Biology subjects

Morris, M.

Publications and source records attributed to Morris, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Neuronal Hyperactivity Induces Tau Phosphorylation Selectively in Excitatory Pyramidal Neurons Which Contributes to GluA2 Regulation

While tau plays a role in regulating neuronal network excitability, a process thought to be dysregulated in Alzheimers disease (AD), the molecular mechanisms linking tau and hyperexcitability remain unclear. To investigate interactions between endogenous tau and neuronal activity, we increased neuronal activity using bicuculline or suppressed activity using tetrodotoxin for 24 hours in rat hippocampal neurons. Chronic neuronal hyperactivity increased dendritic tau phosphorylation at S202/T205. This response was observed only in excitatory CA1 and CA3 pyramidal neurons, but not in inhibitory or dentate granule neurons. Dendritic phospho-tau positively correlated with neuronal activation after bicuculline treatment, as measured by cfos expression, and was prevented with inhibition of protein kinase A (PKA). To examine the functional consequences of tau S202/T205 phosphorylation, hippocampal neurons were transfected with wild-type tau or tau containing mutations preventing phosphorylation at these sites. Wildtype tau overexpression increased tau phosphorylation and reduced neuronal surface GluA2, which was prevented by phospho-site mutation. Extending these findings to mice, chronic low-dose picrotoxin treatment increased endogenous S202/T205 tau phosphorylation in CA3 neurons. In picrotoxin-treated mice, cfos expression was associated with increased tau phosphorylation specifically in CA3 and CA1 neurons. Together, these findings identify activity-dependent, endogenous tau phosphorylation as a selective response to hyperexcitation in excitatory hippocampal neurons downstream of PKA activation. The data further link tau phosphorylation to altered GluA2 regulation, suggesting a potential molecular connection between neuronal hyperactivity, tau phosphorylation, and synaptic dysfunction relevant to AD.

neuroscience↗

bioRxiv2026

Fine-tuning genomic models on rare splicing events identifies a novel biomarker of TDP-43 pathology

Genomic foundation models (GFMs) are pretrained on large genomic datasets, but their ability to predict rare disease-associated events after fine-tuning remains unclear. We tested this using TDP-43 cryptic exons, well characterized splicing events linked to neurodegenerative disease that are poorly represented in standard annotations. We compared the state-of-the-art GFM AlphaGenome with OpenSpliceAI, a specialized splice site prediction model. Fine-tuned OpenSpliceAI detected held-out cryptic exons in human and mouse and captured allele-specific splicing effects at the disease-associated UNC13A locus. In contrast, a splicing prediction head trained on AlphaGenome's frozen pretrained backbone failed to predict cryptic exons. Unfreezing and fine-tuning all model weights, however, enabled AlphaGenome to generalize to held-out data. To investigate cryptic splicing in cell types that are difficult to study experimentally, we applied fine-tuned OpenSpliceAI across the genome to study cell type-specific genes. This led to the identification of new cryptic splicing events in CLDN11 and ARHGAP23, which were subsequently validated in FTLD-TDP brain tissue. Notably, the cryptic exon in CLDN11 is predicted to generate a neoepitope that could serve as an oligodendrocyte-specific biomarker of TDP-43 pathology. Our results show that even a state-of-the-art GFM can fail to generalize to rare splicing events, even with substantial pretraining. However, both foundation and specialized models that learn to generalize to rare biological events can have broad applications in biological discovery and medicine.

genomics↗

bioRxiv2026

Discovery of A Multi-Class Antibiotic Potentiator Against Resistant Klebsiella pneumoniae

The rapid rise of multidrug-resistant (MDR) bacterial infections has severely limited treatment options, particularly for Gram-negative pathogens such as Klebsiella pneumoniae, a leading contributor to pneumonia, bloodstream, urinary tract, and surgical-site infections. One strategy to restore antibiotic efficacy is the use of resistance-mitigating agents (RMAs), compounds that re-sensitize bacteria to existing antibiotics without displaying independent antibacterial activity. Herein, we report the results of a high-throughput screen of a 3,200-compound fragment-based library against an MDR K. pneumoniae isolate in the presence of subinhibitory ciprofloxacin. This screen identified a tetrahydrocarbazole-containing compound, 1, as a ciprofloxacin potentiator. Subsequent structure-activity relationship studies yielded a difluorinated analog, compound 5, which potentiated multiple antibiotic classes in MDR K. pneumoniae, reducing MICs up to [≥]16 fold. Further testing demonstrated synergistic interactions between compound 5 and ciprofloxacin, ceftriaxone, cefoxitin, and tetracycline across four genetically diverse MDR K. pneumoniae strains. These findings suggest that tetrahydrocarbazole-containing compounds constitute a promising new class of RMAs with potential for future development as therapies against MDR K. pneumoniae infections.

