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PubMed2025

LKB1 inactivation promotes epigenetic remodeling-induced lineage plasticity and antiandrogen resistance in prostate cancer.

Epigenetic regulation profoundly influences the fate of cancer cells and their capacity to switch between lineages by modulating essential gene expression, thereby shaping tumor heterogeneity and therapy response. In castration-resistant prostate cancer (CRPC), the intricacies behind androgen receptor (AR)-independent lineage plasticity remain unclear, leading to a scarcity of effective clinical treatments. Utilizing single-cell RNA sequencing on both human and mouse prostate cancer samples, combined with whole-genome bisulfite sequencing and multiple genetically engineered mouse models, we investigated the molecular mechanism of AR-independent lineage plasticity and uncovered a potential therapeutic strategy. Single-cell transcriptomic profiling of human prostate cancers, both pre- and post-androgen deprivation therapy, revealed an association between liver kinase B1 (LKB1) pathway inactivation and AR independence. LKB1 inactivation led to AR-independent lineage plasticity and global DNA hypomethylation during prostate cancer progression. Importantly, the pharmacological inhibition of TET enzymes and supplementation with S-adenosyl methionine were found to effectively suppress AR-independent prostate cancer growth. These insights shed light on the mechanism driving AR-independent lineage plasticity and propose a potential therapeutic strategy by targeting DNA hypomethylation in AR-independent CRPC.

Male↗
PubMed2026

Reversing-or Rewiring-Lineage Plasticity? Lessons from EZH2 Loss in Prostate Cancer.

Enhancer of zeste homolog 2 (EZH2) inhibitors have been proposed to counteract lineage plasticity (LP) in prostate cancer and thereby resensitize tumors to androgen receptor (AR) inhibition. In this issue of Cancer Research, Jacobi and colleagues provide new mechanistic insights into EZH2 biology across prostate cancer progression using a genetically engineered mouse model that recapitulates the transition toward a neuroendocrine (NE) phenotype. Unexpectedly, genetic deletion of Ezh2 did not reverse LP but instead promoted the diversification of transcription factor (TF) programs driving NE differentiation. In particular, the loss of EZH2 activated members of the KLF TF family, which contributed to this transcriptional diversification. Moreover, EZH2 deletion altered the chromatin-binding landscape of AR, redirecting it toward KLF-associated genomic sites. Collectively, these results refine our understanding of EZH2 function in prostate cancer: Rather than simply reversing LP, EZH2 loss rewires transcriptional networks and reshapes the AR cistrome. These findings are timely given the growing number of clinical trials testing EZH2 inhibitors in metastatic prostate cancer and highlight the need to define when and how to deploy EZH2 inhibition to exploit its effects on tumor lineage dynamics. See related article by Jacobi et al., p. 889.

Male↗
PubMed2026

EZH2 Suppression Diversifies Prostate Cancer Lineage Variant Evolution and Lacks Efficacy in Inhibiting Disease Progression.

UNLABELLED: Advanced prostate cancer remains a leading cause of cancer-related death among men due to disease progression in nearly all patients on standard-of-care therapy targeting the androgen receptor. An important mechanism driving therapeutic resistance is lineage plasticity, which enables prostate cancer cells to reprogram into lineage variants no longer dependent on androgen receptor signaling. As inhibitors of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) are being evaluated clinically for the treatment of advanced prostate cancer, we investigated in this study how EZH2 affects prostate cancer lineage plasticity. Data from genetically engineered mice and human clinical samples demonstrated that genetic or pharmacologic suppression of EZH2 altered chromatin to expand active transcription factor programs. These changes in gene expression during prostate cancer progression increased the diversity of prostate cancer lineage variants that arose. EZH2 suppression did not inhibit disease progression nor therapeutic resistance in this context. These findings advance the current understanding of prostate cancer lineage plasticity and suggest that EZH2 inhibitors may be less effective in treating prostate cancer prone to lineage plasticity. SIGNIFICANCE: EZH2 suppression diversifies prostate cancer lineage plasticity, which has implications for EZH2-targeted therapies that are being evaluated for prostate cancer treatment. See related commentary by Thienger et al., p. 827.

