Biology subjects

Varelas, X.

Publications and source records attributed to Varelas, X..

17 recordsLinked to original sources

bioRxiv2026

Age-based shifts in multicellular community organization and abundance in HPV-Negative Head and Neck Cancer

Aging represents a fundamental driver of cancer risk and progression, yet the mechanisms by which aging reshapes the tumor microenvironment remain incompletely understood. To interrogate how aging alters cellular and microenvironmental organization in cancer, we developed an integrated single-cell atlas of HPV-negative head and neck squamous cell carcinoma (HNSCC) encompassing 73 patients aged 18-91 years. Using a multi-layered computational framework combining NMF-based module discovery and partial correlation network analysis, we reveal that age-associated differences in tumor composition are driven primarily by selective shifts in cell type abundance and organization rather than widespread age-dependent transcriptional rewiring. We identify an age-enriched cellular community centered on basal-like squamous epithelial states linked to epithelial-mesenchymal transition, matrix-associated myofibroblast-like CAFs, and FOLR2+ macrophages, which secrete immunosuppressive and ECM-remodeling factors. Cross-dataset in-silico validation via TCGA transcriptomes, spatial transcriptomics, and mouse tumor models confirms the correlation of these cell types across patients, specific ligand-receptor usage, and increased proportions of epithelial and stromal cells in aged mouse models. Among epithelial cell-intrinsic age-associated transcriptional changes, midkine (MDK) emerges as a rare but robust tumor-derived signal linked to stromal remodeling, immunosuppression, and invasive epithelial programs. These findings reveal conserved mechanisms of age-dependent cellular reorganization in the tumor microenvironment and identify MDK and associated stromal-remodeling pathways as potential intervention points for age-stratified cancer therapy.

cancer biology↗

bioRxiv2026

ACKR1-expressing venous endothelial cells establish a pro-fibrotic niche in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by excessive extracellular matrix deposition and irreversible architectural distortion of the lung. Fibrotic remodeling is driven by dynamic interactions among endothelial, fibroblast, epithelial and immune cells. Although pulmonary endothelial cells (ECs) are increasingly recognized as important contributors to IPF pathogenesis, the molecular and cellular events underlying endothelial dysfunction remains poorly understood. Using integrative multi-omics analyses of human IPF lungs combined with functional in vitro assays, we identify ACKR1-expressing venous endothelial cells (ACKR1+ VECs) as critical regulators of a pathogenic niche that promotes lung fibrosis. Single-cell RNA sequencing and spatial transcriptomics analyses reveal that ACKR1+ VECs exhibit a distinct pro-fibrotic and pro-inflammatory transcriptional program enriched for hypoxia responses, extracellular matrix remodeling, and immune cell recruitment. In both mouse and human fibrotic lungs, ACKR1+ VECs localize adjacent to fibroblastic foci and are surrounded by pro-fibrotic CD68+/CCR5+/SPP1+ macrophages-monocytes, suggesting a spatial organized cellular crosstalk supporting fibrotic remodeling. Consistent with these findings, in vitro co-culture assays using ACKR1+ VECs isolated from IPF lungs demonstrate that these cells drive myeloid recruitment and fibroblast activation through ACKR1 dependent mechanisms. Silencing of ACKR1 in IPF-derived VECs suppressed inflammatory and fibrotic transcriptional programs, and pharmacological inhibition of ACKR1 attenuated stromal and immune remodeling and reduced bleomycin-induced lung fibrosis in vivo. Together, these findings identify ACKR1+ VECs as key orchestrators of fibrosis progression and establish ACKR1 and the pathogenic vasculature as promising therapeutic targets for IPF. Clinical RelevanceIdiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited treatment options. We identify ACKR1-expressing venous endothelial cells as key drivers of inflammatory and fibrotic remodeling and show that pharmacologic inhibition of ACKR1 attenuates experimental lung fibrosis. These findings establish endothelial ACKR1 as a promising therapeutic target and highlight the pulmonary vasculature as a novel avenue for disease-modifying therapies in IPF.

molecular biology↗

bioRxiv2025

Dietary Serine Restriction Impacts H3K27 and H3K4 Methyl Epigenomes to Impede Head and Neck Cancer Cell Plasticity and Tumor Growth

