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PubMed2025

Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine: Bringing next-generation precision oncology to patients.

The human genome project ushered in a genomic medicine era that was largely unimaginable three decades ago. Discoveries of druggable cancer drivers enabled biomarker-driven gene- and immune-targeted therapy and transformed cancer treatment. Minimizing treatment not expected to benefit, and toxicity-including financial and time-are important goals of modern oncology. The Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine founded by Drs. John Mendelsohn and Thomas Tursz provided a vision for innovation, collaboration and global impact in precision oncology. Through pursuit of transcriptomic signatures, artificial intelligence (AI) algorithms, global precision cancer medicine clinical trials and input from an international Molecular Tumor Board (MTB), WIN has led the way in demonstrating patient benefit from precision-therapeutics through N-of-1 molecularly-driven studies. WIN Next-Generation Precision Oncology (WINGPO) trials are being developed in the neoadjuvant, adjuvant or metastatic settings, incorporate real-world data, digital pathology, and advanced algorithms to guide MTB prioritization of therapy combinations for a diverse global population. WIN has pursued combinations that target multiple drivers/hallmarks of cancer in individual patients. WIN continues to be impactful through collaboration with industry, government, sponsors, funders, academic and community centers, patient advocates, and other stakeholders to tackle challenges including drug access, costs, regulatory barriers, and patient support. WIN's collaborative next generation of precision oncology trials will guide treatment selection for patients with advanced cancers through MTB and AI algorithms based on serial liquid and tissue biopsies and exploratory omics including transcriptomics, proteomics, metabolomics and functional precision medicine. Our vision is to accelerate the future of precision oncology care.

Humans↗

PubMed2024

Molecular analysis of primary and metastatic sites in patients with renal cell carcinoma.

BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

Humans↗

PubMed2024

A Strong Dysregulated Myeloid Component in the Epigenetic Landscape of Systemic Sclerosis: An Integrated DNA Methylome and Transcriptome Analysis.

OBJECTIVE: Nongenetic factors influence systemic sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome-wide association study. METHODS: We analyzed DNA methylation data from whole-blood samples in 179 patients with SSc and 241 unaffected individuals to identify differentially methylated positions (DMPs) with a false discovery rate (FDR) <0.05. These results were further integrated with RNA sequencing data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels. RESULTS: This analysis yielded 525 DMPs enriched in immune-related pathways, with leukocyte cell-cell adhesion being the most significant (FDR = 4.91 × 10-9), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach, we observed an enrichment of neutrophil-related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT/enhancer-binding protein transcription factor family in SSc, which is crucial in the myeloid lineage development. CONCLUSION: Our findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.

Humans↗

PubMed2025

Blood from septic patients with necrotising soft tissue infection treated with hyperbaric oxygen reveal different gene expression patterns compared to standard treatment.

BACKGROUND: Sepsis and shock are common complications of necrotising soft tissue infections (NSTI). Sepsis encompasses different endotypes that are associated with specific immune responses. Hyperbaric oxygen (HBO2) treatment activates the cells oxygen sensing mechanisms that are interlinked with inflammatory pathways. We aimed to identify gene expression patterns associated with effects of HBO2 treatment in patients with sepsis caused by NSTI, and to explore sepsis-NSTI profiles that are more receptive to HBO2 treatment. METHODS: An observational cohort study examining 83 NSTI patients treated with HBO2 in the acute phase of NSTI, fourteen of whom had received two sessions of HBO2 (HBOx2 group), and another ten patients (non-HBO group) who had not been exposed to HBO2. Whole blood RNA sequencing and clinical data were collected at baseline and after the intervention, and at equivalent time points in the non-HBO group. Gene expression profiles were analysed using machine learning techniques to identify sepsis endotypes, treatment response endotypes and clinically relevant transcriptomic signatures of response to treatment. RESULTS: We identified differences in gene expression profiles at follow-up between HBO2-treated patients and patients not treated with HBO2. Moreover, we identified two patient endotypes before and after treatment that represented an immuno-suppressive and an immune-adaptive endotype respectively, and we characterized the genetic profile of the patients that transition from the immuno-suppressive to the immune-adaptive endotype after treatment. We discovered one gene MTCO2P12 that distinguished individuals who altered their endotype in response to treatment from non-responders. CONCLUSION: The global gene expression pattern in blood changed in response to HBO2 treatment in a direction associated with clinical biochemistry improvement, and the study provides potential novel biomarkers and pathways for monitoring HBO2 treatment effects and predicting an HBO2 responsive NSTI-sepsis profile. TRIAL REGISTRATION: Biological material was collected during the INFECT study, registered at ClinicalTrials.gov (NCT01790698) 04/02/2013.