Enhancer of Zeste Homolog 2 Protein↗
PubMed2026

Mirror worlds: The shared regulatory architecture of cell fate in development and cancer.

Lineage plasticity has emerged as a central mechanism through which cancer cells adapt to therapeutic pressure, evade immune surveillance, and acquire aggressive phenotypes. Although recognized across tumor types, the regulatory principles governing how cancer cells reprogram cellular identity remain incompletely understood. In this review, we propose that lineage plasticity in cancer reflects the redeployment of regulatory frameworks established during normal development. Rather than representing a stochastic byproduct of genomic instability, cancer plasticity frequently unfolds within gene regulatory architectures that also govern cell fate specification, lineage commitment, and controlled state transitions during embryogenesis and tissue homeostasis. Developmental transcription factors, including members of the SOX family, FOXA1, ASCL1, NKX2-1, and epithelial-mesenchymal transition regulators, function as lineage gatekeepers during development but are repurposed in cancer to destabilize lineage commitment and enable phenotypic switching. Similarly, epigenetic regulators that guide developmental trajectories, including chromatin remodeling complexes, Polycomb group proteins, and DNA methylation machinery, are frequently dysregulated or redistributed in tumors, altering the repression of lineage-stabilizing and alternative lineage programs and thereby weakening epigenetic barriers to lineage transitions. Together, these observations support a model in which development and cancer operate as mirror regulatory systems: one establishing and stabilizing cellular identity, the other exploiting the same regulatory architecture to permit adaptive reprogramming under selective pressure. We further discuss how emerging single-cell and spatial multi-omics technologies, integrated with artificial intelligence-based modeling, enable mapping of cell state landscapes and transitional trajectories, transforming lineage plasticity from a descriptive phenomenon into a measurable and predictable property of tumor evolution.

Humans↗
PubMed2026

Epithelial tumor suppressor deletion promotes neuroendocrine differentiation in bladder cancer and reveals homoharringtonine as a candidate vulnerability.

Neuroendocrine bladder carcinoma (NEBC) is a highly aggressive malignancy with unresolved lineage determinants and limited preclinical models, hindering mechanistic investigation and therapeutic development. Here, we sought to assess whether bladder epithelial-derived models are competent to acquire neuroendocrine lineage programs under defined tumor suppressor alterations and to identify candidate therapeutic vulnerabilities in these systems. We integrated genomic and transcriptomic analyses of human NEBC with genetically engineered mouse models, epithelial-derived bladder organoids, and patient-derived NEBC models. Human NEBC exhibited dominant RB1 and TP53 alterations and an epithelial transcriptional continuum consistent with lineage plasticity. In vivo, intravesical Adeno-Cre-mediated tumor suppressor deletion predominantly generated sarcoma-like tumors, whereas epithelial-restricted organoid models recapitulated the molecular and neuroendocrine features of human NEBC, supporting epithelial lineage competence for neuroendocrine differentiation. Patient-derived models and human NEBC specimens further supported epithelial identity in NEBC. Using these complementary platforms, drug screening identified homoharringtonine (HHT) as a candidate therapeutic vulnerability in the tested NEBC systems. HHT suppressed neuroendocrine marker expression, induced apoptosis, and attenuated IL6-JAK-STAT3 signaling. Together, these findings describe complementary epithelial-derived NEBC models and support further investigation of HHT as a candidate therapeutic vulnerability.

Journal Article↗
PubMed2026

Case Report: Immune-driven clonal selection underlying lineage switch from B-Precursor acute lymphoblastic leukemia to acute myeloid leukemia following inotuzumab ozogamicin.