Oral squamous cell carcinoma (OSCC) is an aggressive head and neck malignancy characterized by high morbidity, therapeutic resistance and intratumoral heterogeneity driven by plastic cell states. Given that metabolic inputs can shape cell identities via epigenetic mechanisms, we investigated how metabolism of a non-essential amino acid, serine, affects histone modifications with key roles in cell plasticity: H3K27me3, which represses differentiation genes, and H3K4me3 which activates stemness and epithelial-to-mesenchymal transition (EMT) genes. Using a panel of human OSCC patient-derived cell lines and an orthotopic murine isograft model, we show that OSCC cells depend on exogenous serine for proliferation. Dietary serine deprivation induced de novo serine synthesis with a concomitant increase in -ketoglutarate (KG), a cofactor for KDM6B and KDM5A/B demethylases of H3K27me3 and H3K4me3, respectively. RNA-seq-derived serine deprivation gene signatures revealed activation of keratinization program and suppression of EMT and proliferation genes and tracked with good OSCC patient outcomes in TCGA. Furthermore, CUT & RUN profiling showed site-specific losses of H3K27me3 at differentiation genes and reduction of H3K4me3 at stemness, EMT and cell cycle genes. However, inhibition of KG with 2-hydroxyglutarate was not sufficient to rescue cell proliferation. Instead, genome-wide analysis revealed widespread H3K27me3-H3K4me3 bivalency, with extensive transcriptional repression of proliferation and oncogenic programs. Functionally, serine deprivation impaired orthotopic tumor growth and improved the immune landscape in syngeneic mice. Our studies identify a metabolic serine-KG-KDM-H3K27me3/H3K4me3 bivalency axis that globally reprograms OSCC chromatin as a potential therapeutic strategy to impede tumor plasticity and evolution to advanced disease. ImplicationsThis study identifies the tumor-suppressive role of dietary serine deprivation through epigenetic reprogramming of chromatin in OSCC.

cancer biology↗

bioRxiv2025

LSD1 inhibition corrects dysregulated MHC-I and dendritic cells activation through IFNγ-CXCL9-CXCR3 axis to promote antitumor immunity in HNSCC

Poor infiltration of CD8+ T cells and dysregulated MHC-I confer resistance to anticancer clinical therapies. This study aimed to elucidate the mechanisms of lysine-specific demethylase 1 (LSD1, encoded by KDM1A gene) in antitumor immunity in Head and Neck Squamous cell carcinoma (HNSCC). LSD1 inhibition in syngeneic and chronic tobacco carcinogen-induced HNSCC mice recruited activated dendritic cells (DCs), CD4+ and CD8+ T cells, enriched interferon-gamma (IFN{gamma}) in T cells, CXCL9 in DCs, and CXCR3 in T cells, as evaluated using flow cytometry and single-cell RNA-seq analysis. Humanized HNSCC mice and TCGA data validated the inverse correlation of KDM1A with DC markers, CD8+ T cells, and their activating chemokines. Kdm1a knockout in mouse HNSCC and LSD1 inhibitor treatment to co-culture of human HNSCC cells with human peripheral blood mononuclear cells (PBMCs) resulted in MHC-I upregulation in cancer cells for efficient antigen presentation in tumors. Overall, LSD1 inhibition in tumor cells upregulates MHC class I and induces DCs to produce CXCL9, which in turn activates CD8+ T cells through the CXCL9-CXCR3 axis to produce IFN{gamma}. Finally, we identified a novel mechanism by which LSD1 inhibition promotes the activation of H3K4me2 and its direct interaction with MHC-I to induce antitumor immunity. This may have implications in poorly immunogenic and immunotherapy-resistant cancers. Statement of SignificanceLSD1-mediated unique mechanisms have impact on epigenetic therapy, MHC-I resistant HNSCC therapies, and poor CD8+ and dendritic cell infilterated tumors.

cancer biology↗

bioRxiv2025

A highly resolved integrated single-cell atlas of HPV-negative head and neck cancer

Head and Neck Squamous Cell Carcinomas (HNSCC) are the seventh most prevalent form of cancer and are associated with human papilloma virus infection (HPV-positive) or with tobacco and alcohol use (HPV-negative). HPV-negative HNSCCs have a high recurrence rate, and individual patients responses to treatment vary greatly due to the high level of cellular heterogeneity of the tumor and its microenvironment. Here, we describe a HNSCC single cell atlas, which we created by integrating six publicly available datasets encompassing over 230,000 cells across 54 patients. We contextualized the relationships between existing signatures and cell populations, identified new subpopulations, and show the power of this large-scale resource to robustly identify associations between transcriptional signatures and clinical phenotypes that would not be possible to discover using fewer patients. We reveal a previously undefined myeloid population, sex-associated changes in cell type proportions, and novel interactions between CXCL8-positive fibroblasts and vascular endothelial cells. Beyond our findings, the atlas will serve as a public resource for the high-resolution characterization of tumor heterogeneity of HPV-negative HNSCC.