Humans↗

PubMed2026

Prominent Movement Disorders in RNU2-2-Related Spliceosomopathy.

Pediatric movement disorders often overlap with neurodevelopmental diseases, suggesting shared molecular mechanisms. Variants in small nuclear RNA (snRNA) genes encoding spliceosome components have recently been associated with neurodevelopmental disorders, termed "RNUopathies." We analyzed genome sequencing data from 14 patients with undiagnosed pediatric movement disorders for pathogenic variants in snRNA genes. We identified recurrent de novo RNU2-2 variants (n.35A > G and n.4G > A) in two patients with intellectual disability, epilepsy, and hyperkinetic movement disorders. RNA sequencing of fibroblasts in one patient showed no characteristic transcriptomic signature. Spliceosomopathies should be considered in neurodevelopmental disorders and developmental and epileptic encephalopathies with hyperkinetic features.

Humans↗

PubMed2025

An Immunosenescent CD8+ T Cell Subset in Patients with Axial Spondyloarthritis and Psoriatic Arthritis Links Spontaneous Motility to Telomere Shortening and Dysfunction.

OBJECTIVE: A pathogenetic role of CD8+ T lymphocytes in radiographic axial spondyloarthritis (r-axSpA) and other spondyloarthritis (SpA) is sustained by genome-wide association studies and by the expansion of public T cell clonotypes in the target tissues. This study investigates the migration of CD8+ T cells along with their phenotype and functions in patients with r-axSpA and psoriatic arthritis (PsA). METHODS: Peripheral blood CD8+ and CD4+ T cells were isolated from patients with r-axSpA (n = 128), PsA (n = 60), and rheumatoid arthritis (RA) (n = 74) and healthy donors (HDs) (n = 79). Transwell migration assay was performed in the presence of different chemokines. CD8+ T cell immunoprofiling and effector functions were assessed by multiparametric flow cytometry. Transcriptome signature was evaluated by RNA sequencing analysis, whereas telomere length and dysfunction were measured by reverse transcriptase-polymerase chain reaction and immunofluorescence-fluorescence in situ hybridization, respectively. RESULTS: A significantly higher number of CD8+ T cells migrating in the absence of chemokine stimuli was found in patients with SpA compared with HDs and patients with RA. This subset, producing cytotoxic (granzyme B, perforin, granulysin) and proinflammatory molecules (tumor necrosis factor), was significantly enriched in terminally differentiated (CCR7-CD45RA+) and senescent (CD28-CD57+) cells having a gene expression profile characterized by cytolytic signature and natural killer markers. Remarkably, these spontaneously migrating CD8+ T cells showed DNA damage response activation, telomere shortening, and dysfunction. CONCLUSION: These data describe a terminally differentiated CD8+ T cell subset with a senescent and cytotoxic/proinflammatory profile and an intrinsic invasive potential enriched in patients with SpA that represents a possible player in disease pathogenesis.

Humans↗

PubMed2005

VeloceGenomics: an accelerated in vivo drug discovery approach to rapidly predict the biologic, drug-like activity of compounds, proteins, or genes.