microbiology↗

bioRxiv2026

The metabolic resistance blueprint: Genomic dissection of DDT resistance in historical kdr-free East African Anopheles gambiae

Insecticide resistance in Anopheles gambiae poses a significant threat to malaria control and eradication efforts across sub-Saharan Africa. While target-site resistance mechanisms are well-characterised, the evolutionary origins of metabolic resistance remain poorly understood. We employed bulk segregant analysis (BSA) using unique historical genetic crosses established in the late 1990s between a DDT-resistant ZAN/U strain (Originally from Zanzibar) and a susceptible strain to map the genomic architecture of early metabolic resistance. Critically, the ZAN/U strain exhibited DDT resistance without kdr mutations, providing an ideal genetic background for isolating glutathione S-transferase epsilon (GSTe)-mediated resistance mechanisms that evolved during the DDT control program era. BSA analysis revealed a major quantitative trait locus on chromosome 3R spanning the GSTe gene cluster (GSTe1-8). BSA identified 20 significant amino acid substitutions distributed across all eight GSTe genes, in addition to variations in the promoter region of GSTe2 and GSTe3, which were previously determined to be overexpressed in the ZAN/U strain. East African field-collected samples from the MalariaGEN Ag1000G project confirmed that many of these mutations are under long-term selection pressure in natural populations. This work provides a characterisation of the GSTe clusters role in establishing the metabolic resistance foundation that continues to compromise vector control efforts today. Additionally, BSA analysis was performed on progeny from crosses established in early 2000s between a permethrin-resistant RSP-ST strain originating from Western Kenya and a susceptible strain, identifying expected target-site resistance at the vgsc locus.

genomics↗

bioRxiv2026

Multi-omics analysis identifies loci associated with pyrethroid resistance across sister species in the Anopheles gambiae species complex

The Anopheles gambiae species complex includes An. gambiae, An. coluzzii, and An. arabiensis, three of the four major malaria vector species across Africa. Insecticide-based vector control remains the most critical tool in the fight against malaria, with a heavy reliance on pyrethroid insecticides. However, widespread pyrethroid resistance jeopardises the effectiveness of these methods. Currently, the number of diagnostic markers available to track pyrethroid resistance in endemic settings is limited, focusing mainly on changes at the insecticide target site. Genetic analysis of seven insecticide-resistant populations from West Africa, a region with intense insecticide resistance, reveals shared loci associated with pyrethroid resistance among the sister species of the An. gambiae complex including kdr, GSTE1-8 and the CYP6P region. Notably, a mutation in the voltage-gated sodium channel, I1527T, previously identified in An. coluzzii and An. gambiae, was detected in wild-caught An. arabiensis from Burkina Faso. Additionally, a mutation, L207I, in GSTE7 common to An. coluzzii and An. arabiensis, significantly increases survivorship to deltamethrin. With the additional integration of RNAseq and data from the Anopheles gambiae 1000 genomes project, we were able to identify putative eQTLs associated with the expression of major insecticide resistance-related transcripts, such as CYP6P3, CYP9K1 and CYP6AA1. This study reveals several potential diagnostic markers of resistance that can be implemented in endemic settings and identifies putative introgression between An. arabiensis and An. coluzzii in Burkina Faso.

genetics↗

bioRxiv2025

High-throughput screening reveals mechanisms of environmental control of germination in a fungal thermophile