cancer biology↗

bioRxiv2025

Epithelial miR-149-5p up-regulation is associated with immune evasion in progressive bronchial premalignant lesions

The molecular drivers bronchial premalignant lesion progression to invasive lung squamous cell carcinoma are not well defined. Prior work profiling longitudinally collected bronchial premalignant lesion biopsies by RNA sequencing defined a proliferative subtype, enriched with bronchial dysplasia. We found that a gene co-expression module associated with interferon gamma signaling and antigen processing/presentation was down-regulated in progressive/persistent versus regressive lesions within the proliferative subtype, suggesting a functional impact of these genes on immune evasion. RNA from these same premalignant lesions was profiled by microRNA (miRNA) sequencing and a miRNA-gene network analysis identified hsa-miR-149-5p as a potential regulator of this antigen presentation gene co-expression module associated with lesion progression. hsa-miR-149-5p was found to be predominantly expressed in the epithelium and up-regulated in progressive/persistent versus regressive proliferative lesions while targets of this miRNA, the transcriptional coactivator of MHC-I gene expression, NLRC5, and the genes it regulates were down-regulated. MicroRNA in situ hybridization of hsa-miR-149-5p in tissue from adjacent fixed biopsies showed that hsa-miR-149-5p was increased in areas of bronchial dysplasia in progressive/persistent versus regressive lesions. Imaging mass cytometry showed that NLRC5 protein expression was decreased in progressive/persistent versus regressive lesions within areas of hyperplasia, metaplasia, and dysplasia. Additionally, basal cells with high versus low levels of NLRC5 were found to be in close spatial proximity to CD8 T cells, suggesting that these cells exhibit increased functional MHC-I gene expression in lesions with low hsa-miR-149-5p expression. Collectively, our data suggests a functional role for hsa-miR-149-5p in bronchial premalignant lesions and may serve as a therapeutic target for PML immunomodulation. STATEMENT OF SIGNIFICANCEIntegrative analysis across bronchial premalignant lesions has identified and localized a potential regulator of immune evasion in progressive/persistent lesions that could be a novel therapeutic target.

cancer biology↗

bioRxiv2023

Total RNA sequencing reveals gene expression and microbial alterations shared by oral pre-malignant lesions and cancer.

Head and neck cancers are a complex malignancy comprising multiple anatomical sites, with cancer of the oral cavity ranking among the deadliest and most disfiguring cancers globally. Oral cancer (OC) constitutes a subset of head and neck cancer cases, presenting primarily as tobacco-and alcohol-associated oral squamous cell carcinoma (OSCC), with a 5-year survival rate of [~]65%, partly due to the lack of early detection and effective treatments. OSCC arises from premalignant lesions (PMLs) in the oral cavity through a multi-step series of clinical and histopathological stages, including varying degrees of epithelial dysplasia. To gain insights into the molecular mechanisms associated with the progression of PMLs to OSCC, we profiled the whole transcriptome of 66 human PMLs comprising leukoplakia with dysplasia and hyperkeratosis non-reactive (HkNR) pathologies, alongside healthy controls and OSCC. Our data revealed that PMLs were enriched in gene signatures associated with cellular plasticity, such as partial EMT (p-EMT) phenotypes, and with immune response. Integrated analyses of the host transcriptome and microbiome further highlighted a significant association between differential microbial abundance and PML pathway activity, suggesting a contribution of the oral microbiome towards PML evolution to OSCC. Collectively, this study reveals molecular processes associated with PML progression that may help early diagnosis and disease interception at an early stage. AUTHOR SUMMARYPatients harboring oral premalignant lesions (PMLs) have an increased risk of developing oral squamous cell carcinoma (OSCC), but the underlying mechanisms driving transformation of PMLs to OSCC remain poorly understood. In this study, Khan et al., analyzed a newly generated dataset of gene expression and microbial profiles of oral tissues from patients diagnosed with PMLs from differing histopathological groups, including hyperkeratosis not reactive (HkNR) and dysplasia, comparing these profiles with OSCC and normal oral mucosa. Significant similarities between PMLs and OSCC were observed, with PMLs manifesting several cancer hallmarks, including oncogenic and immune pathways. The study also demonstrates associations between the abundance of multiple microbial species and PML groups, suggesting a potential contribution of the oral microbiome to the early stages of OSCC development. The study offers insights into the nature of the molecular, cellular and microbial heterogeneity of oral PMLs and suggests that molecular and clinical refinement of PMLs may provide opportunities for early disease detection and interception. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/534064v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@86cf7org.highwire.dtl.DTLVardef@129e6d1org.highwire.dtl.DTLVardef@1f0ae31org.highwire.dtl.DTLVardef@3c4d67_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2023