Lineage switch (LS), defined as a change in leukemic lineage during the disease course, is a rare but clinically significant event in acute leukemia and is typically associated with poor prognosis. Although LS has been increasingly reported following targeted immunotherapies, the clonal mechanisms underlying this phenomenon remain incompletely understood, particularly in cases without KMT2A rearrangement. We report a case of LS from B-precursor acute lymphoblastic leukemia (BCP-ALL) to acute myeloid leukemia (AML) following treatment with the CD22-targeted antibody-drug conjugate inotuzumab ozogamicin. To elucidate the clonal architecture underlying LS, targeted next-generation sequencing was performed on bone marrow samples obtained at multiple time points throughout the disease course. Genomic analysis demonstrated that the lymphoid and myeloid disease phases shared ancestral genetic alterations but displayed distinct mutational profiles. At the time of LS, TP53 and SMC1A mutations newly emerged, whereas only a subset of mutations detected at ALL relapse was retained. These findings suggest that the AML phase most likely resulted from the selective expansion of a genetically distinct subclone derived from a common progenitor, rather than the direct transdifferentiation of the dominant ALL clone, consistent with immunotherapy-driven clonal selection. Longitudinal genomic profiling revealed stepwise clonal evolution during disease progression, supporting a model of immunotherapy-driven clonal selection leading to LS. This case provides molecular evidence suggesting that immune-targeted therapy can promote expansion of minor pre-existing subclones with alternative lineage potential within a common progenitor even in non-KMT2A-rearranged leukemia. Our findings highlight the importance of comprehensive genomic monitoring during immunotherapy to identify therapy-resistant subclones and better understand mechanisms of lineage plasticity in acute leukemia.

Humans↗
PubMed2026

Patient-derived models of prostate cancer: Capturing tumour complexity from initiation to metastasis.

Prostate cancer is a growing global health challenge. To identify new ways to improve patient care, researchers need a variety of preclinical models that faithfully recapitulate human tumours across the disease continuum, from initiation to metastasis. These complementary models include primary cultures of prostate epithelial cells (PrECs), co-cultures, patient-derived explants (PDEs), patient-derived organoids (PDOs) and patient-derived xenografts (PDXs). Collectively, these models enable researchers to study tumour biology and therapeutic responses in clinically relevant contexts. Yet, there is still a need to improve the fidelity of preclinical models to human tumours by integrating diverse cell types from the tumour microenvironment and mimicking biomechanical features. By improving culture methods with matrix components that resemble the tumour microenvironment and new formulations of media that imitate human plasma, in vitro models will more accurately reflect human physiology, nutrient availability, and metabolism. In time this may reduce the reliance on animal testing through organ-on-chip and related techniques. These more complex models are suited to more detailed experimental readouts, including single-cell and spatial analyses. Intravital imaging also enables dynamic visualisation of cell-cell interactions and treatment responses in vivo. Collectively, these approaches are facilitating a shift towards sophisticated models that capture patients' tumour heterogeneity, different cellular niches, and provide opportunities to carefully study tumorigenesis, metastasis, lineage plasticity, and therapy resistance. In this review, we discuss the current progress and future directions for patient-derived models of prostate cancer, highlighting how they can be generated, refined, characterised and shared to accelerate the worldwide effort in translational research.

Humans↗
PubMed2025

Genome-wide association meta-regression identifies stem cell lineage orchestration as a key driver of acne risk.

Over 85% of the population experience acne at some point in their lives, with its severity spanning a quantitative spectrum, from mild, transient outbreaks to more persistent, severe forms of the condition. Moderate to severe disease poses a substantial global burden arising from both the physical and psychological impacts of this highly visible condition. The analytical approach taken in this study aimed to address the impact of variation in the dichotomisation of acne case control status, driven by ascertainment and study design, on effect size estimates across independent genetic association studies of acne. Through a fixed intercept meta-regression framework, we combined evidence genome-wide for association with acne across studies in which case-control status had been ascertained in different settings, allowing for different severity threshold definitions. Across a combined sample of 73,997 cases and 1,103,940 controls of European, South Asian and African American ancestry we identify genetic variation at 165 genomic loci that influence acne risk. There is evidence for both shared and ancestry specific components to the genetic susceptibility to acne and for sex differences in the magnitude of effect of risk alleles at three loci. We observe that common genetic variation explains 13.4% of acne heritability on the liability scale. Consistent with the hypothesis that genetic risk primarily operates at the level of individual pilosebaceous units, a polygenic score derived from this case-control study of acne susceptibility is associated with both self-reported and clinically assessed acne severity in adolescence, further strengthening the link between genetic risk and disease severity. Prioritisation of causal genes at the identified acne risk loci, provides genetic validation of the targets of established and emerging acne therapies, including retinoid treatments. The identified acne risk loci are enriched for genes encoding downstream effectors of RXRA signalling, including SOX9 and components of the WNT and p53 pathways. Illustrating that the control of stem cell lineage plasticity and cellular fate are important mechanisms through which genetic variation influences acne susceptibility within the pilosebaceous unit.

