Biology subjects

Horst, D.

Publications and source records attributed to Horst, D..

18 recordsLinked to original sources

bioRxiv2026

Copy number signatures in targeted gene panels associate with patient outcomes in routine clinical data

Targeted gene panels (TGPs) dominate clinical sequencing, yet most copy-number (CN) signature studies rely on genome-wide assays. Whether signatures can be recovered from TGPs and retain clinical relevance remains unclear. We analyzed two real-world TGP cohorts comprising 1,726 patients across 62 tumor types, including 825 with clinical annotations, and made the underlying data publicly available. TGP-derived signatures recapitulated established biological associations, including links to homologous recombination deficiency and TP53 alterations, concordant with published genome-wide assay-derived CN signatures. Using our detailed clinical data, we found TGP-derived CN signatures associated with overall survival under standard therapies in ovarian, pancreatic, and colorectal cancer. In ovarian cancer, CN2 was associated with CCNE1 amplification and shorter survival under paclitaxel/carboplatin, with the survival association validated in an independent SNP-array cohort. These findings demonstrate that routine TGPs yield biologically and clinically relevant CN signatures with potential as biomarkers for therapy stratification.

genetics↗

bioRxiv2026

Tumor-versus-non-tumor T cell enrichment supported by single-cell and spatial phenotyping enables antigen-agnostic prioritization of candidate tumor-reactive TCRs

Introduction: Tumor-reactive T cell receptors (TCRs) are promising candidates for the manufacturing of safe and effective adoptive TCR-T cell therapies, but their efficient identification remains a major challenge. We previously established an antigen-agnostic TCR-repertoire analysis workflow that prioritizes candidate TCRs based on intratumoral clonal expansion and high tumor-to-non-tumor (T/N) frequency ratios. Here, we investigated whether T/N-selected clonotypes show independent transcriptional and spatial features consistent with tumor association. Methods: Bulk and single-cell TCR repertoire sequencing of paired tumor and adjacent non-tumor tissues was used to identify clonotypes with high T/N ratios across 15 cancer cases, comprising six non-small cell lung cancers, five pancreatic cancers, two breast cancers, and two colorectal cancers. Candidate clonotypes were further characterized by paired single-cell TCR and gene expression profiling and, in two PDAC cases, by Xenium spatial transcriptomics to assess their cellular phenotype, spatial localization, and proximity to malignant cells. Results: High T/N ratios consistently marked T cell clonotypes with features of tumor reactivity across the studied solid tumor entities. The analysis included Cluster-A, a lead T cell cluster comprising highly similar TCRs shared among 14 HLA-A*02:01-positive patients in the present cohort. Cluster-A clonotypes were consistently enriched in tumor relative to matched non-tumor tissue, and previous functional studies demonstrated tumor recognition by Cluster-A members. In a focused analysis of a pancreatic cancer case, Cluster-A CD8 T cells were selectively detected in tumor tissue, preferentially localized near malignant epithelial cells, and displayed an antigen-experienced effector-memory phenotype with prominent expression of granzymes A and K (GZMA/GZMK). Importantly, in another PDAC case that lacked Cluster-A clonotypes, these features extended to independent clonotypes, revealing a continuous tumor-association axis in which increasing T/N ratios were associated with progressively closer localization to malignant cells and increased GZMA/GZMK expression. Thus, repertoire enrichment, spatial tumor proximity, and effector-associated transcriptional states converged across independent tumor-enriched clonotypes. Outlook: These findings support the T/N ratio as a robust primary criterion for identifying candidate tumor-reactive TCRs. Integration of single-cell and spatial transcriptomics provides supporting biological evidence of tumor association and a framework for prioritizing therapeutic TCR candidates when functional validation is limited.

immunology↗

bioRxiv2026

Concurrent AXL inhibition enhances RAS and ERK inhibitor efficacy in KRAS-mutant pancreatic and lung cancer