Generation of human alveolar epithelial type I cells from pluripotent stem cells

In the distal lung, alveolar epithelial type I cells (AT1s) comprise the vast majority of alveolar surface area and are uniquely flattened to allow the diffusion of oxygen into the capillaries. This structure along with a quiescent, terminally differentiated phenotype has made AT1s particularly challenging to isolate or maintain in cell culture. As a result, there is a lack of established models for the study of human AT1 biology, and in contrast to alveolar epithelial type II cells (AT2s), little is known about the mechanisms regulating their differentiation. Here we engineer a human in vitro AT1 model system through the directed differentiation of induced pluripotent stem cells (iPSC). We first define the global transcriptomes of primary adult human AT1s, suggesting gene-set benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, that are enriched in these cells. Next, we generate iPSC-derived AT2s (iAT2s) and find that activating nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier which produces characteristic extracellular matrix molecules and secreted ligands. Our results indicate a role for Hippo-LATS-YAP signaling in the differentiation of human AT1s and demonstrate the generation of viable AT1-like cells from iAT2s, providing an in vitro model of human alveolar epithelial differentiation and a potential source of human AT1s that until now have been challenging to viably obtain from patients.

cell biology↗

bioRxiv2023

Single Cell Transcriptomics of Fibrotic Lungs Unveils Aging-associated Alterations in Endothelial and Epithelial Cell Regeneration

Lung regeneration deteriorates with aging leading to increased susceptibility to pathologic conditions, including fibrosis. Here, we investigated bleomycin-induced lung injury responses in young and aged mice at single-cell resolution to gain insights into the cellular and molecular contributions of aging to fibrosis. Analysis of 52,542 cells in young (8 weeks) and aged (72 weeks) mice identified 15 cellular clusters, many of which exhibited distinct injury responses that associated with age. We identified Pdgfra+ alveolar fibroblasts as a major source of collagen expression following bleomycin challenge, with those from aged lungs exhibiting a more persistent activation compared to young ones. We also observed age-associated transcriptional abnormalities affecting lung progenitor cells, including ATII pneumocytes and general capillary (gCap) endothelial cells (ECs). Transcriptional analysis combined with lineage tracing identified a sub-population of gCap ECs marked by the expression of Tropomyosin Receptor Kinase B (TrkB) that appeared in bleomycin-injured lungs and accumulated with aging. This newly emerged TrkB+ EC population expressed common gCap EC markers but also exhibited a distinct gene expression signature associated with aberrant YAP/TAZ signaling, mitochondrial dysfunction, and hypoxia. Finally, we defined ACKR1+ venous ECs that exclusively emerged in injured lungs of aged animals and were closely associated with areas of collagen deposition and inflammation. Immunostaining and FACS analysis of human IPF lungs demonstrated that ACKR1+ venous ECs were dominant cells within the fibrotic regions and accumulated in areas of myofibroblast aggregation. Together, these data provide high-resolution insights into the impact of aging on lung cell adaptability to injury responses.

pathology↗

bioRxiv2021

Discovery of small molecule pathway regulators by image profile matching

Identifying chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions of candidate small molecules are tested in target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized to each disease. Here, our uncustomized, virtual profile-based screening approach instead identifies compounds that match to pathways based on phenotypic information in public cell image data, created using the Cell Painting assay. Our straightforward correlation-based computational strategy retrospectively uncovered the expected, known small molecule regulators for 32% of positive-control gene queries. In prospective, discovery mode, we efficiently identified new compounds related to three query genes, and validated them in subsequent gene-relevant assays, including compounds that phenocopy or pheno-oppose YAP1 overexpression and kill a Yap1-dependent sarcoma cell line. This image profile-based approach could replace many customized labor- and resource-intensive screens and accelerate the discovery of biologically and therapeutically useful compounds. One sentence summaryIf a genetic perturbation impacts cell morphology, a computational query can reveal compounds whose morphology "matches".