PURPOSE: The aim of this study is to test the predictive power of in vivo multiorgan RNA expression profiling in identifying the biologic activity of molecules. METHODS: Animals were treated with compound A or B. At the end of the treatment period, in vivo multiorgan microarray-based gene expression data were collected. Investigators masked to the identity of the compounds analyzed the transcriptome signatures to define the molecular pathways affected by treatment and to hypothesize the biologic activity and potential therapeutic indications of the blinded compounds. RESULTS: For compound A, G-protein-coupled receptors and factors associated with cell growth were affected-growth hormone/insulin-like growth factor-1, glucagon/insulin axes, and general somatomedin-like activity. Deblinding showed the compound to be a somatostatin analog, SOM230, confirming the accuracy of the predicted biologic activity. For compound B, components of the inflammatory cascade potentially mediated by lipopolysaccharide, tumor necrosis factor, or proinflammatory cytokines were affected. The gene expression signatures were most consistent with an interleukin-6 family activity. Deblinding revealed that compound B was leukemia inhibitory factor. CONCLUSIONS: VeloceGenomics is a strategy of coupling in vivo compound testing with genomic technologies. The process enables prediction of the mechanism of action and, coupled with other relevant data, prediction of the suitability of compounds for advancement in the drug development process.

Animals↗

PubMed2026

Motor coordination and behavioural deficits in a mouse model of KMT2B-related dystonia.

INTRODUCTION: Pathogenic variants in KMT2B cause early-onset dystonia, but a mouse model that has undergone comprehensive, dystonia-oriented phenotyping is lacking. METHODS: We conducted detailed phenotyping on heterozygous Kmt2b constitutive knockout mice and wild-type littermates, assessing growth, neurobehavioural traits, motor coordination, sensorimotor gating, social behaviour and metabolic parameters, combined with striatal RNA sequencing. RESULTS: Kmt2b knockout mice of both sexes were viable but significantly smaller and lighter than littermate controls. Knockouts were hyperlocomotive in the open field and showed approximately two-fold larger acoustic startle responses; unexpectedly, prepulse inhibition was enhanced rather than reduced at all prepulse intensities. On the balance beam, knockouts crossed more slowly and paused more frequently; female knockouts also paused more on the ladder rung task. Frame-by-frame video analysis revealed a claw-like hindpaw posture characterized by abnormal inward flexion of the digits. Knockout mice spent less time investigating a novel conspecific, while social recognition memory remained intact. Striatal RNA sequencing confirmed reduction of Kmt2b transcript to approximately half of control levels and identified 177 differentially expressed genes, including Maob, encoding monoamine oxidase B; gene set enrichment analysis implicated neurodevelopmental, glial and mitochondrial processes. Nociception, vision, body-weight-adjusted grip strength, and clinical chemistry and haematological measures were largely unaffected. CONCLUSION: Heterozygous Kmt2b knockout mice show hyperlocomotion, altered sensorimotor gating, impaired motor coordination with dystonic-like paw posturing and reduced sociability, alongside a striatal transcriptomic signature implicating neurodevelopmental processes. The model mirrors aspects of human KMT2B-related dystonia and provides a platform for mechanistic study; environmental or pharmacological challenge may be needed to unmask overt dystonic features.

Dystonia↗

PubMed2025

p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.

Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.

Animals↗

PubMed2026

A module-based approach for post-omics, post-GWAS network-based gene classification.