Resistance limits the clinical efficacy of RAS inhibitors. We applied chemical and genetic screens and identified the AXL receptor tyrosine kinase as a driver of resistance to RAS-ERK inhibition. We determined that combination treatment with the AXL inhibitor bemcentinib (AXLi) together with the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 (RASi) or the ERK-selective inhibitor SCH772984 (ERKi) significantly enhanced growth suppression in human KRAS-mutant pancreatic and lung cancer models. Combined AXLi and RASi treatment of human KRAS-mutant pancreatic cell line-derived xenograft tumors synergistically suppressed ERK activation and MYC expression, and caused tumor regression. Analyses of immunocompetent mouse allograft pancreatic tumor models revealed a largely tumor cell-intrinsic response to inhibitor treatment. We identified an unexpected mechanism whereby KRAS inhibition upregulated the AXL ligand GAS6, activating AXL but inducing an AXL-dependent adaptive resistance mechanism wherein AXL antagonizes RASi efficacy. Our observations support concurrent AXL inhibition as a strategy to enhance RAS inhibitor clinical efficacy. STATEMENT OF SIGNIFICANCEOur findings identify AXL as a driver of resistance to RAS inhibitors, establishing a combination strategy to overcome resistance and enhance RAS inhibitor therapeutic efficacy in KRAS-mutant cancer by maximally inhibiting oncogenic RAS signaling.

cancer biology↗

bioRxiv2026

Spatial multi-omics reveals targetable immunosuppressive macrophage T-cell interactions in human AML bone marrow

The immunosuppressive bone marrow microenvironment is an important contributor to the limited success of immunotherapy in acute myeloid leukemia (AML), but the cellular interactions underlying AML immune evasion are incompletely understood. We therefore generated a single-cell spatial transcriptomic and proteomic atlas using 148 bone biopsies from 113 individuals comprising pediatric and adult AML at diagnosis and non-leukemic controls. We observed an expansion of regulatory T cells (Tregs) in AML, with stronger colocalization between Tregs and macrophages compared to non-leukemic bone marrow. Distinct cellular neighborhoods were enriched for myeloid progenitor-like cells together with macrophages and T cells, which correlated with higher macrophage and T cell immune checkpoint expression. Moreover, these neighborhoods were associated with specific AML subtypes, especially KMT2A-rearranged and RUNX1::RUNX1T1 AML. These spatial patterns were validated by identification of malignant cells via in situ fusion detection in RUNX1::RUNX1T1 cases. Functional experiments revealed that macrophages and AML cells not only actively recruit Tregs, but also promote naive T cell differentiation into Tregs. Spatially informed ligand-receptor analysis predicted the involvement of the Galectin-9 - CD44/TIM-3 axis in this immunosuppressive crosstalk, which was supported by in vitro inhibition of CD44 and/or TIM-3 preventing macrophage- and AML-induced Treg differentiation. Collectively, this comprehensive spatial map of the AML bone marrow identified tripartite crosstalk between AML, macrophages, and T cells mediated by the Galectin-9 - CD44/TIM-3 axis as a key component of the immunosuppressive microenvironment. Targeting Galectin-9 - CD44/TIM-3 interactions may be a promising strategy to overcome immune evasion and enhance immunotherapeutic success in AML. HighlightsO_LISpatial transcriptomic and proteomic atlas of pediatric and adult acute myeloid leukemia (AML) bone marrow C_LIO_LIIncreased colocalization of macrophages and regulatory T cells (Tregs) in AML C_LIO_LIMacrophages and AML cells induce differentiation of naive T cells to Tregs in vitro, which can be prevented by inhibition of CD44 or TIM-3 C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/743431v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@14f313aorg.highwire.dtl.DTLVardef@290bd3org.highwire.dtl.DTLVardef@c749baorg.highwire.dtl.DTLVardef@1b955d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Aberrant brain-type neuronal programs in large-cell pancreatic neuroendocrine carcinoma

High-grade pancreatic neuroendocrine carcinoma (panNEC) is a rare, aggressive cancer with limited tissue availability. Single-nucleus transcriptomics of five large-cell panNECs revealed two clinically relevant neuroendocrine cell states: one highly proliferative with an aberrant brain-specific neuronal differentiation program and another stress-responsive state enriched for heat stress, hypoxia, and glycolysis. Our findings suggest potentially new therapeutic vulnerabilities, highlighting the need to evaluate the efficacy of combination therapies.

cancer biology↗

bioRxiv2024

Super-enhancer-driven CACNA2D2 is an EWSR1::WT1 signature gene encoding a diagnostic marker for desmoplastic small round cell tumor (DSRCT)

