Biology subjects

Mu, P.

Publications and source records attributed to Mu, P..

9 recordsLinked to original sources

bioRxiv2025

ATHENA: A deep learning-based AI for functional prediction of genomic mutations and synergistic vulnerabilities in prostate cancer

Identifying functional mutations that drive therapy resistance remains a major challenge in prostate cancer. Large-scale sequencing often produces extensive lists of mutations but provides limited insight into which alterations are functionally relevant. To overcome this gap, we developed ATHENA (Attention-based Therapeutic Network Analyzer), a deep learning-based AI framework that predicts the functional impact of genomic mutations and reveals their synergistic vulnerabilities. Integrated with our RNA/DNA-informed variant discovery pipeline OncoVar, ATHENA models nonlinear dependencies among mutations to distinguish driver events from passenger variants. Trained on large multi-cohort datasets and interpreted using SHAP analysis, ATHENA not only stratifies patients by clinical outcomes but also predicts which specific mutations alter tumor behavior and therapy response, enabling direct validation through base editing experiments. Applied to prostate cancer progression models, the OncoVar-ATHENA framework identified stage-specific driver signatures across castration-resistant, AR-variant-driven, and metastatic disease, and uncovered cooperative interactions such as SYVN1-STC2 that promote tumor proliferation. By moving beyond simple mutation identification, ATHENA enables functional prediction of genomic interactions. This approach accelerates the discovery of actionable targets and provides a foundation for rational design of next-generation combination therapies in advanced prostate cancer.

cancer biology↗

bioRxiv2025

Graded Notch Signaling Functions as a Rheostat of Lineage Plasticity and Therapy Resistance in Prostate Cancer

Resistance to androgen receptor (AR)-targeted therapies such as enzalutamide in castration-resistant prostate cancer (CRPC) often arises through lineage plasticity, yet the molecular mechanisms that define this process remain incompletely understood. While previous studies reported that Notch1 and Notch2 exert distinct and sometimes opposing effects in prostate cancer differentiation, the integrated role of Notch pathway activity has not been systematically explored. Here, we identify Notch signaling as a graded Rheostat that governs prostate cancer cell fate transitions. Integrative transcriptomic and functional analyses revealed that intermediate Notch activity maintains a stem-like progenitor state, whereas reduced or elevated signaling drives divergent differentiation trajectories toward luminal or neuroendocrine lineages, respectively. During CRPC progression and enzalutamide resistance, Notch signaling becomes dynamically rewired, peaking in progenitor-like populations that sustain plasticity and survival. Both CRISPR-mediated knockout and pharmacologic inhibition of Notch signaling depleted these progenitor cells and restored enzalutamide sensitivity. These findings demonstrate that the level, rather than the binary presence, of Notch signaling dictates lineage directionality and therapeutic response in CRPC, establishing it as a tunable and actionable driver of resistance.

cancer biology↗

bioRxiv2025

RUNX1T1-HDAC Reprogramming of the HOX Code Signaling Drives a Targetable Pan-Cancer Lineage Plasticity

Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression by enabling cancer cells to alter identity and evade targeted therapies. Although genomic and transcriptomic aberrations correlate with lineage plasticity, the absence of pan-cancer markers to rapidly identify plastic subtypes has limited predictive utility. Homeobox (HOX) genes encode transcription factors that define tissue identity through distinct expression patterns, or HOX codes, in specific lineages. By analyzing multi-omics data, including 39 HOX genes from over 80,000 RNA-seq samples across 114 cancer types, we discovered that HOX code expression robustly represents cancer cell lineages and reveals multiple previously unrecognized lineage-plastic subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML), each displaying altered HOX patterns compared to non-plastic subtypes. Differential analysis further identified RUNX1T1 as a novel and consistent marker of plasticity, elevated across all three cancer types and correlating with HOX code and lineage-plastic marker genes. We validated these correlations in bulk and single-cell RNA-seq from extensive preclinical and clinical cohorts and provided direct functional evidence that RUNX1T1 is required for lineage-plastic programs in prostate cancer. Using AI-based modeling, we identified NCOR/HDAC as RUNX1T1 binding partners forming a co-repressor complex that regulates HOX codes and plasticity. Finally, pharmacologic HDAC inhibition selectively suppressed the growth of plastic cells, revealing a novel therapeutic vulnerability. These findings establish ectopic RUNX1T1 as a pan-cancer biomarker and critical mediator of lineage plasticity and identify the RUNX1T1-HDAC complex as a druggable target.