bioinformatics↗

bioRxiv2021

Structure Learning for Hierarchical Regulatory Networks

Network analysis offers a powerful technique to model the relationships between genes within biological regulatory networks. Inference of biological network structures is often performed on high-dimensional data, yet is hindered by the limited sample size of high throughput "omics" data typically available. To overcome this challenge, we exploit known organizing principles of biological networks that are sparse, modular, and likely share a large portion of their underlying architecture. We present SHINE - Structure Learning for Hierarchical Networks - a framework for defining data-driven structural constraints and incorporating a shared learning paradigm for efficiently learning multiple networks from high-dimensional data. We show through simulations SHINE improves performance when relatively few samples are available and multiple networks are desired, by reducing the complexity of the graphical search space and by taking advantage of shared structural information. We evaluated SHINE on TCGA Pan-Cancer data and found learned tumor-specific networks exhibit expected graph properties of real biological networks, recapture previously validated interactions, and recapitulate findings in literature. Application of SHINE to the analysis of subtype-specific breast cancer networks identified key genes and biological processes for tumor maintenance and survival as well as potential therapeutic targets for modulating known breast cancer disease genes.

bioinformatics↗

bioRxiv2021

Inactivation of the Hippo Tumor Suppressor Pathway Promotes Melanoma

Human melanomas are commonly driven by activating mutations in BRAF, which promote melanocyte proliferation through constitutive stimulation of the MAPK pathway. However, oncogenic BRAF alone is insufficient to promote melanoma; instead, its expression merely induces a transient burst of proliferation that ultimately ceases with the development of benign nevi (i.e. moles) comprised of growth-arrested melanocytes. The tumor suppressive mechanisms that induce this melanocytic growth arrest remain poorly understood. Recent modeling studies have suggested that the growth arrest of nevus melanocytes is not solely due to oncogene activation in individual cells, but rather due to cells sensing and responding to their collective overgrowth, similar to what occurs in normal tissues. This cell growth arrest is reminiscent of the arrest induced by activation of the Hippo tumor suppressor pathway, which is an evolutionarily conserved pathway known to regulate organ size. Herein, we demonstrate that oncogenic BRAF signaling activates the Hippo pathway in vitro, which leads to inhibition of the pro-growth transcriptional co-activators YAP and TAZ, ultimately promoting the growth arrest of melanocytes. We also provide evidence that the Hippo tumor suppressor pathway is activated in growth-arrested nevus melanocytes in vivo, both from single-cell sequencing of mouse models of nevogenesis and human tissue samples. Mechanistically, we observe that oncogenic BRAF promotes both ERK-dependent alterations in the actin cytoskeleton and whole-genome-doubling events, and that these two effects independently promote Hippo pathway activation. Lastly, we demonstrate that abrogation of the Hippo pathway, via melanocyte-specific deletion of the Hippo kinases Lats1/2, enables oncogenic BRAF-expressing melanocytes to bypass nevus formation, thus leading to the rapid onset of melanoma with 100% penetrance. This model is clinically relevant, as co-heterozygous loss of LATS1/2 is observed in [~]15% of human melanomas. Collectively, our data reveal that the Hippo pathway enforces the stable growth arrest of nevus melanocytes and therefore represents a critical and previously unappreciated barrier to melanoma development.

cancer biology↗

bioRxiv2020

ZNF416 is a pivotal transcriptional regulator of fibroblast mechano-activation

Matrix stiffness is a central regulator of fibroblast function. However, the transcriptional mechanisms linking matrix stiffness to changes in fibroblast phenotype are incompletely understood. Here, we evaluated the effect of matrix stiffness on genome-wide chromatin accessibility in freshly-isolated lung fibroblasts using assay for transposase-accessible chromatin followed by sequencing (ATAC-seq). We found higher matrix stiffness profoundly increased global chromatin accessibility relative to lower matrix stiffness, and these alterations were in close genomic proximity to known pro-fibrotic gene programs. Motif analysis of these regulated genomic loci identified ZNF416 as a putative mediator of fibroblast stiffness responses. Similarly, motif analysis of the promoters of differentially expressed genes observed in freshly sorted fibroblasts from an experimental bleomycin lung fibrosis model also identified ZNF416 as a putative mediator of in vivo fibroblast activation. Genome occupancy analysis using chromatin-immunoprecipitation followed by sequencing (ChIP-seq) confirmed that ZNF416 occupies a broad range of genes implicated in fibroblast activation and tissue-fibrosis, with relatively little overlap in genomic occupancy with other mechanoresponsive and pro-fibrotic transcriptional regulators. Using loss and gain of function studies we demonstrated that ZNF416 plays a critical role in fibroblast proliferation, extracellular matrix synthesis and contractile function. Together these observations identify ZNF416 as novel mechano-activated transcriptional regulator of fibroblast biology.