Desmoplastic small round cell tumor (DSRCT) is a highly aggressive cancer predominantly occurring in male adolescents and young adults. The lack of a comprehensive understanding on the biology of the disease is paralleled by its dismal survival rates (5-20%). To overcome this challenge, we first identified and prioritized urgently needed resources for clinicians and researchers. Thus, we established genome-wide single-cell RNA-sequencing and bulk proteomic data of in vitro and in vivo-generated knockdown models of the pathognomonic DSRCT fusion oncoprotein (EWSR1::WT1) and combined them with an original systems-biology-based pipeline including patient data and the largest histology collection of DSRCTs and morphological mimics available to date. These novel tools were enriched with curated public datasets including patient- and cell line-derived ChIP-seq, bulk and single-cell RNA-seq studies resulting in a multi-model and multi-omic toolbox for discovery analyses. As a proof of concept, our approach revealed the alpha-2/delta subunit of the voltage-dependent calcium channel complex, CACNA2D2, as a highly overexpressed, super-enhancer driven, direct target of EWSR1::WT1. Single-cell and bulk-level analyses of patient samples and xenografted cell lines highlighted CACNA2D2 as a critical component of our newly established EWSR1::WT1 oncogenic signature, that can be employed to robustly identify DSRCT in reference sets. Finally, we show that CACNA2D2 is a highly sensitive and specific single biomarker for fast, simple, and cost-efficient diagnosis of DSRCT. Collectively, we establish a large-scale multi-omics dataset for this devastating disease and provide a blueprint of how such toolbox can be used to identify new and clinically relevant diagnostic markers, which may significantly reduce misdiagnoses, and thus improve patient care.

cancer biology↗

bioRxiv2024

Reporter-based screening identifies RAS-RAF stabilizing mutations as drivers of resistance to broad-spectrum RAS inhibition in colorectal cancer

Therapy-induced acquired resistance limits the clinical effectiveness of mutation-specific RAS inhibitors in colorectal cancer. It is unknown whether broad-spectrum active-state RAS inhibitors meet similar limitations. Here, we identify and categorize mechanisms of resistance to the broad-spectrum active-state RAS inhibitor RMC-7977 in colorectal cancer cell lines. We found that KRAS-mutant colorectal cancer cell lines are universally sensitive to RMC-7977, inhibiting the RAS-RAF-MEK-ERK axis, halting proliferation and in some cases inducing apoptosis. To monitor KRAS downstream effector pathway activity, we developed a compartment-specific dual-color ERK activity reporter. RMC-7977 treatment reduced reporter activity. However, long-term dose escalation with RMC-7977 revealed multiple patterns of reporter reactivation in emerging resistant cell populations that correlated with phosphorylation states of compartment-specific ERK targets. Cells sorted for high, low, or cytoplasmic reporter activity exhibited distinct patterns of genomic mutations, phospho-protein, and transcriptional activities. Notably, all resistant subpopulations showed dynamic ERK regulation in the presence of the RAS inhibitor, unlike the parental sensitive cell lines. High levels of RAS downstream activities were observed in cells characterized by a KRAS Y71H resistance mutation. In contrast, RAS inhibitor-resistant populations with low, or cytoplasmic ERK reporter reactivation displayed different genetic alterations, among them RAF1 S257L and S259P mutations. Colorectal cancer cells resistant to RMC-7977 and harboring the RAF1 mutation specifically exhibited synergistic sensitivity to concurrent RAS and RAF inhibition. Our findings endorse reporter-assisted screening together with single-cell analyses as a powerful approach for dissecting the complex landscape of therapy resistance. The strategy offers opportunities to develop clinically relevant combinatorial treatments to counteract emergence of resistant cancer cells.

cancer biology↗

bioRxiv2024

A quantitative tumor-wide analysis of morphological heterogeneity of colorectal adenocarcinoma

