Biology subjects

Reuss, D.

Publications and source records attributed to Reuss, D..

4 recordsLinked to original sources

bioRxiv2022

A detailed landscape of genomic alterations in malignant peripheral nerve sheath tumor cell lines challenges the current MPNST diagnosis

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise from the peripheral nervous system. Half of the tumors develop in the context of the genetic disease Neurofibromatosis type 1 (NF1) and the rest are sporadic sarcomas. MPNSTs have a dismal prognosis due to their aggressiveness and tendency to metastasize, and new treatment options are needed. The diagnosis of MPNSTs can be challenging, especially outside of the NF1 context since specific histological criteria have not been completely established. Genomic analysis may both facilitate differential diagnoses and suggest precision medicine strategies. MethodsWe generated a complete genomic resource of a set of widely used human NF1-related and sporadic MPNST cell lines by applying ploidy analysis, whole genome and whole exome sequencing and SNP-array analysis, complemented by methylome-based classification and immunofluorescence of cell identity markers (SOX9, SOX10, S100B). ResultsNF1 MPNST cell lines faithfully recapitulated the genomic copy number profile of primary MPNSTs. Structural variants were key players in the complete inactivation of most recurrently altered tumor suppressor genes (TSGs) (NF1, CDKN2A, SUZ12/EED), while small variants played a minor role in the NF1 context, both concerning TSG inactivation and due to the absence of gain-of-function mutations. In clear contrast, the sporadic cell lines (STS-26T, HS-Sch-2, HS-PSS) did not recapitulate the copy number profile of primary MPNSTs. They carried different TSG inactivation and exhibited gain-of-function mutations by predicted kinase activation or generation of fusion genes. Mutational frequencies and signatures emerged as promising informative tools for aiding in MPNST differential diagnosis. Due to the multiple genomic differences exhibited, we complemented their characterization using a methylome-based classifier. All NF1-related cell lines were assigned within the MPNST group, while sporadic cell lines clustered either with melanomas or with an uncertain MPNST-like sarcoma group. The staining of cell identity markers reinforced the idea of a potential misdiagnose of the MPNSTs used to derive the sporadic cell lines analyzed. ConclusionsDeep genomic analysis, together with methylome-based sarcoma classification and cell identity marker analysis, challenged the MPNST identity of sporadic cell lines. Results presented here open an opportunity to revise MPNST differential diagnosis and classification.

genomics↗

bioRxiv2021

Conserved induction of distinct antiviral signalling kinetics by primate interferon lambda 4 proteins

Interferon lambdas (IFN{lambda}) (also known as type III IFNs) are critical cytokines that combat infection predominantly at barrier tissues, such as the lung, liver and gastrointestinal tract. Humans have four IFN{lambda}s (1-4) where IFN{lambda}1-3 show [~]80-95% homology and IFN{lambda}4 is the most divergent displaying only [~]30% sequence identity. Variants in IFN{lambda}4 in humans are associated with the outcome of infection, such as with hepatitis C virus. However, how IFN{lambda}4 variants impact cytokine signalling in other tissues and how well this is conserved is largely unknown. In this study we address whether differences in antiviral signalling exist between IFN{lambda}4 variants in human hepatocyte and intestinal cells, comparing them to IFN{lambda}3. We demonstrate that compared to IFN{lambda}3, wild-type human IFN{lambda}4 induces a signalling response with distinct magnitudes and kinetics, which is modified by naturally-occurring variants P70S and K154E in both cell types. IFN{lambda}4s distinct antiviral response was more rapid yet transient compared to IFN{lambda}1 and 3. Additionally, divergent antiviral kinetics were also observed using non-human primate IFN{lambda}s and cell lines. Furthermore, an IFN{lambda}4-like receptor-interacting interface failed to alter IFN{lambda}1s kinetics. Together our data provide further evidence that major functional differences exist within the IFN{lambda} gene family. These results highlight the possible tissue specialisation of IFN{lambda}s and encourage further investigation of the divergent, non-redundant activities of IFN{lambda}4 and other IFN{lambda}s. Contribution to the FieldViral infections remain major causes of death and disease in humans and other animals. Interferons (IFNs) are a diverse group of host signalling proteins that can induce a potent antiviral state in cells and are intimately involved in the outcome of infection. Genetic variants within one IFN (interferon lambda 4, IFN{lambda}4) are associated with the outcome of hepatitis C infection in humans. However, how IFN{lambda}4 functions - and how natural variants affect its activity - remains poorly understood. Comparing how the antiviral activity changes over time following stimulation with different IFN{lambda}s, we identified that IFN{lambda}4 induces a more rapid antiviral state compared to other IFN{lambda}s in liver and intestinal cells. Importantly, this response was conserved within human variants and between humans and non-human primates (chimpanzee and Rhesus macaque). Our results shed light on the unique functions of the divergent IFN{lambda}4 protein.