Journal Article↗
PubMed2026

Neurotropism and Therapeutic Targeting of Brain Metastases in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive malignancy marked by rapid progression, early dissemination, and a pronounced propensity for brain metastases (BM), which develop in up to 80% of patients. SCLC is defined by profound genomic instability, lineage plasticity, and rapid drug resistance. The establishment of BM is promoted by neuronal mimicry, enhanced intercellular adhesion, and dynamic cross-talk with astrocytes and microglia. Emerging therapies targeting delta-like ligand 3 and B7H3 have demonstrated encouraging intracranial activity. Despite these advances, treatment resistance and limited brain drug penetration remain major unmet needs. This review highlights recent advances in SCLC BM biology and precision therapeutic strategies.

Humans↗
PubMed2026

ATP-Dependent Chromatin Remodelers in Prostate Cancer Progression and Therapeutic Resistance.

ATP-dependent chromatin remodelers (ACRs) have emerged as central determinants of prostate cancer (PCa) progression and therapy resistance. Organized into four mechanistically distinct families (SWI/SNF, ISWI, CHD, and INO80/SWR), ACRs govern nucleosome positioning genome-wide and thereby occupy a central position in the epigenomic regulatory landscape that dictates where and when transcription factors, including the androgen receptor (AR), can engage chromatin. This review discusses ACR dysregulation in PCa through both mutational and non-mutational mechanisms. These are illustrated by discussing how the functional consequences are highly context-dependent, varying with disease stage, prior treatment exposure, and tumor ancestry. Loss of the tumor suppressors RB1, TP53, and PTEN each generates specific ACR dependencies that are potentially therapeutically exploitable, including synthetic lethal relationships between PTEN deficiency and SWI/SNF ATPase activity. Across the spectrum of AR signaling states, from hormone-sensitive disease through therapy-resistant neuroendocrine and double-negative PCa subtypes, ACR complex composition and genomic targeting are continuously reprogrammed to enable and sustain lineage plasticity and endocrine therapy escape. Therapeutic strategies targeting SWI/SNF, ISWI, and INO80/SWR complexes are at varying stages of preclinical and clinical development and are attractive novel avenues to target therapy resistant PCa.

ATP dependent chromatin remodeling↗
PubMed2026

Advanced and underlying therapeutic strategies in transformed small cell lung cancer.

Transformed small-cell lung cancer (T-SCLC) is a clinically important form of histologic transformation and a mechanism of acquired resistance in non-small-cell lung cancer (NSCLC). It is associated with poor prognosis, with a median overall survival of only about 9-13 months. This review summarizes recent advances in the mechanisms, diagnosis, monitoring, and treatment of T-SCLC. Repeat biopsy remains the gold standard for confirming histologic transformation, whereas molecular profiling and liquid biopsy may facilitate early detection and longitudinal disease monitoring. Platinum-etoposide remains the most commonly used clinical standard after transformation, but its benefit is typically transient and durable disease control remains uncommon. Continuation of EGFR tyrosine kinase inhibitors combined with chemotherapy may prolong progression-free survival in selected patients but has not consistently improved overall survival. Anti-angiogenic therapy, particularly anlotinib, and chemo-immunotherapy have shown encouraging activity in selected patients, while emerging strategies targeting DLL3, MYC, SOX2, and epigenetic regulators may broaden the therapeutic landscape. Prospective studies integrating repeat tissue sampling, comprehensive genomic profiling, biomarker-guided patient stratification, pharmacogenomics, functional drug-sensitivity testing where feasible, and integrated multi-omics approaches are needed to advance molecularly guided and individualized treatment for T-SCLC.

advanced therapy↗
PubMed2026

IRAK4 constrains cellular plasticity during chemically-induced cell fate reprogramming into multiple lineages.

