Biology subjects

Tschurtschenthaler, M.

Publications and source records attributed to Tschurtschenthaler, M..

6 recordsLinked to original sources

bioRxiv2026

Distinct colorectal cancer genotypes shape microbial ecosystems and reveal stage-specific microbiota dependencies

The gut microbiota has emerged as an important modifier of colorectal cancer (CRC), yet how tumor genotype influences host-microbiota interactions and whether microbial signals are required throughout tumor progression remain unclear. Here, we combined genetically engineered mouse models, microbial multi-omics and a germ-free-compatible orthotopic transplantation system to define the functional contribution of the microbiota across distinct stages of CRC evolution. Across multiple CRC genotypes, we identified tumor-associated microbial ecosystem states characterized by distinct taxonomic, functional and metabolic configurations. To directly test their contribution to tumor progression, we established the first orthotopic CRC transplantation platform compatible with long-term experimentation in germ-free mice, enabling side-by-side comparison of genetically identical tumors in the presence or absence of microbiota. Using organoids spanning low-grade adenoma, high-grade adenoma and adenocarcinoma states, we found that the dependence on the presence of microbiota progressively decreases during malignant evolution. Whereas adenoma-derived organoids exhibited profound dependence on microbial exposure and failed or were markedly impaired in establishing tumors under germ-free conditions, adenocarcinoma organoids engrafted and metastasized in both germ-free and specific pathogen-free (SPF) hosts. Unexpectedly, comprehensive histological, immunological and transcriptomic analyses revealed highly similar tumor ecosystem states in advanced tumors arising under both microbial conditions, arguing against broad immune or epithelial defects as a primary explanation for the observed phenotype. Together, our findings demonstrate that distinct oncogenic drivers establish specific microbial ecosystem states and reveal a stage-dependent role of the microbiota during colorectal tumorigenesis. Whereas microbial signals are critical during early stages of tumor progression and may promote malignant transformation, advanced tumors progressively acquire microbiota-independent growth programs and increasingly impose genotype-specific ecological signatures on the surrounding microbial ecosystem. More broadly, we establish a versatile framework for the causal dissection of tumor-microbiota interactions in cancer.

cancer biology↗

bioRxiv2026

STING safeguards epithelial genome integrity and protects from carcinogenesis via mitotic checkpoint control

STING is canonically known for mediating interferon responses to cytosolic DNA, yet its cell-intrinsic role in genome maintenance beyond the immune context is unknown. Here we show that epithelial STING functions as a type I interferon-independent genome-integrity checkpoint. STING loss impairs homologous recombination repair, attenuates ATM-associated damage signaling, elevates CDK1 activity, and causes chromosomal instability revealed by single-cell Strand-seq, culminating in spontaneous intestinal adenocarcinoma. These defects arise before tumor formation and confer selective vulnerability to CDK inhibition in tumor organoids and human colorectal cancer cells. Our findings identify STING as a cell-autonomous guardian of epithelial genome stability that restrains chromosomal instability-driven tumor evolution beyond its canonical immune function.

cancer biology↗

bioRxiv2025

A microbial metabolite protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in allo-HSCT patients. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DATs beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DATs dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

immunology↗

bioRxiv2024

Deletion of epithelial HKDC1 decelerates cellular proliferation and impairs mitochondrial function of tumorous epithelial cells thereby protecting from intestinal carcinogenesis in mice

