Biology subjects

Schober, M.

Publications and source records attributed to Schober, M..

7 recordsLinked to original sources

bioRxiv2026

Melanoma evolution in the lymph node shapes systemic outcomes

Lymph node (LN) metastasis predicts poor patient outcomes, but the mechanistic drivers that shape metastatic fitness, immune evasion, and clinical impact remain elusive. While preclinical models indicate that active tumor adaptation is necessary for LN metastasis, observations of clonal heterogeneity in human tumors has supported a stochastic model of passive and continuous seeding. Reconciling LN metastasis as a passive or active process is essential to understanding if LN metastasis is simply a marker of disease progression or a clinically informative therapeutic target. Here, we report evidence that LNs are active niches that facilitate ongoing melanoma evolution to progressively subvert immune surveillance and enable progression. To construct a spatial trajectory of LN metastasis, we examined paired primary melanomas and metastatic sentinel LNs through integrated genomic, phenotypic, and immunologic analyses. In contrast to a model of continuous seeding, we observe that early dissemination from the primary tumor is followed by extensive intra-nodal diversification, indicating that metastatic outgrowth requires ongoing adaptation within the LN. As clones evolve in the LN, they re-differentiate towards a melanocytic state and reprogram the microenvironment for immune exclusion. In further evolved clones, loss of inflammatory interferon signaling and induction of p53 and mitochondrial stress are associated with decreased overall survival. Collectively, these results implicate the LN as a critical battleground for melanoma progression, where tumor evolution drives adaptation and immune escape to biologically link regional metastasis to patient survival.

cancer biology↗

bioRxiv2026

Lymphatic egress recycles tumor-experienced effector CD8 T cells to sustain immune surveillance

Successful anti-tumor immune surveillance depends on stem-like CD8+ T cells that are enriched in tumor-draining lymph nodes (LN), but how they are maintained over time remains poorly understood. Here, we identify a continuous lymphatic circuit that sustains stem-like CD8+ T cells. Using photoconversion to fate-map intratumoral T cells we demonstrate that effector cells exit the tumor microenvironment and migrate back to the draining LN. These tumor-specific, migratory effector T cells avoid chronic antigen stimulation, re-express the transcription factor associated with self-renewal, TCF1, and enter a stem-like state in the LN. Antigen presentation in LNs by dendritic cells drives their proliferation thereby inflating the LN stem-like population. Consequently, maintenance of stem-like T cells and ICB response depends on constitutive lymphatic transport, while LN metastasis compromises the stem-like niche, diminishing ICB response. We, therefore, define a continuous, peripheral lymphatic circuit that recycles tumor-experienced effector T cells to fuel durable, systemic immune surveillance.

immunology↗

bioRxiv2026

NF1 Loss Remodels Tumor Niches for Immune Evasion

Genetic and transcriptional alterations in cancer cells shape their interactions with immune and stromal compartments, influencing tumor progression, immune evasion, and response to immune checkpoint inhibitors (ICI). Yet, how these interactions are organized within tumor architecture and linked to clinical outcomes remains unclear. Neurofibromin 1 (NF1) is a tumor suppressor gene that is frequently inactivated across multiple cancer types. NF1 loss-of-function mutations occur in up to 27% of melanoma cases and are associated with poor clinical outcomes. Here, we used spatial multi-omics analysis to uncover 12 meta-niches, each comprising distinctive cell types with distinct characteristics, in human melanoma tissues. We found that niches containing immunosuppressive cancer-associated fibroblasts (CAFs) and macrophages were significantly enriched in NF1 mutant melanoma (NF1Mut) tissues. In contrast, niches containing cytotoxic CD8 T cells were significantly diminished. NF1 loss correlates with increased epidermal growth factor signaling (EGFR) signaling and reduced antigen presentation in tissues with limited CD8 T cell infiltration in both human and mouse melanoma. We demonstrate that EGFR inhibition restores antigen presentation and activates immune responses in a syngeneic Nf1 knockdown model resistant to ICIs. These data, therefore, define functionally distinctive niches enriched in NF1Mut melanoma that likely contribute to their aggressive nature and nominate EGFR signaling as a specific target to reinvigorate ICI responses. We therefore link an understudied genetic driver to specific immune architectures and ultimately therapy resistance and suggest a therapeutic strategy expected to improve treatment outcomes in NF1Mut melanoma patients.

cancer biology↗

bioRxiv2024

A targetable developmental program co-regulates angiogenesis and immune evasion

Ultraviolet (UV)-induced DNA mutations produce genetic drivers of cutaneous melanoma initiation and numerous neoantigens that can trigger anti-tumor immune responses in the host. Consequently, melanoma cells must rapidly evolve to evade immune detection by simultaneously modulating cell-autonomous epigenetic mechanisms and tumor-microenvironment interactions. Angiogenesis has been implicated in this process; although an increase of vasculature initiates the immune response in normal tissue, solid tumors manage to somehow enhance blood flow while preventing immune cell infiltration. By comparing the expression of transcription factors (TFs) across early-stage melanoma, naevi, and other cancer types, we found the homeodomain-containing TF HOXD13 drives a melanoblast-like developmental program, which is upregulated in melanoma and strongly correlated with angiogenesis and immune cell exclusion. Using transcriptomics, 3D chromatin profiling, and in vivo models, we demonstrate that HOXD13 upregulation promotes tumor growth in vivo by concomitantly enhancing angiogenesis and suppressing T-cell infiltration. HOXD13 orchestrates 3D chromatin contacts between distal enhancers and promoters, simultaneously activating VEGFA, SEMA3A, and CD73. VEGFA and SEMA3A remodel the tumor vasculature and CD73 elevates extracellular levels of adenosine, a vasodilator and immune suppressor that binds adenosine receptors (AdR) on endothelial and T cells. In line with these findings, HOXD13-induced growth advantage in vivo was significantly reversed by the concomitant administration of VEGFR and AdR inhibitors. By revealing a dual pro-angiogenic and immunosuppressive HOXD13-CD73/VEGF gene regulatory axis, we identify a subset of patients who might benefit from combinations of AdR and VEGFR inhibitors which are both currently being tested in clinical trials.