immunology↗

bioRxiv2021

Integrated phospho-proteogenomic and single-cell transcriptomic analysis of meningiomas establishes robust subtyping and reveals subtype-specific immune invasion

Meningiomas are the most frequent primary intracranial tumors. They can follow a wide clinical spectrum from benign to highly aggressive clinical course. No specific therapy exists for refractory cases or cases not amenable to resection and radiotherapy. Identification of risk of recurrence and malignant transformation for the individual patients is challenging. However, promising molecular markers and prognostic subgrouping by DNA methylation are emerging. Still, the biological underpinnings of these diagnostic subgroups are elusive, and, consequently, no novel therapeutic options arise thereof. Here we establish robust subgroups across the full landscape of meningiomas, consistent through DNA methylation, mutations, the transcriptomic, proteomic and phospho-proteomic level. Pronounced proliferative stress and DNA damage repair signals in malignant cells and in clusters exclusive to recurrent tumors are in line with their higher mitotic activity, but also provide an explanation for the accumulation of genomic instability in anaplastic meningiomas. Although homozygous deletion of CDKN2A/B is a diagnostic marker of high-grade meningioma, the expression of its gene product increased from low to non-deleted high-grade cases. Differences between subgroups in lymphocyte and myeloid cell infiltration, representing a majority of tumor mass in low-grade NF2 tumors, could be assigned to cluster-specific interaction with tumor cells. Activation to a more proinflammatory phenotype and decreased infiltration of myeloid cells in high-grade cases correlated with lower expression of CSF1, located on chromosome arm 1p, whose deletion is known as prognostic marker, with no proposed mechanism before. Our results demonstrate a robust molecular subclassification of a tumor type across multiple layers, provide insight into heterogeneous growth dynamics despite shared pathognomonic mutations, and highlight immune infiltration modulation as a novel target for meningioma therapy.

genomics↗

bioRxiv2020

Resistance to serine in Bacillus subtilis: Identification of the serine transporter YbeC and of a metabolic network that links serine and threonine metabolism

The Gram-positive bacterium Bacillus subtilis uses serine not only as building block for proteins but also as an important precursor in many anabolic reactions. Moreover, a lack of serine results in the initiation of biofilm formation. However, in excess serine inhibits the growth of B. subtilis. To unravel the underlying mechanisms, we isolated suppressor mutants that can tolerate toxic serine concentrations by three targeted and non-targeted genome-wide screens. All screens as well as genetic complementation in Escherichia coli identified the so far uncharacterized permease YbeC as the major serine transporter of B. subtilis. In addition to YbeC, the threonine transporters BcaP and YbxG make minor contributions to serine uptake. A strain lacking these three transporters was able to tolerate 100 mM serine whereas the wild type strain was already inhibited by 1 mM of the amino acid. The screen for serine-resistant mutants also identified mutations that result in increased serine degradation and in increased expression of threonine biosynthetic enzymes suggesting that serine toxicity results from interference with threonine biosynthesis. Originality-Significance StatementSerine is an important precursor for many biosynthetic reactions, and lack of this amino acid can induce biofilm formation in Bacillus subtilis. However, serine is toxic for the growth of B. subtilis. To understand the reason(s) for this toxicity and to identify the so far unknown serine transporter(s) of this bacterium, we performed exhaustive mutant screens to isolate serine-resistant mutants. This screen identified YbeC, the major serine transporter of B. subtilis. Moreover, we observed an intimate link between serine and threonine metabolism that is responsible for serine toxicity by inhibiting threonine biosynthesis.

microbiology↗