Biology subjects

Kleiner, D. E.

Publications and source records attributed to Kleiner, D. E..

6 recordsLinked to original sources

bioRxiv2026

Tumor-specific Kinase Motif Enrichment Analysis Identifies Personalized Therapeutic Cancer Targets

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are an uncommon and poorly understood malignancy with low mutational burden, lacking well-defined oncogenic drivers. GEP-NET mortality frequently results from extensive hepatic metastases. Accordingly, we interrogated phosphoproteomic data from GEP-NET liver metastases and patient-matched uninvolved liver to identify tumor-specific signaling and targetable tumor vulnerabilities using Kinase Motif Enrichment Analysis (KMEA), a new tool leveraging the recent Kinase Library compendium of the substrate motif specificity for nearly the entire human kinome. KMEA identified patient tumor-specific upregulation of mTOR or casein kinase 2 (CK2) activity that would be undiscoverable by standard personalized genomic and transcriptomic approaches. Striking concordance was observed between KMEA predictions for specific tumors, and their sensitivity to inhibitors of mTOR or CK2 using patient tumor-derived organoids. These findings reveal potential clinically-actionable protein kinases hyperactivated in GEP-NETs, and more broadly indicate a general method for personalized cancer treatment using phosphoproteomics and KMEA-derived kinase activity signatures.

cancer biology↗

bioRxiv2026

Hepatobiliary Progenitor-like Reprogramming in Liver Metastases

Metastatic progression requires cancer cells to adapt to the unique constraints of distant organ microenvironments, yet the mechanisms that drive organ-specific adaptations remain poorly understood. Here, we show that the liver actively rewrites metastatic cancer cell identity, driving tumor cells toward a hepatobiliary progenitor-like state. Through integrated transcriptomic, proteomic, metabolomic, and epigenomic analyses of patient-derived rapid-autopsy samples and experimental models, we identify this state as selectively enriched in liver metastases. It is characterized by co-activation of hepatic and biliary/progenitor regulators HNF4A and SOX9 and is observed across multiple epithelial cancers, indicating a conserved response to the hepatic niche. Mechanistically, hepatocyte-derived TGF-{beta} and hypoxia converge to activate a HIF-1-ACLY axis, increasing nuclear acetyl-coenzyme A availability and histone acetylation at hepatic lineage regulatory elements to drive hepatobiliary reprogramming. This coordinated niche-response program can be captured transcriptionally and is associated with inferior overall survival. Disruption of this pathway suppresses hepatic reprogramming and impairs liver metastatic fitness. These findings identify the liver as an active determinant of metastatic cell fate, linking microenvironmental signaling to metabolic and chromatin remodeling programs that enable lineage plasticity. More broadly, they reveal organ-specific reprogramming as a fundamental principle of metastasis and a therapeutic vulnerability in liver metastases.

cancer biology↗

bioRxiv2025

Exhausted-like effector CD8 T cells mediate immune-stromal interactions at mucosal Chronic Graft-versus-Host Disease onset

Chronic graft-versus-host disease (cGVHD) frequently follows allogeneic hematopoietic stem cell transplantation and impacts the mucosa. This atlas study highlights the role of exhausted-like effector CD8+ T cells (TEXEF) in oral mucosal cGVHD pathogenesis. Biopsies from the oral mucosa were collected at oral cGVHD onset or at six months post-transplant and analyzed using single-cell RNA sequencing and other modalities. At cGVHD onset, in addition to changes in the myeloid compartment, two distinct populations of CD8+T cells with a TEXEF phenotype were prevalent: an inflammatory CD8T cell cluster (CD8T_4) expressing CCL4, CD69, and TNFSF9, and an exhausted CD8T cell cluster (CD8T_5) characterized by the expression of CXCL13, HIF1A, and HLA-DRA, both correlated with clinical disease severity. Pseudo-time analysis suggests a transition from the inflammatory pre-exhausted CD8T_4 cluster to the cytolytic, terminally exhausted CD8T_5 cluster. The CXCL9-CXCR3 interactions among CD8+ T cells, fibroblasts and myeloid cells are implicated in tissue damage. Onset of cGVHD despite frequent oral mucosal FOXP3 regulatory CD4T cells suggests potential impaired Treg function or CD8+T cell dysfunction. These findings highlight TEXEF cells as key contributors to oral cGVHD pathology and potential therapeutic targets for mitigating sustained tissue injury in cGVHD.