Thermothelomyces thermophilus is a filamentous fungus isolated from self-heating compost. Unlike most of the fungal kingdom, this species exhibits a growth optimum at 45{degrees}C and is intolerant of temperatures below 30{degrees}C. To investigate genetic contributors to temperature-dependent fitness in this system, we implemented a large-scale insertional mutagenesis approach. We generated thousands of T. thermophilus mutants and cultured them at temperature extremes in standard medium. Phenotyping-by-sequencing identified dozens of disrupted loci representing candidate determinants of thermophilic life history, including several annotated in metal transport. We then validated a subset of screen hits with a directed, single-gene knockout paradigm. The results revealed a temperature-dependent regulatory logic for germination, the developmental decision by which a fungal spore initiates growth. Surprisingly, most mutants germinated far better at 50{degrees}C than the wild-type in standard medium and showed markedly slower germination at lower temperatures, consistent with altered germination regulation rather than enhanced intrinsic heat tolerance. We hypothesized that T. thermophilus has evolved sophisticated regulatory machinery to block germination at high temperature unless environmental conditions are favorable. As a proof of concept, we surveyed media conditions and established that elevated zinc dampened germination of wild-type T. thermophilus at 50{degrees}C but promoted it at lower temperature; mutation experiments made clear that such sensitivity was mediated in part by the zinc transporter zip. We interpret these results under a model in which T. thermophilus integrates temperature and nutrient availability to control the transition from spore dormancy to vegetative growth, a developmental decision that shapes fitness outcomes across temperatures. SignificanceFungal thermophiles thrive at temperatures that represent the upper limits of eukaryotic life. The regulatory and developmental mechanisms that shape their temperature-dependent fitness remain poorly understood. In this work, we elucidate how Thermothelomyces thermophilus integrates temperature cues with other environmental inputs during germination, a key life-cycle stage for dispersal. Our findings highlight germination regulation as an important contributor to fitness at elevated temperatures in a thermophilic eukaryote. These insights are of basic biological interest and provide a foundation for rational strategies to modulate temperature-dependent performance in industrial strains, with applications for high-temperature bioprocessing.

microbiology↗

bioRxiv2025

Constitutive NF-kB Activation is Amplified by VSV in Aggressive PC3 Prostate Cancer Cells that Resist Viral Oncolysis

Cancer cells often have defects in antiviral pathways, making them susceptible to oncolytic viruses like vesicular stomatitis virus (VSV). However, some cancer cells resist viral infection through the constitutive expression of interferon-stimulated genes. This study examined whether NF-{kappa}B activation and NF-{kappa}B-dependent antiviral signaling contributes to resistance to VSV infection in the PC3 cell line, derived from an aggressive metastatic prostate cancer (PrCa) tumor. We found that NF-{kappa}B localized to the nucleus in VSV-infected PC3 cells, but not in the VSV-susceptible LNCaP PrCa cell line. Analysis of the upstream NF-{kappa}B inhibitor I{kappa}B- revealed higher levels of both total and phosphorylated I{kappa}B- in PC3 cells compared to LNCaP cells, indicating constitutive activation of the NF-{kappa}B pathway via an I{kappa}B--dependent mechanism. Notably, VSV infection did not alter I{kappa}B- phosphorylation in PC3 cells, suggesting that VSV may amplify NF-{kappa}B signaling through an I{kappa}B--independent pathway. Furthermore, PC3 cells displayed elevated levels of the NF-{kappa}B p65 protein subunit compared to LNCaP cells, with its phosphorylated form significantly increased upon VSV infection. These results from phosphorylation assays confirm that multiple steps in the NF-{kappa}B pathway are differentially activated in PC3 and LNCaP cells. Additionally, the expression of several NF-{kappa}B-dependent cytokine and proinflammatory genes, including IL12 and IL6, were upregulated following VSV infection in PC3 cells, as compared to LNCaP cells. Blocking the NF-{kappa}B pathway using a pharmaceutical inhibitor resulted in increased PC3 cell death with VSV infection. Collectively, these findings suggest that enhanced NF-{kappa}B signaling may underlie the resistance of PC3 cells to VSV oncolysis, potentially offering new insights into therapeutic strategies targeting NF-{kappa}B in resistant prostate cancers.

cancer biology↗

bioRxiv2025

Long-Term Potentiation and Closed-Loop Learning in Paired Brain Organoids for CNS Drug Discovery

Learning and memory, central to cognitive function and critical targets for drug discovery in neurological disorders, fundamentally rely on synaptic plasticity, such as long-term potentiation (LTP). We developed an embedded electrode array (EEA) capable of supporting paired CNS-3D brain organoids, derived from human, induced pluripotent stem cells (iPSCs), that were interconnected via guided axonal growth, as a novel functional biomarker model for probing learning-related plasticity in vitro. Using open-loop stimulation protocols, a robust, network-level LTP in trained organoids was demonstrated that was not observed in untrained organoids. Importantly, LTP was enhanced in the presence of elevated levels of brain-derived neurotrophic factor (BDNF), and it was prevented by the NMDA receptor antagonist AP5. Furthermore, a closed-loop "maze-game", inspired by Pac-Man(R), demonstrated that paired brain organoids could learn to perform better in the game when given reinforcement feedback, and that this effect depended on BDNF. This integrated platform provides a human-relevant in vitro model of synaptic plasticity and cognitive function, establishing a functional biomarker platform for central nervous system (CNS) drug discovery and linking game performance as a measurable readout of learning-related plasticity to the emerging field of organoid intelligence.

