the TDLN niche. Transcriptional profiling of fibroblastic reticular cells (FRCs), the dominant stromal population of the LN, revealed reprogramming of these cells in immune related pathways, but also in fibroblast activation and mitochondrial function. However, tumor derived factors driving the changes in FRCs remained to be identified. Taking an unbiased approach, we show that lactate, a metabolite released by cancer cells, elicits upregulation of Pdpn and Thy1 in FRCs of TDLNs, making them akin to activated fibroblasts found at the primary tumor site. Furthermore, we show that tumor-derived lactate alters mitochondrial function of FRCs of TDLNs. Thus, our results demonstrate a novel mechanism by which a tumor-derived metabolite modulates the function of fibroblasts in TDLNs.

cancer biology↗

bioRxiv2017

Single cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation

Non-lymphoid tissues (NLTs) harbour a pool of adaptive immune cells, the development and phenotype of which remains largely unexplored. Here, we used single-cell RNA-seq to characterise CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, the respective draining lymph nodes and spleen. From this data, we modelled a continuous lymphoid-to-NLT trajectory for Treg, and reconstructed the mechanisms of cell migration and NLT adaption. This revealed a shared transcriptional programme of NLT priming in both skin and colon-associated lymph nodes, followed by tissue-specific adaptation. Predicted migration kinetics were validated using a melanoma-induction model, emphasizing the relevance of key regulators and receptors, including Batf, Rora, Ccr8, Samsn1. Finally, we profiled human blood and NLT Treg and Tmem cells, identifying cross-mammalian conserved tissue signatures. In summary, we have identified molecular signals mediating NLT Treg recruitment and tissue adaptation through the combined use of computational prediction and in vivo validation.

immunology↗