Biology subjects

Jarosch, S.

Publications and source records attributed to Jarosch, S..

5 recordsLinked to original sources

bioRxiv2024

Susceptibility to inflammatory bowel diseases promotes invasive carcinomas in a murine model of ATF6-driven colon cancer

Chronic inflammation in inflammatory bowel disease (IBD) patients represents a risk factor for developing colitis-associated cancer (CAC). We previously linked the endoplasmic reticulum unfolded protein response (UPRER) signal transducer activating transcription factor 6 (ATF6) with spontaneous microbiota-dependent colonic adenoma development in mice expressing epithelial-specific activated ATF6 (nATF6IEC). To investigate IBD-related risk factors in ATF6-mediated tumorigenesis, we crossed tumor-free monoallelic (tg/wt) nATF6IEC mice with Interleukin-10 deficient mice (Il10-/-). IL10 deficiency initiated tumor susceptibility, with 77% of 12-week tg/wt;Il10-/- mice developing colonic adenomas and invasive carcinomas in this novel CAC mouse model. Tumor formation correlated with mucosal immune cell infiltration, characterized by CD11b+ granulocytes and monocytes, and mucosa-associated dysbiosis. Colonization of germ-free nATF6IEC;Il10-/- mice with minimal biosynthetic consortia and IBD stool re-established CAC, confirming microbiota-dependent ATF6-driven tumorigenesis. Increased ATF6 expression in IBD patients during active disease highlights its human relevance. Our findings show that IBD susceptibility heightens the risk for ATF6-driven tumorigenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/624835v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@17e280eorg.highwire.dtl.DTLVardef@177ceacorg.highwire.dtl.DTLVardef@a1916borg.highwire.dtl.DTLVardef@152374f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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↗

bioRxiv2023

Spatial Transcriptomic Characterization of Novel Pathologic Niches in IPF

An unmet medical need persists in Idiopathic Pulmonary fibrosis (IPF), for which treatments additional to anti-fibrotic therapy are needed. Single cell RNA sequencing (scRNA-seq) has advanced our understanding of IPF with cell type-specific insights but lacks cellular tissue context. Spatial transcriptomics addresses this by providing spatially resolved gene expression, enabling gene and cell type localization within the tissue environment. We profiled IPF and control patient lung tissue sections using spatial transcriptomics and combined the data with an atlas of integrated IPF scRNA-seq datasets. Through computational analysis, we identified three disease-associated pathologic niches with unique cellular composition / localization and analyzed their cell-cell communication. We identified the Fibrotic niche, comprising Myofibroblasts and Aberrant Basaloid cells, preferentially located around airways and close to the Airway Macrophage niche in the lumen, containing SPP1+ Macrophages. We also identified the Immune niche, distinct foci of lymphoid cells in fibrotic tissue, surrounded by remodeled endothelial vessels. TEASERSpatial transcriptomics localizes genes and cell types in the tissue and identifies pathological cellular niches in IPF and control lungs.

systems biology↗

bioRxiv2023

Mitochondrial perturbation of the epithelium causes microbial dysbiosis and unresolved tissue injury in intestinal inflammation

Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBD). To understand how microbial-metabolic circuits contribute to intestinal tissue injury, we disrupt mitochondrial function in the epithelium by deleting heat shock protein 60 (Hsp60{Delta}/{Delta}IEC). While metabolic perturbation causes self-resolving tissue injury, regeneration is disrupted in the absence of aryl hydrocarbon receptor (Hsp60{Delta}/{Delta}IEC;AhR-/-) or IL-10 (Hsp60{Delta}/{Delta}IEC;Il10-/-) leading to IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60{Delta}/{Delta}IEC mice, highlighting bacterial control of metabolic injury. Selective colonization of GF Hsp60{Delta}/{Delta}IEC mice with the synthetic community OMM12 confirms consistent expansion of metabolically-flexible Bacteroides spp. across all models and mono-colonization with B. caecimuris recapitulates injury. Transcriptional profiling of metabolically-impaired epithelium identifies gene signatures, including Ido1, Nos2, and Duox2, distinguishing active from inactive tissue inflammation in 343 resected samples from Crohns disease patients. In conclusion, mitochondrial perturbation of the epithelium causes microbiota-dependent tissue injury and discriminative inflammatory gene profiles relevant for IBD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/549844v6_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@240c5forg.highwire.dtl.DTLVardef@a84382org.highwire.dtl.DTLVardef@e829e3org.highwire.dtl.DTLVardef@163625_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Control of metabolic injury by microbial signals. C_FIG O_LIMitochondrial perturbation of the intestinal epithelium induces tissue injury C_LIO_LILoss of IL-10 and AhR-related host mechanisms accelerate injury and inflammation C_LIO_LIMitochondrial dysfunction induces dysbiosis and expansion of Bacteroides spp. C_LIO_LIMetabolic injury gene signature discriminates inflamed vs. non-inflamed IBD samples C_LI

microbiology↗

bioRxiv2022

High-resolution profiling of neoantigen-specific T cell receptor activation signatures links moderate stimulation patterns to resilience and sustained tumor control

Neoantigen-specific T cell receptors (neoTCRs) promise a safe, highly personalized therapeutic approach in anti-tumor immunotherapy. Substantial progress has been made regarding their identification whereas detailed functional assessment of single TCR characteristics impacting therapeutic efficacy is lacking. We previously identified and functionally characterized neoTCRs specific for neoepitopes derived from KIF2C and SYTL4 demonstrating differences in functional avidity in a patient with metastatic melanoma. In this work, we now combined single-cell TCR- and RNA-sequencing using stimulated peripheral blood derived CD8+ T cells of this patient and thereby identified two new neoTCRs recognizing the previously identified mutated epitope KIF2CP13L. Analyzing patient-derived neoTCR expressing T cells, we detected distinct activation patterns as a measure for substantial heterogeneity within oligoclonal T cell responses towards neoantigens upon specific ex vivo-restimulation. Moreover, neoTCR-transgenic T cells from healthy donors were employed for detailed in vitro and in vivo fine-characterization focusing on TCR-intrinsic functional patterns. Most importantly, in a xenogeneic mouse model experimentally simulating rechallenge of tumor infiltrating lymphocytes (TILs) after adoptive T cell transfer, we found that T cells expressing neoTCRs with a moderate activation profile provide a stable and more sustained anti-tumor response upon repeated in vivo tumor challenge as compared to neoTCRs with a stronger, burst-like reactivity. These insights have significant implications for engineering TCR-transgenic T cells for therapeutic purposes. One Sentence SummaryCombining TCR specificity linked single-cell transcriptomics with in vitro and in vivo characterization of transgenic T cells helps to decipher functional potential and persistence of neoantigen-specific T cell receptors (TCRs) for TCR-transgenic T cell-based adoptive cellular anti-tumor immunotherapy.

immunology↗