bioengineering↗

bioRxiv2025

Metabolic reprogramming by endothelial ANGPTL4 depletion protects against diabetic kidney disease

The role of cell-specific ANGPTL4 is not well known in the context of ECs, specifically in pathological angiogenesis and its relation to diabetic kidney disease. Here, we demonstrate that endothelial ANGPTL4 is required to induce a metabolic phenotype that favors mesenchymal activation in ECs and tubules in diabetic conditions. Diabetes accelerates mesenchymal activation and fibrogenesis in control mice however, the same effects were not observed in endothelial-cell specific knock out mice. This mesenchymal activation in diabetes is directly linked with pathological neovascularization, endothelial leakage, lipid and glycolysis metabolite load, de novo lipogenesis (DNL) and related mitochondrial damage, activation of the immune system, c-GAS-STING activation and transcription of pro-inflammatory cytokines. However, endothelial ANGPTL4-depleted mice had stable vessels, improved levels of lipid and glucose metabolism, suppressed levels of DNL, restored mitochondrial function, and mitigated levels of c-GAS-STING-mediated inflammation. Moreover, Inhibition of DNL, and STING via small molecule inhibitors suppressed pathological neovascularization and endothelial leakage, normalized fatty acid oxidation and reduced pathological glycolysis and de novo lipogenesis (DNL). These data demonstrate the crucial roles of endothelial ANGPTL4 in regulating pathogenic angiogenesis in the renal vasculature during diabetes.

molecular biology↗

bioRxiv2025

The origin, invasion history and resistance architecture of Anopheles stephensi in Africa.

The invasion of Africa by the Asian urban malaria vector, Anopheles stephensi, endangers 126 million people across a rapidly urbanising continent where malaria is primarily a rural disease. Control of An. stephensi requires greater understanding of its origin, invasion dynamics, and mechanisms of widespread resistance to vector control insecticides. We present a genomic surveillance study of 551 An. stephensi sampled across the invasive and native ranges in Africa and Asia. Our findings support a hypothesis that an initial invasion from Asia to Djibouti seeded separate incursions to Sudan, Ethiopia, and Yemen before spreading inland, aided by favourable temperature, vegetation cover, and human transit conditions. Insecticide resistance in invasive An. stephensi is conferred by detoxification genes introduced from Asia. These findings, and a companion genomic data catalogue, will form the foundation of an evidence base for surveillance and management strategies for An. stephensi.

genomics↗

bioRxiv2025

mzLearn, a data-driven LC/MS signal detection algorithm, enables pre-trained generative models for untargeted metabolomics

Metabolite alterations are linked to diseases, yet large-scale untargeted metabolomics remains constrained by challenges in signal detection and integration of diverse datasets for developing pre-trained generative models. Here, we introduce mzLearn, a data-driven MS1 signal-detection and alignment method that runs from mzML files without user-set parameters. Across 15 public datasets, mzLearn detects 11,442 signals on average vs 7,100 (XCMS) and 4,655 (ASARI), with higher TP (89.0% vs 77.4% vs 49.6%) and lower FP (12.5% vs 17.3% vs 18.8%), while correcting instrument drifts across large cohorts without experimental QC samples. mzLearn detected 2,736 robust metabolite signals from 22 public studies (20,548 blood samples), enabling the development of pre-trained variational autoencoder for untargeted metabolomics. Learned metabolite representations reflected demographic data and when fine-tuned on unseen renal cell carcinoma data, improved risk stratification and overall survival predictions, while feature-importance analysis (SHAP) highlighted biologically plausible lipid and carnitine signals. By producing a consistent, high-quality MS1 feature matrix at scale, mzLearn paves the way for developing pre-trained foundation models for untargeted metabolomics.

bioinformatics↗

bioRxiv2024

Discovery of active mouse, plant and fungal cytochrome P450s in endogenous proteomes and upon expression in planta.