BackgroundA metabolic switch favoring glycolysis over aerobic oxidative phosphorylation, namely the "Warburg effect", represents a hallmark of cancer cells. Hexokinases (HK) catalyze the first step of glycolysis, thereby regulating its rate. Dysregulated HKDC1 (HK domain containing 1) expression has been associated with various cancer types and blocking HKDC1 prevents disease progression for hepatic carcinoma T cell lymphoma and lung adenocarcinoma, but its implication for colorectal cancer (CRC) remained unknown. Here, we functionally investigated the role of HKDC1 for intestinal carcinogenesis. MethodsFirst, we analyzed HKDC1 expression in the intestinal mucosa of healthy controls (HC) and CRC patients and in different tumor tissues using transcriptomic data from publicly available databases. We then generated HKDC1-deficient human and murine colonic epithelial cell lines as well as intestinal organoids and profiled their phenotypic functions. Next, we screened for proteins interacting with HKDC1 by immunoprecipitation. Finally, we generated tumor-bearing ApcMin/+ mice with a conditional deletion of HKDC1 in intestinal epithelial cells and also performed a xenograft mouse model to test the role of HKDC1 for intestinal carcinogenesis in vivo. ResultsHKDC1 was found to be overexpressed in tumor compared to normal tissue of CRC patients. In vitro, HKDC1-deficient human Caco-2 and murine CMT-93 cells displayed reduced proliferation, altered susceptibility to cell death induction, and disrupted mitochondrial functions, particularly mitochondrial respiration. These altered cancer hallmarks were then corroborated in HKDC1-deficient normal and tumor-derived ApcMin/+ intestinal organoids. Immunoprecipitation and mass spectometry proteomic analyses revealed interactions of HKDC1 with several mitochondria-related proteins. In vivo, two distinct mouse models demonstrated that epithelial deletion of HKDC1 protected from carcinogenesis. First, ApcMin/+-Hkdc1{Delta}IEC mice showed mildly improved disease phenotypes in the colon accompanied with reduced numbers of Ki67-positive proliferating epithelial cells. Finally, HKDC1-deficient Caco-2 cells completely failed to form any tumor mass in a xenograft model when implanted into immunodeficient mice. ConclusionsWe demonstrate that HKDC1 influences cancer cell proliferation and susceptibility to cell death, potentially through interactions with mitochondrial proteins that regulate membrane permeability, ultimately impacting intestinal carcinogenesis. Collectively, these findings highlight the significance of HKDC1 for CRC pathobiology, presenting it as a promising target for further investigation and potential therapeutic interventions.

cancer biology↗

bioRxiv2024

Tissue-adapted Tregs harness inflammatory signals to promote intestinal repair from therapy-related injury

Intestinal stem cells (ISC) promote tissue repair after genotoxic or immune-mediated injury. However, ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses such as interferon-{gamma} (IFN{gamma})-mediated killing. In mouse models of gut damage and biopsies from patients having undergone allo-hematopoietic stem cell transplantation, we observed IFNy expression by intestinal Treg cells. Treg cells leverage combined IFN{gamma} and interleukin 10 (IL-10) stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways. Similarly, Treg cells or the combined addition of recombinant IFN{gamma} and IL-10 promote the regeneration of organoids after irradiation. Exposure of organoids to Wnt- or EGF-free culture conditions revealed distinct growth factor-like properties of IFN{gamma} and IL-10. While IFN{gamma} induced epithelial proliferation and differentiation, combined addition of IFN{gamma} and IL-10 led to balanced proliferation, ensuring ISC maintenance. Our results uncover a context-dependent role of inflammatory signaling in ISC, through which Treg cells promote epithelial repair.

immunology↗

bioRxiv2024

Dissecting heterogeneity of tumor microenvironment in colorectal cancer using high-resolution single-cell atlas

The immune composition of the tumor microenvironment (TME) has a major impact on the therapeutic response and clinical outcome in patients with colorectal cancer (CRC). Here, we comprehensively characterize the TME at the single-cell level by first building a large-scale atlas that integrates 4.27 million single cells from 1,670 patient samples. We then complemented the atlas with single-cell profiles from four CRC cohorts with 266 patients, including cells with low mRNA content, spatial transcriptional profiles from 3.7 million cells, and protein profiles from 0.7 million cells. The analysis of the atlas allows refined tumor classification into four immune phenotypes: immune desert, B cell enriched, T cell enriched, and myeloid cell enriched subtypes. Within the myeloid compartment we uncover distinct subpopulations of neutrophils that acquire new functional properties in blood and in the TME, including anti-tumorigenic capabilities. Further, spatial multimodal single-cell profiling reveals that neutrophils are organized in clusters within distinct functional niches. Finally, using an orthotopic mouse model we show that cancer-derived systemic signals modify neutrophil production in the bone marrow, providing evidence for tumor-induced granulopoiesis. Our study provides a big data resource for the CRC and suggests novel therapeutic strategies targeting neutrophils.

bioinformatics↗