MOTIVATION: Complex traits and diseases are highly polygenic and understanding the full set of genes involved is a central challenge in biomedicine. However, due to sample size limitations and noise (technical and biological), experimental approaches for disease-gene discovery such as transcriptomics and GWAS result in long, noisy, heterogeneous gene lists, which may be trimmed to a subset of likely relevant genes while leaving several false negatives. Computational gene classification approaches, especially those using genome-scale molecular interaction networks, are promising avenues for complementing such experimental findings by analytically expanding observed gene lists based on the functional relatedness between genes. We previously introduced the network-based gene classification approach, GenePlexus, which was rigorously benchmarked to show state-of-the-art performance, especially for predicting novel genes associated with biological processes and fine-grained phenotypes. Network-based gene classification performance,however, declines for diseases, especially when the inputs are omics and GWAS-based long gene lists. RESULTS: Here, we show that these disease gene lists span multiple biological processes spread across the molecular network, and we propose ModGenePlexus, a new network-based gene classification method that takes a two-stage approach. First, clustering and semi-supervised learning decomposes the input gene list into coherent, denoised network gene modules. Then, ModGenePlexus trains supervised (GenePlexus) classifiers for each module and aggregates predictions to return genome-wide rankings. We benchmarked ModGenePlexus across simulated data, transcriptomic signatures, and GWAS datasets (together spanning hundreds of diseases), showing improved recovery of known disease genes compared to GenePlexus. Beyond improved classification, the results of enrichment analysis of ModGenePlexus outputs are much more interpretable by virtue of revealing nuanced biological processes. Together, these results establish ModGenePlexus as a scalable, interpretable tool for gene classification of GWAS- and omics-derived gene lists across diverse biological contexts. AVAILABILITY AND IMPLEMENTATION: ModGenePlexus is freely available on GitHub at https://github.com/krishnanlab/ModGenePlexus, and the full source code and results supporting this study are available on Zenodo at https://zenodo.org/records/19857910.

Genome-Wide Association Study↗

PubMed2006

Transcriptomic footprints disclose specificity of reactive oxygen species signaling in Arabidopsis.

Reactive oxygen species (ROS) are key players in the regulation of plant development, stress responses, and programmed cell death. Previous studies indicated that depending on the type of ROS (hydrogen peroxide, superoxide, or singlet oxygen) or its subcellular production site (plastidic, cytosolic, peroxisomal, or apoplastic), a different physiological, biochemical, and molecular response is provoked. We used transcriptome data generated from ROS-related microarray experiments to assess the specificity of ROS-driven transcript expression. Data sets obtained by exogenous application of oxidative stress-causing agents (methyl viologen, Alternaria alternata toxin, 3-aminotriazole, and ozone) and from a mutant (fluorescent) and transgenic plants, in which the activity of an individual antioxidant enzyme was perturbed (catalase, cytosolic ascorbate peroxidase, and copper/zinc superoxide dismutase), were compared. In total, the abundance of nearly 26,000 transcripts of Arabidopsis (Arabidopsis thaliana) was monitored in response to different ROS. Overall, 8,056, 5,312, and 3,925 transcripts showed at least a 3-, 4-, or 5-fold change in expression, respectively. In addition to marker transcripts that were specifically regulated by hydrogen peroxide, superoxide, or singlet oxygen, several transcripts were identified as general oxidative stress response markers because their steady-state levels were at least 5-fold elevated in most experiments. We also assessed the expression characteristics of all annotated transcription factors and inferred new candidate regulatory transcripts that could be responsible for orchestrating the specific transcriptomic signatures triggered by different ROS. Our analysis provides a framework that will assist future efforts to address the impact of ROS signals within environmental stress conditions and elucidate the molecular mechanisms of the oxidative stress response in plants.

Arabidopsis↗

PubMed2025

Tonoplast sucrose transporter SUT4-dependent sugar partitioning modulates phenological transitions and reproductive success in poplar.