Morphologic heterogeneity of colorectal adenocarcinoma (CRC) is poorly understood. Previously, we identified morphological patterns associated with CRC molecular subtypes, and showed that these patterns have distinct molecular motifs (Budinska et al., 2023). Here, we evaluated the heterogeneity of these patterns across CRC. Three pathologists evaluated dominant, secondary, and tertiary morphology on four different tissue blocks per tumor in a pilot set of 22 CRCs (n=88). An artificial intelligence (AI) image analysis tool was trained using the pathologist-rated tumors to assess the morphologic heterogeneity on an expanded set of 161 CRCs (644 images). Heterogeneity was expressed as a combination of morphology patterns (morphotypes) across slides and normalized Shannons index (NSI). All pathologists agreed that the majority of tumors had 2-3 different dominant morphotypes, and that the complex tubular (CT) morphotype was the most common. AI analysis confirmed these observations in the full set. CT morphotype combined with all other dominant morphotypes within a tumor. Desmoplastic (DE) morphotype was rarely dominant and rarely combined with other dominant morphotypes. Mucinous (MU) was most often combined with solid/trabecular (TB) and papillary (PP). Most tumors showed medium or high NSI, but without clinical consequence. The proportion of DE morphotype was associated with higher T-stage, N-stage, metastasis, AJCC-stage, and shorter relapse-free survival, and MU morphotype was associated with higher grade, right side, microsatellite instability, and shorter overall survival. In conclusion, we observed high intratumoral morphological heterogeneity of CRC, and that not heterogeneity per se, but the proportion of certain morphotypes showed associations with clinical outcome. This has implications for molecular profiling of CRC.

cancer biology↗

bioRxiv2024

High-confidence calling of normal epithelial cells allows identification of a novel stem-like cell state in the colorectal cancer microenvironment

Single-cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could potentially adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Somatic Mutations) to exploit genomic single nucleotide variants for the disambiguation of cancer cells from genomically normal non-cancer epithelial cells in single-cell data. In colorectal cancer datasets, we find that our method and others based on gene expression or allelic imbalances identify overlapping sets of cancer versus normal epithelial cells, depending on molecular characteristics of individual cancers. Further, we define consensus cell identities of normal and cancer epithelial cells with higher transcriptome cluster homogeneity than those derived using existing tools. Using the consensus identities, we identify significant shifts of cell state distributions in genomically normal epithelial cells developing in the cancer microenvironment, with immature states increased at the expense of terminal differentiation throughout the colon, and a novel stem-like cell state arising in the left colon. Trajectory analyses show that the new cell state extends the pseudo-time range of normal colon stem-like cells in a cancer context. We identify cancer-associated fibroblasts as sources of WNT and BMP ligands potentially contributing to increased plasticity of stem cells in the cancer microenvironment. Our analyses advocate careful interpretation of cell heterogeneity and plasticity in the cancer context and the consideration of genomic information in addition to gene expression data when possible. Novelty and ImpactSingle-cell analyses have become standard to assess cell heterogeneity and developmental hierarchies in cancer tissues. However, these datasets are complex and contain cancer and non-cancer lineage cells. Here, we develop and systematically benchmark tools to distinguish between cancer and non-cancer single-cell transcriptomes, based on gene expression or different levels of genomic information. We provide strategies to combine results of different tools into consensus calls tailored to the biology and genetic characteristics of the individual cancer.

cancer biology↗

bioRxiv2023

Robust detection of clinically relevant features in single-cell RNA profiles of patient-matched fresh and formalin-fixed paraffin-embedded (FFPE) lung cancer tissue

Single-cell transcriptional profiling reveals cell heterogeneity and clinically relevant traits in intra-operatively collected patient-derived tissue. However, the established approach to perform such analyses on freshly collected tissue constitutes an important limitation since it requires prospective collection and immediate processing. Therefore, the ability to perform single-cell RNA sequencing from archived tissues would be very beneficial in a clinical setting. Here, we benchmark single-cell gene expression profiles from patient-matched fresh, cryopreserved and FFPE cancer tissue. We find that fresh tissue and FFPE routine blocks can be employed for the robust detection of clinically relevant traits on the single-cell level. Specifically, single-cell maps of fresh patient tissues and corresponding FFPE tissue blocks could be integrated into common low-dimensional representations, and cell subtype clusters showed highly correlated transcriptional strengths of signaling pathways, Hallmark and clinically useful signatures, despite some variability in expression of individual genes due to technological differences. FFPE tissue blocks revealed higher cell diversity compared to fresh tissue. In contrast, single-cell profiling of cryopreserved tissue was prone to artifacts in the clinical setting. Our analysis suggests that single-cell RNA sequencing from FFPE tissues is comparable to and can replace analyses from fresh tissue. This highlights the potential of single-cell profiling in the analysis of retrospectively and prospectively collected archival pathology cohorts and dramatically increases the applicability in translational projects.

pathology↗

bioRxiv2022

Patient-derived tumoroids of advanced high-grade neuroendocrine neoplasms mimic patient chemotherapy responses and guide the design of personalized combination therapies