Chemical reprogramming holds transformative potential for regenerative medicine. However, the regulatory mechanisms governing cell fate transitions are not well understood. Here, we identify Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a barrier to multi-lineage reprogramming. Pharmacological inhibition of IRAK4 enhances the reprogramming of mouse embryonic fibroblasts (MEFs) through a chemically activated multi-lineage priming (CaMP) state and extraembryonic endoderm (XEN)-like intermediates, increasing colony formation, and the expression of core XEN regulators (Sox17, Gata4, Sall4, and Foxa2). Genetic knockdown of Irak4 similarly accelerates reprogramming, whereas its overexpression blocks cell fate transitions. IRAK4 inhibition enhances chromatin accessibility and reshapes cell cycle dynamics, characterized by G0/G1 shortening and G2/M lengthening, potentially contributing to multi-lineage state establishment. Furthermore, IRAK4 suppression enhances the direct conversion of MEFs to neuron-like and hepatocyte-like cells, which exhibit enhanced functional maturity, including increased glycogen storage and improved detoxification capacity. Our findings establish IRAK4 as a regulator that constrains cellular plasticity potentially by coordinating chromatin accessibility and cell cycle dynamics.

Animals↗
PubMed2026

Next-generation brain proteomics: Integrating single-cell, spatial, and multi-omics for clinical biomarker discovery.

The mammalian brain's functional complexity arises from the sophisticated architecture of neurons and glia. This network is essentially defined by its dynamic proteome, which reveals the functional execution underlying neural computation and disease. This review integrates the technological leap in neuroproteomics. It has moved beyond bulk tissue proteome cataloguing to high-sensitivity single-cell and spatial resolution. We detail how next-generation platforms, such as TIMS-PASEF and Orbitrap-Astral, have enabled deeper and faster phenotypic profiling of limited brain samples. However, the proteome coverage remains constrained by dynamic range, sample loss, ionisation bias and incomplete detection of low-abundance regulatory proteins. We further examine how such studies have revealed the proteomic remodelling that drives lineage specification and synaptic plasticity by linking temporal protein expression waves to biological function. Crucially, we delineate the clinical translational trajectory, illustrating how aberrant signatures are verified in cerebrospinal fluid (CSF) and validated in plasma to support precision medicine. Finally, we argue for the necessity of "fused" multi-omics integration and Artificial Intelligence (AI) to decode the non-linear molecular logic of brain pathology.

Humans↗
PubMed2025

Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation.

Disruptions to regulatory signals governing stem cell fate open the pathway to tumorigenesis. To determine how these programs become destabilized, we fate-map thousands of murine wild-type and KrasG12D-mutant alveolar type II (AT2) stem cells in vivo and find evidence for two independent AT2 subpopulations marked by distinct tumorigenic capacities. By combining clonal analyses with single-cell transcriptomics, we unveil striking parallels between lung regeneration and tumorigenesis that implicate Il1r1 as a common activator of AT2 reprogramming. We show that tumor evolution proceeds through the acquisition of lineage infidelity and reversible transitions between mutant states, which, in turn, modulate wild-type AT2 dynamics. Finally, we discover how sustained nuclear factor κB (NF-κB) activation sets tumorigenesis apart from regeneration, allowing mutant cells to subvert differentiation in favor of tumor growth.

Animals↗
PubMed2025

Hybridization as driving force for cryptic species diversity in the Caribbean coral genus Madracis.

Species boundaries in scleractinian corals remain highly elusive due to conflicting patterns between morphological and molecular phylogenies, often caused by morphological plasticity, occurrence of cryptic species, incomplete lineage sorting or introgressive hybridization. Here, we use an integrated systematics approach, which combines reduced representation genome sequencing (nextRAD), micro-morphometric characterization, SEM analyses and compilation of life history traits, to infer phylogenetic relationships among closely related species in the Caribbean coral genus Madracis. In total, we analyzed 235 Madracis specimens from Curaçao and Bermuda collected from 10-90 m depth. Sequence- and SNP-based analyses for 115 samples generated unprecedented species resolution in Madracis, greatly supporting the morphology-based taxonomy of the current, accepted Caribbean species M. senaria, M. decactis, M. formosa, M. carmabi and M. mirabilis (M. auretenra). The exception was M. pharensis, in which we found evidence for three separate lineages, and for which we found signatures of admixture and introgression. These three M. pharensis lineages showed distinct depth distributions (thus classified as shallow, deep and very deep) and were partially distinguishable on the basis of fine microstructural elements of the collumella, septa and coenosteum. Further taxonomic comparisons are needed to formalize these putative cryptic species. Overall, our integrated systematics approach further resolves species relationships in the Caribbean genus Madracis, supports the morphological descriptions for most of the recognized species, but also reveals the existence of cryptic diversity in groups marked by high admixture, thus suggesting hybridization as a driving force in coral species diversity.