Climate uncertainty is intensifying the need for greater plasticity in carbohydrate reserve utilization to support winter survival and spring growth in woody perennials. In poplar, the single-copy SUT4, which encodes a tonoplast-localized sucrose transporter, and the SUT5/SUT6 genome duplicates, which encode plasma membrane-localized transporters, are expressed year-round, with SUT4 showing the highest expression during cool seasons. Given its role in vacuolar sucrose efflux and winter-predominant expression, SUT4 may play a key role in modulating seasonal carbohydrate dynamics. While SUT4-knockdown and knockout effects have been studied under greenhouse conditions, their impact under field conditions remains unexplored. Here, we report a field-based study comparing CRISPR knockout mutants of winter-expressed SUT4 and SUT5/SUT6 in Populus tremula × alba. We show that sut4, but not sut5/6, mutants exhibited earlier autumn leaf senescence, delayed spring bud flush, reduced stem growth, and altered sugar partitioning in winter xylem and bark relative to controls. After 2 years in the field, all genotypes flowered before leaf flush in early spring; however, sut4 mutants produced sterile ovules despite developing normal-looking catkins. Metabolic profiling revealed disrupted sucrose and raffinose dynamics in elongating sut4 catkins. This was accompanied by transcriptomic signatures of elevated stress and downregulation of proanthocyanidin biosynthesis and circadian clock genes. These findings highlight the critical role of SUT4 in coordinating sugar allocation, stress responses, and seasonal development in poplar.

Populus↗

PubMed2026

Molecular and Immune Landscape of Recurrent and/or Distant Metastatic Squamous Cell Carcinoma of the Head and Neck: An EORTC/IMMUCAN Project.

PURPOSE: Recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is a heterogeneous clinical entity with a poor prognosis. The molecular and immune landscape of R/M SCCHN is underexplored. To offer a comprehensive view of the tumor microenvironment and molecular profile of R/M SCCHN, we performed an in-depth molecular and immune characterization, evaluating the impact of human papillomavirus (HPV) status, tobacco and alcohol history, primary tumor site, relapse pattern, and treatment history at the genomic, transcriptomic, and immune levels. EXPERIMENTAL DESIGN: We analyzed 253 R/M SCCHN fresh tumor biopsies from the IMMUcan project using RNA sequencing (RNA-seq), whole-exome sequencing, and multiplex immunofluorescence (mIF). RESULTS: The primary clinical factor affecting the immune microenvironment was the number of treatment lines, with significant declines in T cells and B cells observed via mIF and RNA-seq as the number of R/M treatment lines progressed. IL6, IL13, IL15, and NRF2 pathways were enriched in HPV-negative R/M SCCHN compared with HPV-positive tumors, whereas no immune differences were detected between these two clinical groups. Specific genomic alterations were observed in laryngeal cancer (DDR2, FOXP1, KLF5, and ROBO2), whereas nonsmokers/nondrinkers exhibited alterations in SPEN, PBRM1, and CYLD. 11q13.3 amplification was linked to HPV-negative metastatic tumors and hypopharyngeal cancer. HPV-negative SCCHN with locoregional recurrence showed elevated EGFR and CXCL12 pathway activity. Partial epithelial-mesenchymal transition transcriptomic signatures correlated with poor survival, whereas lymphocyte infiltration, especially in the context of tertiary lymphoid structures, was associated with improved survival. CONCLUSIONS: Our study highlights key molecular and immune differences across R/M SCCHN subgroups, identifies potential biomarkers, and suggests biological rationales for tailored therapeutic strategies.

Humans↗

PubMed2023

Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging.

Reactivation and dysregulation of the mTOR signaling pathway are a hallmark of aging and chronic lung disease; however, the impact on microvascular progenitor cells (MVPCs), capillary angiostasis, and tissue homeostasis is unknown. While the existence of an adult lung vascular progenitor has long been hypothesized, these studies show that Abcg2 enriches for a population of angiogenic tissue-resident MVPCs present in both adult mouse and human lungs using functional, lineage, and transcriptomic analyses. These studies link human and mouse MVPC-specific mTORC1 activation to decreased stemness, angiogenic potential, and disruption of p53 and Wnt pathways, with consequent loss of alveolar-capillary structure and function. Following mTOR activation, these MVPCs adapt a unique transcriptome signature and emerge as a venous subpopulation in the angiodiverse microvascular endothelial subclusters. Thus, our findings support a significant role for mTOR in the maintenance of MVPC function and microvascular niche homeostasis as well as a cell-based mechanism driving loss of tissue structure underlying lung aging and the development of emphysema.