There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous epithelial malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and applied this model for targeted rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug response to patients clinical response to chemotherapy, and investigated treatment-induced adaptive stress responses. PD tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked clinical response to cisplatin and temozolomide ex vivo. When we investigated treatment-induced adaptive stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5A and interferon-beta, which act synergistically in combination with cisplatin. Since ex vivo drug response in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our rapid and functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN.

cancer biology↗

bioRxiv2021

The single-cell transcriptional landscape of lung carcinoid tumors

Lung carcinoid tumors, also referred to as pulmonary neuroendocrine tumors or lung carcinoids, are rare neoplasms of the lung with a more favorable prognosis than other subtypes of lung cancer. Still, some patients suffer from relapsed disease and metastatic spread while no consensus treatment exists for metastasized carcinoids. Several recent single-cell studies have provided detailed insights into the cellular heterogeneity of more common lung cancers, such as adeno- and squamous cell carcinoma. However, the characteristics of lung carcinoids on the single-cell level are yet completely unknown. To study the cellular composition and single-cell gene expression profiles in lung carcinoids, we applied single-cell RNA sequencing to three lung carcinoid tumor samples and normal lung tissue. The single-cell transcriptomes of carcinoid tumor cells reflected intertumoral heterogeneity associated with clinicopathological features, such as tumor necrosis and proliferation index. The immune microenvironment was specifically enriched in noninflammatory monocyte-derived myeloid cells. Tumor-associated endothelial cells were characterized by distinct gene expression profiles. A spectrum of vascular smooth muscle cells and pericytes predominated the stromal microenvironment. We found a small proportion of myofibroblasts exhibiting features reminiscent of cancer-associated fibroblasts. Stromal and immune cells exhibited potential paracrine interactions which may shape the microenvironment via NOTCH, VEGF, TGF{beta} and JAK/STAT signaling. Moreover, single-cell gene signatures of pericytes and myofibroblasts demonstrated prognostic value in bulk gene expression data. Here, we provide first comprehensive insights into the cellular composition and single-cell gene expression profiles in lung carcinoids, demonstrating the non-inflammatory and vessel-rich nature of their tumor microenvironment, and outlining relevant intercellular interactions which could serve as future therapeutic targets.

cancer biology↗

bioRxiv2021

Archival influenza virus genomes from Europe reveal genomic and phenotypic variability during the 1918 pandemic

The 1918 influenza pandemic was the deadliest respiratory pandemic of the 20th century and determined the genomic make-up of subsequent human influenza A viruses (IAV). Here, we analyze the first 1918 IAV genomes from Europe and from the first, milder wave of the pandemic. 1918 IAV genomic diversity is consistent with local transmission and frequent long-distance dispersal events and in vitro polymerase characterization suggests potential phenotypic variability. Comparison of first and second wave genomes shows variation at two sites in the nucleoprotein gene associated with resistance to host antiviral response, pointing at a possible adaptation of 1918 IAV to humans. Finally, phylogenetic estimates based on extended molecular clock modelling suggests a pure pandemic descent of seasonal H1N1 IAV as an alternative to the hypothesis of an intrasubtype reassortment origin. One Sentence SummaryMuch can be learned about past pandemics by uncovering their footprints in medical archives, which we here demonstrate for the 1918 flu pandemic.

microbiology↗

bioRxiv2020

Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma

Recent developments in immuno-oncology demonstrate that not only cancer cells, but also features of the tumor microenvironment guide precision medicine. Still, the relationship between tumor and microenvironment remains poorly understood. To overcome this limitation and identify clinically relevant microenvironmental and cancer features, we applied single-cell RNA sequencing to lung adenocarcinomas. While the highly heterogeneous carcinoma cell transcriptomes reflected histological grade and activity of relevant oncogenic pathways, our analysis revealed two distinct microenvironmental patterns. We identified a prognostically unfavorable group of tumors with a microenvironment composed of cancer-associated myofibroblasts, exhausted CD8+ T cells, proinflammatory monocyte-derived macrophages and plasmacytoid dendritic cells (CEP2 pattern) and a prognostically favorable group characterized by myeloid dendritic cells, anti-inflammatory monocyte-derived macrophages, normal-like myofibroblasts, NK cells and conventional T cells (MAN2C pattern). Our results show that single-cell gene expression profiling allows to identify patient subgroups based on the tumor microenvironment beyond cancer cell-centric profiling.

