Biology subjects

Tiefenbacher, A.

Publications and source records attributed to Tiefenbacher, A..

5 recordsLinked to original sources

bioRxiv2025

Worldwide spread of Hylurgus ligniperda (Coleoptera: Scolytinae), and the potential role of bridgehead invasions

Hylurgus ligniperda (F.) is a highly successful invader among bark beetles (Scolytinae) and forest insects in general. Native to the western Palearctic region, it has become established in every continent where its host plants (Pinus spp.) occur. Especially in southern hemisphere regions with large pine plantations, it is often highly abundant. As a repeat invader with a wealth of information on various aspects relevant for biological invasions, it is highly suitable as a model organism for studying the role of international trade, the planting of non-native trees, and the potential occurrence of bridgehead invasions (where abundant non-native populations precipitate further invasions). In the present study, our specific objectives were to reconstruct the worldwide invasions of H. ligniperda and the pathways involved by using a multi-pronged approach including population genetics, analysis of historic interception data generated from inspections of imports, and records of establishments in the literature. Our review of the native and non-native ranges of H. ligniperda and the chronology of establishments revealed at least 13 separate invasions of non-native regions, beginning with Madeira (Portugal) before 1850, and, most recently, eastern China in 2019. We compared the population genetics of 464 specimens from eight countries in the native range and eight countries in the non-native range. Sequencing of the mitochondrial COI gene revealed the presence of 29 haplotypes in six well-supported clades, based on a Bayesian analysis. Non-native populations had significantly lower haplotype diversity (mean h = 0.219) than populations in the native range (mean h = 0.691). Countries in the non-native range had an average of about two haplotypes compared with about four haplotypes in native countries. In the non-native range, only one or two haplotypes were dominant, and these differed among invaded regions except for haplotype HL-H3 which occurred in Australia, New Zealand and China as well as in four countries in southern Europe, and HL-H4 which was dominant in New Zealand, California, New York State, and eastern China as well as two countries in southern Europe. Analyses of interceptions of H. ligniperda with imports arriving in five countries revealed that between 74% and 99% of interceptions originated from other non-native regions while in the USA, most interceptions were linked to imports from the native range beginning in the 1970s. Based on the combined evidence of the chronology of invasions, interception data, and analysis of haplotype distribution, we conclude that the early invasions (before 1950) probably all originated from the native range, while several of the more recent invasions probably originated from parts of the non-native range (suggestive of a bridgehead effect). However, it cannot be determined with certainty what the original sources of each of the invading populations were.

ecology↗

bioRxiv2025

Biobank of genetically defined murine prostate cancer tumoroids uncovers oncogenic pathways and drug vulnerabilities driven by PTEN-loss

Prostate cancer (PCa) is the second most common cancer in men and shows high inter- and intra-patient heterogeneity. Consequently, treatment options are limited and there is a lack of representative preclinical models. Here we establish a comprehensive biobank of murine organoids and tumoroids that reflect common patient mutations. We demonstrate that the deletion of Pten alone, or in combination with Stat3, or Tp53, drives the activation of cancer-related pathways in both prostate organoids and tumour-derived tumoroids. A medium-throughput drug screen identified two potent compounds, the PDPK1/AKT/FLT dual pathway inhibitor and the sirtuin inhibitor tenovin-6, which effectively suppressed tumoroid proliferation. Notably, these compounds also inhibited the growth of several human PCa cell lines and displayed synergistic effects when combined with the standard-of-care antiandrogen enzalutamide. Together, our findings provide evidence that murine tumoroids are versatile preclinical models for studying PCa tumorigenesis and drug sensitivities to develop novel therapeutic options for PCa patients.

cancer biology↗

bioRxiv2024

Aggressive KRAS mutations direct TGF-β response towards partial EMT in patient-derived colorectal cancer tumoroids

Transforming growth factor beta (TGF-{beta}) exhibits complex and context-dependent cellular responses. While it mostly induces tumor-suppressive effects in early stages of tumorigenesis, its tumor promoting properties are evident in advanced disease. This TGF-{beta} duality is still not fully understood, and whether TGF-{beta} supports invasion and metastasis by influencing cancer cells directly, or rather through the stromal tumor compartment remains a matter of debate. Here, we utilized a library of colorectal cancer (CRC) patient-derived tumoroids (PDTs), representing a spectrum of tumor stages, to study cancer cell-specific responses to TGF-{beta}. Using medium conditions allowing for the differentiation of PDTs, we observed TGF-{beta} induced tumor-suppressive effects in early-stage tumoroids. PDTs with TGF-{beta} pathway mutations or PDTs derived from metastatic tumors were insensitive to the treatment. Notably, one tumoroid line harboring an atypical KRASQ22K mutation underwent partial epithelial-to-mesenchymal transition (EMT), associated with morphological changes and increased invasiveness. On a molecular level, this was accompanied by elevated expression of mesenchymal genes, as well as deregulation of pathways associated with matrix remodeling and cell adhesion. Our results suggest that tumor cell intrinsic responses to TGF-{beta} are critical in determining its tumor-suppressive or -promoting effects.

cancer biology↗

bioRxiv2022

Mimicking tumor cell heterogeneity of colorectal cancer in a patient-derived organoid-fibroblast model

Patient-derived organoid (PDO) cancer models are generated from epithelial tumor cells. Although they reflect the molecular tumor characteristics, they lack the complexity of the tumor microenvironment, which is a key driver of tumorigenesis and therapy response. Here, we present a colorectal cancer (CRC) organoid model that incorporates epithelial cells and stromal fibroblasts from the same patient. Molecular characterization of primary cancer associated fibroblasts (CAFs) and matched normal fibroblasts (NF) revealed proteomic, secretome and gene expression differences in pathways associated with tumor related fibroblast function. Further, CAFs retained higher motility compared to NFs in vitro. Importantly, both CAFs and NFs supported cancer cell proliferation in 3D co-cultures, without the addition of classical niche factors. PDOs grown together with fibroblasts displayed a larger cellular heterogeneity of tumor cells compared to mono-cultures, and closely resembled the in vivo tumor morphology. This was also confirmed by the calculation of cellular proportions of epithelial cell subtypes in organoid mono-versus co-cultures, which were inferred through bioinformatics deconvolution of bulk RNA sequencing data using published single cell RNA sequencing datasets from CRC tissues. Additionally, we observed a mutual crosstalk between tumor cells and fibroblasts in the co-cultures. This was manifested by majorly deregulated pathways such as cell-cell communication and extracellular matrix remodeling in the organoids. For the fibroblasts, we observed enhanced expression of tumor induced marker genes and cytokines characteristic for myo- and immunogenic fibroblasts. This model will be vital as a physiological personalized tumor model to study disease mechanisms and therapy response in CRC. One Sentence SummaryPatient matched fibroblasts support tumor organoid growth in 3D co-culture and maintain intratumoral cellular heterogeneity and histo-morphology.

cancer biology↗

bioRxiv2020

Requirement of DNMT1 to orchestrate epigenomic reprogramming during NPM-ALK driven T cell lymphomagenesis

Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T cell-specific lymphoma model based on the human oncogenic NPM-ALK translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK positive tumors show a loss of collaborative methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis. STATEMENT OF SIGNIFICANCEEpigenetic alterations are causally involved in tumorigenesis. Here we show that induction of a single human oncogene in murine T cells induces specific deregulation of epigenetic enzymes resulting in epigenomic alterations similar to human tumors. Our findings are of broader implication to understand how epigenomic processes are shaped by oncogene induced transformation.

cancer biology↗