Research
Our laboratory investigates how fusion oncogenes, the extracellular matrix and tumor microenvironmental cues regulate cellular identity, lineage plasticity and therapeutic response in sarcoma. Using bioengineering, single-cell and spatial omics, functional genomics and multiplex imaging, we define how mechanical and molecular signals shape tumor cell states and differentiation trajectories. We collaborate with pharmaceutical partners to study therapeutic vulnerabilities in fusion-driven sarcomas, with a particular focus on the IGF1/PI3K/mTOR signaling axis and mechanisms of drug resistance. Leveraging access to one of the world's largest sarcoma patient populations at MD Anderson, we develop patient-informed models that faithfully recapitulate native tumor biology. Our research centers on rare sarcomas like Ewing sarcoma and desmoplastic small round cell tumor (DSRCT), two aggressive EWSR1 fusion-driven malignancies. Ultimately, we integrate multimodal clinical, omics, spatial, and radiomic data to build AI-powered digital twins that predict tumor evolution, therapeutic response and personalized treatment strategies.
Mapping Cellular Differentiation and Lineage Plasticity in Sarcoma
Sarcomas are among the most biologically diverse human cancers, encompassing more than 50 subtypes with distinct genetic drivers, cellular phenotypes and developmental origins. A central question in our laboratory is how normal mesenchymal differentiation programs influence susceptibility to oncogenic transformation and shape tumor behavior. Although many sarcomas are classified according to their resemblance to mature mesenchymal tissues, the precise differentiation states from which these tumors arise and the mechanisms by which these states influence tumor evolution remain largely unknown. Leveraging advances in single-cell genomics, computational biology and cancer systems biology, our research seeks to define the cellular hierarchies that govern sarcoma initiation, progression, and therapeutic response.
To enable these studies, we developed the Mesenchymal Tissue Landscape (MTL), a high-resolution single-cell reference atlas of human mesenchymal differentiation spanning osteogenic, adipogenic and chondrogenic lineages. Using normalized non-negative matrix factorization (N-NMF)-based archetype analysis, we identified conserved transcriptional programs that define discrete mesenchymal cell states and lineage trajectories. This framework provides a powerful platform for mapping sarcoma cells onto normal developmental programs, uncovering the cellular states most susceptible to transformation, and identifying lineage-associated vulnerabilities that may serve as novel therapeutic targets.
Truong, Danh D., et al. "Mapping the single-cell differentiation landscape of osteosarcoma." Clinical Cancer Research 30.15 (2024): 3259-3272.
Denu, Ryan A., et al. "Spatially-resolved single cell atlas of liposarcoma reveals lineage hierarchies, immune niches, and regulatory circuits." bioRxiv (2026).
Understanding Resistance Mechanisms and Developing Treatment Strategies in Sarcoma
Our laboratory investigates how lineage plasticity drives tumor progression and therapeutic resistance in desmoplastic small round cell tumor (DSRCT), a rare and aggressive sarcoma. We previously identified androgen receptor (AR) signaling as a critical dependency in DSRCT and uncovered epigenetic mechanisms that maintain tumor identity.
Building on these findings, we recently discovered that DSRCT can undergo neural (NE) reprogramming, a phenomenon associated with resistance to androgen-targeted therapies. Current studies focus on defining the cellular and molecular mechanisms underlying these lineage transitions, including whether DSRCT cells dedifferentiate through a stem-like intermediate state or directly transdifferentiate into NE-like cells. Using single-cell genomics, epigenomics and functional perturbation approaches, we aim to identify the regulatory networks that enable cell-state plasticity and uncover therapeutic strategies to prevent or reverse treatment-resistant tumor states.
Lamhamedi-Cherradi, Salah-Eddine, et al. "The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma." Nature communications 13.1 (2022): 3057.
Magrath, Justin W., et al. "Enzalutamide induces cytotoxicity in desmoplastic small round cell tumor independent of the androgen receptor." Communications Biology 7.1 (2024): 411
Truong, Danh D., Roberto Cardenas-Zuniga, and Joseph A. Ludwig. "Desmoplastic Small Round Cell Tumors and the Role of Androgen Receptors." Current treatment options in oncology 26.7 (2025): 638-647.
Spatial Image Omics of Sarcoma
Our laboratory leverages advanced spatial biology approaches to define how tumor cells interact with their microenvironment and how fusion oncogenes shape cellular identity in sarcoma. We utilize highly multiplexed immunofluorescence (mIF) to characterize the composition, organization, and functional states of tumor, immune, and stromal cell populations in Ewing sarcoma (ES), desmoplastic small round cell tumor (DSRCT), and other rare sarcomas. The Lunaphore COMET™ platform enables quantitative imaging of more than 40 markers simultaneously from archival formalin-fixed paraffin-embedded (FFPE) tissues, providing a robust and reproducible framework for studying tumor ecosystem architecture at single-cell resolution.
To complement protein-level analysis, we integrate spatial transcriptomics and RNA in situ hybridization (RNAscope) to map gene expression programs directly within their histologic context. A particular focus of our work is the detection and spatial localization of fusion-driven neotranscripts generated by oncogenic fusion proteins such as EWSR1::FLI1 and EWSR1::WT1. By combining spatial transcriptomics, RNAscope and multiplex imaging, we can identify fusion-specific transcriptional programs, characterize intratumoral heterogeneity and determine how distinct cellular states interact with the immune and stromal microenvironment. These studies provide critical insight into how fusion oncogenes regulate tumor identity, lineage plasticity and therapeutic response, while enabling the discovery of spatially informed biomarkers and therapeutic vulnerabilities in rare sarcomas.
Truong, Danh D., et al. "EWS:: WT1 Isoform-Dependent Regulation of Neogenes in Desmoplastic Small Round Cell Tumors." bioRxiv (2025).
Advanced Clinical Trials and Digital Twins for Precision Sarcoma Medicine
Our laboratory develops innovative clinical trial frameworks and AI-powered digital twins to accelerate precision medicine for patients with rare sarcomas. By integrating longitudinal clinical data, radiomics, pathology, patient-reported outcomes and multiomic profiling, we create dynamic computational models that continuously learn from each patient's disease trajectory and predict treatment response, toxicity, and relapse risk. We leverage these platforms to support adaptive and platform trial designs, optimize patient selection, identify biomarkers of response, and evaluate novel therapeutics more efficiently in rare cancer populations. Through collaborations with clinicians, industry partners and data scientists, we aim to transform sarcoma care from a reactive, population-based approach to a predictive, patient-specific strategy. This work builds on our vision of a sarcoma digital twin that integrates multimodal clinical, molecular, spatial and imaging data to guide individualized treatment decisions and accelerate drug development.