cancer biology↗

bioRxiv2022

Speeded Inference Game: Opening a new chapter in the assessment of error awareness

Influential theories on error processing assume that when we conduct errors adaptive processes are triggered to improve our behaviour and prevent errors in the future. These processes appear to be more effective after participants have detected an error. Therefore, the assessment of error awareness allowing a differential analysis of detected and undetected errors in the context of cognitive control and behavioural adjustments has gained more and more attention in the past decades. A common methodological challenge posed on all studies investigating error detection is that the number of undetected errors is usually relatively low. Here, we introduce a gamified experimental task that uses an adaptive algorithm to generate a robust and stable amount of errors with a high rate of undetected errors. Further, we were able to identify error types, which interestingly differed in terms of their detection rate. Moreover, the game-like appearance of the novel experimental task led to highly motivated participants. The results of the first study were replicated and extended by a second behavioural study. Notably, in study 2, a change in task design specifically modulated error detection, while these changes did not affect the total error rate. Potential applications of the open-source code will be discussed. With this newly developed paradigm, we wish to lay the ground for future research to understand better (neural) processes associated with error awareness.

neuroscience↗

bioRxiv2021

SOX2-phosphorylation toggles a bistable differentiation-switch in squamous cell carcinoma

The fate choice between stem cell self-renewal and differentiation is regulated by bistable transcriptional networks, which are balanced in homeostasis and imbalanced in tumors. Yet, how stem cells switch from self-renewal to differentiation remains a conundrum. Here, we discover a molecular mechanism that allows stem cell-like tumor propagating cells (TPCs) in squamous cell carcinomas (SCCs) to switch from a mutually exclusive SOX2-PITX1-TP63 self-renewal circuit to a KLF4 driven differentiation program, dependent on the relative occupancy of a novel Klf4-regulatory enhancer cluster (Klf4EC944) by SOX2 or KLF4, respectively. We find SOX2 occupies this site in TPCs to inhibit Klf4 transcription, but upon phosphorylation SOX2 becomes evicted from Klf4EC944, allowing residual KLF4 to occupy this site instead, boost the expression of KLF4 and its downstream targets, and differentiate self-renewing TPCs into post-mitotic SCC cells. This mechanism allows SOX2 to promote self-renewal and tumor formation, while preserving the differentiation potential in SCC cells. Our data suggest that stochastic cell fate decisions depend on the effective concentration of enzymatically regulated transcription factors. The surprising specificity by which SOX2-phosphorylation governs the bistable Klf4EC944 network-switch in SCCs reveals a conceptual framework for the identification of similar switches in other stem cell and cancer types and their potential development into cell type specific differentiation therapies for diseases in which tissue homeostasis has gone awry.

cancer biology↗

bioRxiv2021

Evaluating 87Sr/86Sr isotope ratios and Sr mass fractions in otoliths of different European freshwater fish species as fishery management tool in an Alpine foreland with limited geological variability

The focus of this study was to assess the potential of otolith microchemistry as a fishery management tool for different European freshwater fish species in an Alpine foreland with a diverse range of different water bodies but low geological variation. 87Sr/86Sr isotope and Sr/Ca ratios in water samples from 26 habitat sites in a pre-alpine catchment region around lake Chiemsee, Germany, an important region for recreational and economic fisheries, were analysed. 87Sr/86Sr isotope ratios and the Sr mass fractions in otoliths of 246 fish out of 16 species were determined using (laser ablation) inductively coupled plasma mass spectrometry ((LA)-ICP-MS). Habitats could be discriminated into three distinct strontium isotope regions (SIGs) and seven clusters with characteristic 87Sr/86Sr isotope and Sr/Ca ratios. The direct comparison of 87Sr/86Sr isotope ratios in water and otolith samples allowed to identify fish that might have been a) migrating b) transferred from other water bodies or c) stocked from fish farms. Sr/Ca ratios in water and the Sr mass fraction in otoliths were highly correlated, although significant differences between species from the same environment could be documented. Sr mass fractions in sagittae of Perca fluviatilis were about 60 % of those in sagittae of Coregonus spp and of lapilli of roach Rutilus rutilus from the same habitats. Different partition factors for water to otolith Sr/Ca mass fractions were determined for different species. Discrimination of fish otoliths by 87Sr/86Sr isotope ratios and Sr mass fractions according to habitat clusters was possible with success rates ranging from 92 % to 100 % for cyprinids, European perch Perca fluviatilis, whitefish Coregonus spp. and European grayling Thymallus thymallus, and was 74 % for salmonids. Otolith microchemistry proved to have great potential to serve as a fishery management tool at smaller spatial scales such as in the studied Alpine foreland when considering the limited variation of 87Sr/86Sr isotope and Sr/Ca ratios, the type and spatial distribution of habitats, and the species and question under investigation. HighlightsO_LIOtolith microchemistry applied in in area with limited geological variability C_LIO_LIFish transferred, stocked or migrated were identified C_LIO_LIRegressions between Sr/Ca ratios in water predict Sr mass fractions in otoliths C_LIO_LISpecies specific Sr discrimination from water into otoliths C_LIO_LIEuropean freshwater fish species assigned to habitat clusters of origin C_LI

ecology↗