Animals↗
PubMed2026

Paired analysis of primary adenoid cystic carcinoma and derived cell lines reveals a mesenchymal and stem-like shift associated with therapy resistance.

Adenoid cystic carcinoma (ACC) is a salivary gland malignancy characterized by slow but persistent growth, frequent local recurrence, and late metastatic progression. Patients with unresectable, recurrent, or metastatic disease have limited therapeutic options. Efforts to identify effective therapeutic targets have been hindered by the limited availability of well-characterized ACC models. In this study, we established 11 ACC cell lines and performed RNA sequencing of nine cell lines and their matched primary tumors to evaluate the preservation and evolution of molecular and lineage-associated characteristics during cell line establishment. Comparative transcriptomic analysis revealed reduced epithelial and luminal differentiation programs in the cell lines, accompanied by enrichment of myoepithelial, EMT-, and cancer stem cell-associated transcriptional programs. Digital deconvolution and single-sample gene set enrichment analysis supported enrichment of hybrid EMT/stem-like states during in vitro propagation, while comparison with publicly available primary-recurrent ACC data demonstrated partial preservation of recurrence-associated plasticity and invasion programs. Protein-level validation of representative epithelial, myoepithelial, EMT, and stemness markers supported the major transcriptomic changes. In addition, a cell line with a higher stemness signature showed reduced sensitivity to cisplatin. Together, these findings indicate that ACC cell line establishment is associated with transcriptional reprogramming and enrichment of plastic, EMT/stem-like states while retaining selected ACC lineage characteristics. These models provide experimentally tractable platforms for investigating ACC progression, therapeutic response, and mechanisms of treatment resistance.

Adenoid cystic carcinoma↗
PubMed2025

Evolutionary fingerprints of epithelial-to-mesenchymal transition.

Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1-5. The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.

Animals↗
PubMed2026

Whole-genome characterization and phylogenetic placement of Fusarium oxysporum f. sp. vasinfectum isolates.

Fusarium wilt of cotton, caused by Fusarium oxysporum f. sp. vasinfectum (Fov), remains a persistent threat to cotton production worldwide. Among the known races, Fov race 4 and its extra-virulent variants cause particularly severe losses in Upland cotton. Although several Fov genome assemblies have been assigned to races, the genomic diversity and evolutionary relationships among pathogenic and non-pathogenic isolates associated with cotton outbreaks remain poorly understood at the whole-genome level. This study addressed these gaps by generating and comparing high-quality genome assemblies of four Fusarium isolates collected from Texas cotton fields: two pathogenic (TX17-24 and TX18-9) and two non-pathogenic (TX17-6 and TX18-6). Draft assemblies were generated using Oxford Nanopore long reads and polished with Illumina reads. Comparative genomic analyses showed that pathogenic isolates possessed larger genomes and more conserved orthologous families, whereas non-pathogenic isolates contained more unique genes. Analyses of predicted secreted effectors, transposable elements, and carbohydrate-active enzymes further distinguished pathogenic and non-pathogenic lineages, suggesting roles in virulence adaptation and genome plasticity. Phylogenomic analyses using k-mer-based, assembly- and alignment-free methods incorporated all available long-read Fov genomes and revealed substantial genetic diversity within races 1 and 4, clustering isolates into multiple sublineages. These findings show that Fov race diversification is underestimated when based on traditional classification schemes and may be shaped by host specialization, geographic separation, or horizontal gene transfer. This work advances our understanding of the genomic diversity and evolutionary dynamics of Fov and establishes a foundation for improved race identification and characterization of Fusarium wilt pathogenesis in cotton.

Fusarium oxysporum↗