Mice↗

PubMed2025

Integrative analyses of mendelian randomization and bioinformatics reveal casual relationship and genetic links between COVID-19 and knee osteoarthritis.

BACKGROUND: Clinical and epidemiological analyses have found an association between coronavirus disease 2019 (COVID-19) and knee osteoarthritis (KOA). Infection with COVID-19 may increase the risk of developing KOA. OBJECTIVES: This study aimed to investigate the potential causal relationship between COVID-19 and KOA using Mendelian randomization (MR) and to explore the underlying mechanisms through a systematic bioinformatics approach. METHODS: Our investigation focused on exploring the potential causal relationship between COVID-19, acute upper respiratory tract infection (URTI) and KOA utilizing a bidirectional MR approach. Additionally, we conducted differential gene expression analysis using public datasets related to these three conditions. Subsequent analyses, including transcriptional regulation analysis, immune cell infiltration analysis, single-cell analysis, and druggability evaluation, were performed to explore potential mechanisms and prioritize therapeutic targets. RESULTS: The results indicate that COVID-19 has a one-way impact on KOA, while URTI does not play a causal role in this association. Ribosomal dysfunction may serve as an intermediate factor connecting COVID-19 with KOA. Specifically, COVID-19 has the potential to influence the metabolic processes of the extracellular matrix, potentially impacting the joint homeostasis. A specific group of genes (COL10A1, BGN, COL3A1, COMP, ACAN, THBS2, COL5A1, COL16A1, COL5A2) has been identified as a shared transcriptomic signature in response to KOA with COVID-19. Imatinib, Adiponectin, Myricetin, Tranexamic acid, and Chenodeoxycholic acid are potential drugs for the treatment of KOA patients with COVID-19. CONCLUSIONS: This study uniquely combines Mendelian randomization and bioinformatics tools to explore the possibility of a causal relationship and genetic association between COVID-19 and KOA. These findings are expected to provide novel perspectives on the underlying biological mechanisms that link COVID-19 and KOA.

Humans↗

PubMed2026

Integrative multi-omics and single-cell analysis identifies EGFR pathway activation and metabolic reprogramming as potential synthetic lethal vulnerabilities in resistance to the FGFR inhibitor AZD4547.

BACKGROUND: Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a critical bottleneck, severely compromising their long-term clinical efficacy. The pan-cancer molecular landscape and heterogeneous mechanisms driving this resistance, ranging from genetic alterations to dynamic network rewiring, remain poorly understood. METHODS: We integrated large-scale pharmacogenomic profiling of the FGFR inhibitor AZD4547 from the GDSC2 and PRISM databases with single-cell RNA sequencing to dissect the multi-omics landscape of FGFRi resistance across 312 cell lines from 8 cancer types. This multi-omics framework was further extended by machine learning modeling and systematic synthetic lethality screening to uncover actionable therapeutic targets. In vitro viability assays and western blot analysis were subsequently conducted to experimentally evaluate the predicted FGFR-EGFR synthetic lethality. RESULTS: Our dual-database analysis unveiled a multi-dimensional atlas of FGFRi resistance. We identified cancer-specific genomic drivers, such as ELF4 amplification in glioblastoma, alongside key transcriptomic markers including UCP2 and FSCN1, highlighting a shift towards metabolic reprogramming and epithelial-mesenchymal transition (EMT). Single-cell analysis unveiled that resistance is linked to the heterogeneous enrichment of baseline subpopulations characterized by distinct metaprograms, including cell-cycle dysregulation. Furthermore, a random forest model built on a LASSO-derived transcriptomic signature was constructed, demonstrating promising predictive capability for AZD4547 sensitivity (mean test-set AUC = 0.73, 95% CI [0.63, 0.80]); the signature generalized well to erdafitinib but showed limited transferability to some other FGFR inhibitors (e.g. pemigatinib, BGJ398). Most notably, our synthetic lethal screening revealed a convergent reliance on compensatory RTK signaling (specifically EGFR pathway enrichment) and downstream MAPK/PI3K cascades in resistant phenotypes, providing converging computational evidence for EGFR pathway activation as an adaptive bypass mechanism. This predicted synthetic lethality was experimentally supported in two FGFR-dependent cell line models (RT112 and CCLP1), in which combined FGFR-EGFR inhibition produced marked synergistic antiproliferative effects. CONCLUSIONS: This study establishes a comprehensive multi-omics atlas of resistance to the FGFR inhibitor AZD4547, delineating convergent mechanisms of metabolic reprogramming and EGFR-mediated bypass signaling. Our findings characterize the resistance as a dynamic network rewiring and nominate rational combination strategies to overcome this therapeutic bottleneck. While FGFR-EGFR co-inhibition is experimentally supported, metabolic co-targeting remains a computationally derived, hypothesis-generating strategy.