immunology↗

bioRxiv2024

Spatial Deconvolution of Cell Types and Cell States at Scale Utilizing TACIT

Identifying cell types and states remains a time-consuming and error-prone challenge for spatial biology. While deep learning is increasingly used, it is difficult to generalize due to variability at the level of cells, neighborhoods, and niches in health and disease. To address this, we developed TACIT, an unsupervised algorithm for cell annotation using predefined signatures that operates without training data, using unbiased thresholding to distinguish positive cells from background, focusing on relevant markers to identify ambiguous cells in multiomic assays. Using five datasets (5,000,000-cells; 51-cell types) from three niches (brain, intestine, gland), TACIT outperformed existing unsupervised methods in accuracy and scalability. Integration of TACIT-identified cell with a novel Shiny app revealed new phenotypes in two inflammatory gland diseases. Finally, using combined spatial transcriptomics and proteomics, we discover under- and overrepresented immune cell types and states in regions of interest, suggesting multimodality is essential for translating spatial biology to clinical applications.

bioinformatics↗

bioRxiv2022

Comparative Analysis of Global Hepatic Gene Expression in Adolescents and Adults with Non-alcoholic Fatty Liver Disease

IntroductionTo gain insights into the mechanisms underlying distinct nonalcoholic fatty liver disease (NAFLD) histological phenotypes between children and adults, we compared hepatic gene expression profiles associated with NAFLD phenotypes between the two age groups. MethodsHistological characteristics of intra-operative liver biopsies from adolescents and adults undergoing bariatric surgery were assessed by the same pathologist using the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Hepatic gene expression was measured by microarray analysis. Transcriptomic signatures of histological phenotypes between the two groups were compared, with significance defined as p-value <0.05 and a fold change >1.5. ResultsIn 67 adolescents and 76 adults, distribution of histological phenotypes was: not-NAFLD (controls) 51% vs 39%, NAFL 39% vs 37%, and NASH 10% vs 24%, respectively. There were 279 differentially expressed genes in adolescents and 213 in adults with NAFLD vs controls. In adolescents, transcriptomes for NAFL vs controls, and borderline vs definite NASH were undifferentiable, whereas in adults, NAFL and borderline NASH demonstrated a transcriptomic gradient between controls and definite NASH. When applied to adolescents, significant adult genes discriminated borderline and definite NASH from control and NAFL, but the majority of significant pediatric genes were not portable to adults. Genes associated with NASH in adolescents and adults showed some ontological consistency but notable differences. ConclusionsThere is some similarity but major differences in the transcriptomic profiles associated with NAFLD between adolescents and adults with severe obesity. These data suggest different mechanisms contribute to the pathogenesis of NAFLD severity at different stages in life. Study HighlightsO_ST_ABSWHAT IS KNOWNC_ST_ABSO_LINonalcoholic fatty liver disease (NAFLD) is the most common liver disease in children and adults C_LIO_LINAFLD histological features and severity differ between children and adults but reasons for these differences are not clear. C_LI WHAT IS NEW HEREO_LIComparison of hepatic gene expression profiles between adolescents and adults with severe obesity and NAFLD showed some similarities but major differences in expressed genes C_LIO_LIThe findings suggest the mechanisms driving different NAFLD severity and phenotypes are different at different stages in life. C_LI

genetics↗

bioRxiv2020

Single-cell atlas of tumor clonal evolution in liver cancer

Tumor evolution is a key feature of tumorigenesis and plays a pivotal role in driving intratumor heterogeneity, treatment failure and patients prognosis. Here we performed single-cell transcriptome profiling of 46 primary liver cancers from 37 patients enrolled for interventional studies. We surveyed the landscape of ~57,000 malignant and non-malignant cells and determined tumor cell clonality by developing a machine learning-based consensus clustering method. We found evidence of tumor cell branching evolution using hierarchical clustering, RNA velocity as well as reverse graph embedding methods. Interestingly, an increasing tumor cell clonality was tightly linked to patients prognosis, accompanied by a polarized immune cell landscape. We identified osteopontin as a key player for tumor cell evolution and microenvironmental reprogramming. Our study offers insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers for tumor evolution in response to therapy.

cancer biology↗