cancer biology↗

bioRxiv2020

An Integrative Genetic, Epigenetic and Proteomic Characterization of Pancreatic Neuroendocrine Neoplasms (PanNENs) defines Distinct Molecular Features of α- and β-cell like Subgroups

Pancreatic Neuroendocrine Carcinomas (PanNECs) are high-grade, poorly-differentiated tumors grouped together with Pancreatic Neuroendocrine Tumors (PanNETs) and placed within the Pancreatic Neuroendocrine Neoplasms (PanNENs) WHO tumor classification. Despite recent studies suggesting the endocrine origin of low-grade PanNETs, high-grade PanNEC origin remains unknown. DNA methylation analysis using the Illumina 850K beadchip array was conducted on 57 PanNEN samples, including 14 PanNECs. Distinct methylation profiles separated PanNEN samples into two major groups, clearly distinguishing high-grade PanNECs from other PanNETs including high-grade NETG3. DNA mutations, copy number changes and Immunohistochemistry of pancreatic cell-type markers PDX1, ARX and SOX9 were utilized to further characterize PanNECs and their hierarchical cell of origin in the pancreas. Phylo-epigenetic and cell-type signature features using methylation data from normal alpha, beta, acinar and ductal adult cells indicate an exocrine cell of origin for PanNECs, thus separating them in cell lineage from other PanNENs of endocrine origin. Our study provides a robust and clinically relevant method relying on methylation profiles to clearly distinguish PanNECs from PanNETG3s to improve patient stratification and treatment.

cancer biology↗

bioRxiv2020

Olfactory transmucosal SARS-CoV-2 invasion as port of Central Nervous System entry in COVID-19 patients

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease presenting with fever, cough, and often pneumonia. Moreover, thromboembolic events throughout the body including the central nervous system (CNS) have been described. Given first indication for viral RNA presence in the brain and cerebrospinal fluid and in light of neurological symptoms in a large majority of COVID-19 patients, SARS-CoV-2-penetrance of the CNS is likely. By precisely investigating and anatomically mapping oro- and pharyngeal regions and brains of 32 patients dying from COVID-19, we not only describe CNS infarction due to cerebral thromboembolism, but also demonstrate SARS-CoV-2 neurotropism. SARS-CoV-2 enters the nervous system via trespassing the neuro-mucosal interface in the olfactory mucosa by exploiting the close vicinity of olfactory mucosal and nervous tissue including delicate olfactory and sensitive nerve endings. Subsequently, SARS-CoV-2 follows defined neuroanatomical structures, penetrating defined neuroanatomical areas, including the primary respiratory and cardiovascular control center in the medulla oblongata.

neuroscience↗

bioRxiv2020

A census of cell types and paracrine interactions in colorectal cancer

In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue lacking visible organization. We sought to define colorectal cancer cell types and signals controlling their development. More than 30,000 epithelial single cell transcriptomes of tumors and matched non-cancerous tissues of twelve colorectal cancer patients were clustered into six patient-overarching groups defined by differential activities of oncogenic signaling pathways such as mitogen-activated protein kinase and oncogenic traits such as replication stress. RNA metabolic labeling and assessment of RNA velocity in patient-derived organoids revealed developmental trajectories of colorectal cancer cells organized along a mitogen-activated protein kinase activity gradient. This was in contrast to normal colon organoid cells developing along graded Wnt activity. Experimental targeting of EGFR-BRAF-MEK in cancer organoids affected signaling and gene expression contingent on predictive KRAS/BRAF mutations and induced cell plasticity overriding default developmental trajectories, providing a basis for non-genetic resistance to targeted therapies.

cancer biology↗

bioRxiv2019

The history of measles: from a 1912 genome to an antique origin

Many infectious diseases are thought to have emerged in humans after the Neolithic revolution. While it is broadly accepted that this also applies to measles, the exact date of emergence for this disease is controversial. Here, we sequenced the genome of a 1912 measles virus and used selection-aware molecular clock modeling to determine the divergence date of measles virus and rinderpest virus. This divergence date represents the earliest possible date for the establishment of measles in human populations. Our analyses show that the measles virus potentially arose as early as the 4th century BCE, rekindling the recently challenged hypothesis of an antique origin of this disease. One Sentence SummaryMeasles virus diverged from rinderpest virus in the 4th century BCE, which is compatible with an emergence of measles during Antiquity.

evolutionary biology↗