Eukaryotes produce a large number of cytochrome P450s that mediate the synthesis and degradation of diverse endogenous and exogenous metabolites. Yet, most of these P450s are uncharacterized and global tools to study these challenging, membrane-resident enzymes remain to be exploited. Here, we applied activity profiling of plant, mouse and fungal P450s with chemical probes that become reactive when oxidized by P450 enzymes. Identification by mass spectrometry revealed labeling of a wide range of active P450s, including six plant P450s, 40 mouse P450s and 13 P450s of the fungal wheat pathogen Zymoseptoria tritici. We next used transient expression of GFP-tagged P450s by agroinfiltration to show ER-targeting and NADPH-dependent, activity-based labeling of plant, mouse and fungal P450s. Both global profiling and transient expression can be used to detect a broad range of active P450s to study e.g. their regulation and discover selective inhibitors.

plant biology↗

bioRxiv2023

Genome evolution is surprisingly predictable after initial hybridization

Over the past two decades, evolutionary biologists have come to appreciate that hybridization, or genetic exchange between distinct lineages, is remarkably common - not just in particular lineages but in taxonomic groups across the tree of life. As a result, the genomes of many modern species harbor regions inherited from related species. This observation has raised fundamental questions about the degree to which the genomic outcomes of hybridization are repeatable and the degree to which natural selection drives such repeatability. However, a lack of appropriate systems to answer these questions has limited empirical progress in this area. Here, we leverage independently formed hybrid populations between the swordtail fish Xiphophorus birchmanni and X. cortezi to address this fundamental question. We find that local ancestry in one hybrid population is remarkably predictive of local ancestry in another, demographically independent hybrid population. Applying newly developed methods, we can attribute much of this repeatability to strong selection in the earliest generations after initial hybridization. We complement these analyses with time-series data that demonstrates that ancestry at regions under selection has remained stable over the past [~]40 generations of evolution. Finally, we compare our results to the well-studied X. birchmannixX. malinche hybrid populations and conclude that deeper evolutionary divergence has resulted in stronger selection and higher repeatability in patterns of local ancestry in hybrids between X. birchmanni and X. cortezi.

evolutionary biology↗

bioRxiv2023

A foundational atlas of autism protein interactions reveals molecular convergence

Translating high-confidence (hc) autism spectrum disorder (ASD) genes into viable treatment targets remains elusive. We constructed a foundational protein-protein interaction (PPI) network in HEK293T cells involving 100 hcASD risk genes, revealing over 1,800 PPIs (87% novel). Interactors, expressed in the human brain and enriched for ASD but not schizophrenia genetic risk, converged on protein complexes involved in neurogenesis, tubulin biology, transcriptional regulation, and chromatin modification. A PPI map of 54 patient-derived missense variants identified differential physical interactions, and we leveraged AlphaFold-Multimer predictions to prioritize direct PPIs and specific variants for interrogation in Xenopus tropicalis and human forebrain organoids. A mutation in the transcription factor FOXP1 led to reconfiguration of DNA binding sites and altered development of deep cortical layer neurons in forebrain organoids. This work offers new insights into molecular mechanisms underlying ASD and describes a powerful platform to develop and test therapeutic strategies for many genetically-defined conditions.

systems biology↗

bioRxiv2023

Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease

Angiopoietin-like 4 (ANGPTL4) is the key protein involved in lipoprotein metabolism and has been shown to have diverse effects on tissue protection. In clinical settings, there is a reported association between higher levels of plasma Angptl4 and features of diabetic kidney disease, however, the association between kidney Angptl4 with features of diabetic kidney disease has not been well investigated. We show that both podocyte-and tubule-specific ANGPTL4 are crucial fibrogenic molecules in diabetes. Results from mRNA-array analysis in control (non-fibrotic) and diabetic (fibrotic) kidneys suggest time-dependent emergence of Angplt4 expression. Diabetes accelerates the fibrogenic phenotype in control mice but not in ANGPTL4 mutant mice. The protective effect observed in ANGPTL4 mutant mice is correlated with a reduction in the levels of pro-inflammatory cytokines, epithelial-to-mesenchymal transition, endothelial-to-mesenchymal transition and augmented fatty acid oxidation. Mechanistically, we demonstrate that podocyte-or tubule-secreted Angptl4 interacts with Integrin-{beta}1 and influences the association between dipeptidyl-4 with Integrin-{beta}1 and promotes heterodimerization of transforming growth factor-{beta} receptor 1 (TGF{beta}R1) and TGF{beta}R2 in cultured cells. This in turn results in Smad3 phosphorylation and subsequent downregulation of the expression of genes involved in fatty acid oxidation; these cumulative effects led to the activation of fibrogenic phenotypes. We demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the kidneys and protects diabetic kidneys from proteinuria and fibrosis. Importantly, use of this kidney-specific targeted strategy is beneficial and does not cause any harmful effect suggesting it can be used as a novel drug molecule for treatment of diabetic kidney disease. Taken together, these data demonstrate that podocyte-and tubule-derived Angptl4 is fibrogenic in diabetic kidneys.