cancer biology↗

bioRxiv2025

Notch as a Driver of Lineage Plasticity and Therapeutic Target in Enzalutamide-Resistant Prostate Cancer

Resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, in castration-resistant prostate cancer (CRPC) remains a significant clinical challenge, often driven by mechanisms including lineage plasticity. The precise molecular mechanisms driving this process, particularly downstream effectors, remain incompletely understood. Given its established roles in cell fate and stemness, alongside its complex functions in prostate cancer, the Notch signaling pathway presented a compelling focus for study. This study investigates the role of Notch signaling in mediating lineage plasticity and therapeutic resistance in CRPC. Employing transcriptomic analysis and functional assays, we identified Notch activity is elevated across prostate cancer progression resistance. Notably, both CRISPR-mediated knockout and targeted inhibition of Notch reversed enzalutamide resistance in vitro. Collectively, this study delineates dynamic alterations in Notch signaling activity during prostate cancer progression and establishes its function as a crucial and druggable driver of therapy resistance. These findings underscore Notch signaling as a promising therapeutic target to counteract resistance to AR-targeted therapies in advanced prostate cancer.

cancer biology↗

bioRxiv2025

Pan-cancer Analysis Identified Ectopic RUNX1T1 Associated with Lineage Plasticity

Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression, allowing cancer cells to rapidly alter their identity and evade targeted therapies. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the lack of pan-cancer gene markers quantifying lineage plasticity has limited its utility as a predictive biomarker. Homeobox (HOX) genes encode a family of transcription factors that play critical roles in embryonic development and tissue identity by establishing distinct expression patterns, known as HOX codes, in specific cell lineages. Through comprehensive bioinformatic analysis of multi-omics data--including expression profiles of 39 HOX genes from over 80,000 RNA sequencing samples across 114 cancer types--we first demonstrated that HOX codes effectively represent the lineages of cancer cells. We then identified multiple lineage-plastic cancer subtypes by applying the calculated HOX codes. Specifically, we identified lineage-plastic tumor subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML), which exhibit altered HOX codes compared to non-plastic subtypes. Downstream differential expression analysis revealed significantly elevated RUNX1T1 levels across all three lineage-plastic cancer types, which was further validated through bulk and single-cell RNA sequencing data derived from preclinical and clinical samples. Together, our findings provide a novel strategy for characterizing lineage plasticity in pan-cancer cells and suggest ectopic RUNX1T1 expression as a pan-cancer marker and critical mediator of lineage plasticity.

cancer biology↗

bioRxiv2025

Androgen Deprivation-Induced TET2 Activation Fuels Prostate Cancer Progression via Epigenetic Priming and Slow-Cycling Cancer Cells

Advanced prostate cancer (PCa) frequently develops resistance to androgen deprivation therapy through various mechanisms including lineage plasticity. Slow-cycling cells (SCCs) have emerged as key players in adaptive responses to therapy, yet their role in PCa remains unclear. Through in silico analysis of single-cell RNA sequencing (scRNA-seq) data, we discovered that SCCs are enriched during pivotal stages of PCa progression, including the transition from androgen-dependent to castration-resistant states and the emergence of neuroendocrine PCa (NEPC). Using a tetracycline-inducible H2BeGFP reporter system, we confirmed SCC enrichment following androgen deprivation in both in vitro and in vivo models. Furthermore, we identified TET2 as a key regulator of SCCs, with its expression upregulated by androgen deprivation and positively correlated with SCC signature scores in PCa. Genome-wide 5-hydroxymethylcytosine (5hmC) profiling revealed increased hydroxymethylation after androgen deprivation, while TET2 knockdown reduced 5hmC levels at specific loci. Functional studies demonstrated that TET2 governs SCC maintenance, cell cycle progression, and DNA damage repair. Targeting TET2, either alone or in combination with an ATM inhibitor, significantly suppressed tumor growth, highlighting TET2 as a promising therapeutic target. Our study provides the first single-nucleotide resolution map of 5hmC dynamics in PCa, identifies a cell state driving epigenetic rewiring, and underscores the transformative potential of novel therapeutic strategies for advanced PCa.