cell biology↗

bioRxiv2019

Yap suppresses T cell function and infiltration in the tumor microenvironment

A major challenge for cancer immunotherapy is sustaining T cell activation and recruitment in immunosuppressive solid tumors. Here we report that Yap levels are sharply induced upon activation of CD4+ and CD8+ T cells and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap in T cells results in enhanced T cell activation, differentiation and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors. Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicates Yap as a mediator of global T cell responses in the tumor microenvironment and as a key negative regulator of T cell tumor infiltration and patient survival in diverse human cancers. Collectively, our results indicate that Yap plays critical roles in T cell biology, and suggest that inhibiting Yap activity improves T cell responses in cancer.

cancer biology↗

bioRxiv2019

iEDGE: integration of Epi-DNA and Gene Expression and applications to the discovery of somatic copy number-associated drivers in cancer

The emergence of large-scale multi-omics data warrants method development for data integration. Genomic studies from cancer patients have identified epigenetic and genetic regulators - such as methylation marks, somatic mutations, and somatic copy number alterations (SCNAs), among others - as predictive features of cancer outcome. However, identification of \"driver genes\" associated with a given alteration remains a challenge. To this end, we developed a computational tool, iEDGE, to model cis and trans effects of (epi-)DNA alterations and identify potential cis driver genes, where cis and trans genes denote those genes falling within and outside the genomic boundaries of a given (epi-)genetic alteration, respectively.\n\nFirst, iEDGE identifies the cis and trans genes associated with the presence/absence of a particular epi-DNA alteration across samples. Tests of statistical mediation are then performed to determine the cis genes predictive of the trans gene expression. Finally, cis and trans effects are annotated by pathway enrichment analysis to gain insights into the underlying regulatory networks.\n\nWe used iEDGE to perform integrative analysis of SCNAs and gene expression data from breast cancer and 18 additional cancer types included in The Cancer Genome Atlas (TCGA). Notably, cis gene drivers identified by iEDGE were found to be significantly enriched for known driver genes from multiple compendia of validated oncogenes and tumor suppressors, suggesting that the remainder are of equal importance. Furthermore, predicted drivers were enriched for functionally relevant cancer genes with amplification-driven dependencies, which are of potential prognostic and therapeutic value. All the analyses results are accessible at https://montilab.bu.edu/iEDGE.

bioinformatics↗

bioRxiv2017

CaDrA: A computational framework for performing candidate driver analyses using binary genomic features

Identifying complementary genetic drivers of a given phenotypic outcome is a challenging task that is important to gaining new biological insight and discovering targets for disease therapy. Existing methods aimed at achieving this task lack analytical flexibility. We developed Candidate Driver Analysis or CaDrA, a framework to identify functionally-relevant subsets of binary genomic features that, together, are associated with a specific outcome of interest. We evaluate CaDrAs sensitivity and specificity for typically-sized multi-omic datasets, and demonstrate CaDrAs ability to identify both known and novel drivers of oncogenic activity in cancer cell lines and primary tumors.

bioinformatics↗

bioRxiv2016

Systematic morphological profiling of human gene and allele function reveals Hippo-NF-κB pathway connectivity

We hypothesized that human genes and disease-associated alleles might be systematically functionally annotated using morphological profiling of cDNA constructs, via a microscopy-based Cell Painting assay. Indeed, 50% of the 220 tested genes yielded detectable morphological profiles, which grouped into biologically meaningful gene clusters consistent with known functional annotation (e.g., the RAS-RAF-MEK-ERK cascade). We used novel subpopulation-based visualization methods to interpret the morphological changes for specific clusters. This unbiased morphologic map of gene function revealed TRAF2/C-REL negative regulation of YAP 1/WWTR1-responsive pathways. We confirmed this discovery of functional connectivity between the O_SCPCAPNF-C_SCPCAP{kappa}O_SCPCAPBC_SCPCAP pathway and Hippo pathway effectors at the transcriptional level, thereby expanding knowledge of these two signaling pathways that critically regulate tumor initiation and progression. We make the images and raw data publicly available, providing an initial morphological map of major biological pathways for future study.

systems biology↗