cell biology↗

bioRxiv2023

"Tranq-Dope" Overdose and Mortality: Lethality Induced by Fentanyl and Xylazine

The recreational use of fentanyl in combination with xylazine (i.e., "tranq-dope") represents a rapidly emerging public health threat characterized by significant toxicity and mortality. This study quantified the interactions between these drugs on lethality and examined the effectiveness of potential rescue medications to prevent a lethal overdose. Male and female mice were administered acute doses of fentanyl, xylazine, or their combination via intraperitoneal injection, and lethality was determined 30, 60, 90, 120, and 1440 min (24 hr) after administration. Both fentanyl and xylazine produced dose-dependent increases in lethality when administered alone. A nonlethal dose of fentanyl (56 mg/kg) produced an approximately 5-fold decrease in the estimated LD50 for xylazine (i.e., the dose estimated to produce lethality in 50% of the population). Notably, a nonlethal dose of xylazine (100 mg/kg) produced an approximately 100-fold decrease in the estimated LD50 for fentanyl. The opioid receptor antagonist, naloxone (3 mg/kg), but not the alpha-2 adrenergic receptor antagonist, yohimbine (3 mg/kg), significantly decreased the lethality of a fentanyl-xylazine combination. Lethality was rapid, with death occurring within 10 min after a high dose combination and generally within 30 min at lower dose combinations. Males were more sensitive to the lethal effects of fentanyl-xylazine combinations under some conditions, suggesting biologically relevant sex differences in sensitivity to fentanyl-xylazine lethality. These data provide the first quantification of the lethal effects of "tranq-dope" and suggest that rapid administration of naloxone may be effective at preventing death following overdose.

pharmacology and toxicology↗

bioRxiv2022

Recurrent evolution of small body size and loss of the sword ornament in Northern Swordtail fish

Across the tree of life, species have repeatedly evolved similar phenotypes. While well-studied for ecological traits, there is also evidence for convergent evolution of sexually selected traits. Swordtail fish (Xiphophorus) are a classic model system for studying sexual selection, and female Xiphophorus exhibit strong mate preferences for large male body size and a range of sexually dimorphic ornaments. However, sexually selected traits have been lost multiple times in the genus. Phylogenetic relationships between species in this group have historically been controversial, likely as a result of prevalent gene flow, resulting in uncertainty over the number of losses of ornamentation and large body size. Here, we use whole-genome sequencing approaches to re-examine phylogenetic relationships within a Xiphophorus clade that varies in the presence and absence of sexually selected traits. Using wild-caught individuals, we determine the phylogenetic placement of a small, unornamented species, X. continens, confirming an additional loss of ornamentation and large body size in the clade. With these revised phylogenetic relationships, we analyze evidence for coevolution between body size and other sexually selected traits using a phylogenetically independent contrasts approach. These results provide insights into the evolutionary pressures driving the recurrent loss of suites of sexually selected traits.

evolutionary biology↗

bioRxiv2021

Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients

Progression to metastatic disease remains the main cause of cancer death. Yet, the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we present MSK-MET, an integrated pan-cancer cohort of tumor genomic and clinical outcome data from more than 25,000 patients. We analyzed this dataset to identify associations between tumor genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma and HR-positive breast ductal carcinoma, but not in others, such as colorectal adenocarcinoma, pancreatic adenocarcinoma and high-grade serous ovarian cancer. We also identified specific somatic alterations associated with increased metastatic burden and specific routes of metastatic spread. Our data offer a unique resource for the investigation of the biological basis for metastatic spread and highlight the crucial role of chromosomal instability in cancer progression.

cancer biology↗