cancer biology↗

bioRxiv2023

ZNF397 Loss Triggers TET2-driven Epigenetic Rewiring, Lineage Plasticity, and AR-targeted Therapy Resistance in AR-dependent Cancers

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide co-activator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate and breast cancers acquire lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Statement of SignificanceThis study reveals a novel epigenetic mechanism regulating tumor lineage plasticity and therapy response, enhances understanding of drug resistance and unveils a new therapeutic strategy for prostate cancer and other malignancies. Our findings also illuminate TET2s oncogenic role and mechanistically connect TET2-driven epigenetic rewiring to lineage plasticity and therapy resistance.

cancer biology↗

bioRxiv2023

Mapping Cell-to-cell Interactions from Spatially Resolved Transcriptomics Data

Cell-cell communication (CCC) is essential to how life forms and functions. However, accurate, high-throughput mapping of how expression of all genes in one cell affects expression of all genes in another cell is made possible only recently, through the introduction of spatially resolved transcriptomics technologies (SRTs), especially those that achieve single cell resolution. However, significant challenges remain to analyze such highly complex data properly. Here, we introduce a Bayesian multi-instance learning framework, spacia, to detect CCCs from data generated by SRTs, by uniquely exploiting their spatial modality. We highlight spacias power to overcome fundamental limitations of popular analytical tools for inference of CCCs, including losing single-cell resolution, limited to ligand-receptor relationships and prior interaction databases, high false positive rates, and most importantly the lack of consideration of the multiple-sender-to-one-receiver paradigm. We evaluated the fitness of spacia for all three commercialized single cell resolution ST technologies: MERSCOPE/Vizgen, CosMx/Nanostring, and Xenium/10X. Spacia unveiled how endothelial cells, fibroblasts and B cells in the tumor microenvironment contribute to Epithelial-Mesenchymal Transition and lineage plasticity in prostate cancer cells. We deployed spacia in a set of pan-cancer datasets and showed that B cells also participate in PDL1/PD1 signaling in tumors. We demonstrated that a CD8+ T cell/PDL1 effectiveness signature derived from spacia analyses is associated with patient survival and response to immune checkpoint inhibitor treatments in 3,354 patients. We revealed differential spatial interaction patterns between {gamma}{delta} T cells and liver hepatocytes in healthy and cancerous contexts. Overall, spacia represents a notable step in advancing quantitative theories of cellular communications.

bioinformatics↗

bioRxiv2021

JAK-STAT Signaling Enables Lineage Plasticity-driven AR Targeted Therapy Resistance

Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity-driven resistance, the molecular mechanisms of acquiring lineage plasticity have not been fully elucidated. Through integrated transcriptomic and single cell RNA-Seq (scRNA-Seq) analysis of more than 80,000 cells, we reveal for the first time that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven AR targeted therapy resistance in prostate cancer. Ectopic activation of JAK-STAT signaling is specifically required for the AR targeted therapy resistance of subclones expressing multilineage, stem-like and epithelial-to-mesenchymal transition (EMT) lineage transcriptional programs and represents a potential therapeutic target for overcoming AR targeted therapy resistance. One-Sentence SummaryJAK-STAT signaling is a crucial executor in promoting lineage plasticity-driven AR therapy resistance in prostate cancer.

cancer biology↗