Benzamides↗

PubMed2005

Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas.

PURPOSE: Pre-existing and acquired drug resistance are major obstacles to the successful treatment of glioblastomas. METHODS: We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O6-alkylating agents in glioblastoma cells. RESULTS: We identified a transcriptomic signature that predicts a common in vitro and in vivo resistance phenotype to these agents, a proportion of which is imprinted recurrently by gene dosage changes in the resistant glioblastoma genome. This signature was highly enriched for genes with functions in cell death, compromise, and survival. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-kappaB (NF-kappaB), which included the persistent alterations of various NF-kappaB pathway elements. Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) was identified as a new regulatory component of a putative cytoplasmic signaling cascade that mediates NF-kappaB activation in response to DNA damage caused by O6-alkylating agents. Expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was inversely related to NF-kappaB activation status in the resistant cells. A prediction model based on the resistance signature enabled the subclassification of an independent, validation cohort of 31 glioblastomas into two outcome groups (P = .037) and revealed TNFAIP3 as part of an optimized four-gene predictor associated significantly with patient survival (P = .022). CONCLUSION: Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-kappaB en route to O6-alkylating agent resistance in glioblastoma cells. This pathway may be an attractive target for therapeutic modulation of glioblastomas.

Antineoplastic Agents, Alkylating↗

PubMed2005

Human side population keratinocytes exhibit long-term proliferative potential and a specific gene expression profile and can form a pluristratified epidermis.

The aim of the present study was to characterize human side population (SP) epidermal keratinocytes isolated from primary cell cultures. For that purpose, keratinocytes were isolated from normal adult breast skin samples and the Hoechst 33342 exclusion assay described for hematopoietic cells was adapted to keratinocytes. Three types of keratinocytes were studied: the SP, the main population (MP), and the unsorted initial population. SP keratinocytes represented 0.16% of the total population. In short-term cultures, they exhibited an increased colony-forming efficiency and produced more actively growing colonies than did unsorted and MP keratinocytes. In long-term cultures, SP cells exhibited an extensive expansion potential, performing a mean of 44 population doublings for up to 12 successive passages after cell sorting. Moreover, even in long-term cultures, SP keratinocytes were able to form a pluristratified epidermis when seeded on a dermal substrate. Unsorted and MP keratinocytes promoted a reduced expansion: mean values of 14 population doublings for five passages and 12 population doublings for four successive passages, respectively. To further characterize SP cells, cDNA microarrays were used to identify their molecular signature. Transcriptome profiling showed that 41 genes were differentially expressed in SP (vs. MP) cells, with 37 upregulated genes and only four downregulated genes in SP cells. The majority of these genes were functionally related to the regulation of transcription and cell signaling. In conclusion, SP human keratinocytes isolated from primary cultures exhibited both short- and long-term high proliferative potential, formed a pluristratified epidermis, and were characterized by a specific gene expression profile.

Adult↗