Nakagawa Lab

Our lab investigates how esophageal squamous cell carcinoma (ESCC) arises and evolves, with a focus on the molecular events that transform normal epithelium into therapy-resistant cancer. Using patient- and mouse-derived organoids, engineered cell systems, and complementary in vivo models, we recreate the continuum from normal tissue to preneoplasia to invasive carcinoma and even metastasis. These platforms allow us to probe oncogenic signaling pathways, cellular heterogeneity, and evolutionary pressures that shape tumor behavior. Coupled with high-throughput screening of large compound libraries, our work identifies vulnerabilities that can be translated into more effective treatments.

This research establishes a mechanistic foundation for precision therapy in ESCC, enabling drug discovery efforts in models that closely reflect patient biology. These models provide the experimental backbone that supports virtually all other research objectives in the lab, including environmental exposures, DNA damage responses, and epithelial stress pathways.

Alcohol exposure remains one of the strongest environmental risk factors for ESCC, yet the cellular mechanisms linking exposure to cancer progression are far from completely understood. This objective explores how metabolic stress and impaired mitochondrial homeostasis influence epithelial cell fate and carcinogenesis, particularly in the context of ALDH2 biology, responsible for alcohol detoxification in the cell. Through organoid systems, genetically modified models, and mechanistic molecular studies, we examine how environmental insults reshape tissue responses, promote genomic instability, and create conditions permissive for cancer initiation.

By defining how common exposures drive disease at the cellular level, this work opens pathways for prevention strategies and targeted interventions aimed at reducing cancer risk. Findings from this objective directly inform our ESCC models and connect closely to studies of DNA repair pathways, including Fanconi anemia–associated vulnerability.

Inherited defects in DNA repair pathways, such as those seen in Fanconi anemia (FA), create profound susceptibility to young-onset squamous cell carcinomas (SCC). This objective uses organoid models to investigate how epithelial cells with impaired DNA damage responses react to environmental stress and accumulate oncogenic alterations. By modeling these interactions in physiologically relevant systems, we aim to identify early events that predispose cells to malignant transformation as well as DNA repair pathway addiction of SCC.

This work provides critical insight into cancer prevention in high-risk populations while uncovering universal mechanisms of DNA repair failure and addiction relevant to sporadic SCC. Mechanisms uncovered here feed directly into our broader studies of environmental risk and SCC pathogenesis, informing both mechanistic understanding and therapeutic targeting.

Epithelial tissues constantly respond to inflammatory and environmental stress, and these responses can shape long-term disease risk. This objective investigates how autophagy and stress-response pathways regulate epithelial remodeling in esophageal disease states. Using advanced 3D culture systems and molecular analysis, we examine how adaptive cellular processes influence tissue architecture, survival, and progression toward pathology in the context of Eosinophilic Esophagitis, a chronic inflammatory disease of the esophagus, driven by food allergens.

Understanding how epithelial tissues adapt—or fail to adapt—to stress reveals mechanisms that may underlie both inflammatory disease and malignant transformation. Insights into autophagy and remodeling provide important biological context for our cancer-focused projects, highlighting shared pathways between tissue repair, chronic inflammation, and carcinogenesis.

(P30DK132710  — Organoid and Cell Culture Core, OCCC)

A central mission of the lab is the development and dissemination of cutting-edge three-dimensional culture systems that bring human biology into experimental research. Through leadership of the Organoid and Cell Culture Core (OCCC), we develop, engineer, and distribute well-annotated organoid models derived from patients and mouse models, spanning normal tissue, preneoplasia, and cancer. The core also provides training, genetic engineering support, and scalable platforms for collaborative research across the cancer and digestive disease communities.

By enabling investigators to work in physiologically relevant models, the OCCC accelerates discovery, improves reproducibility, and supports translational precision oncology research at scale. The organoid platform is the unifying axis across all research objectives, allowing discoveries in one project to rapidly inform and advance others.

To learn more about the OCCC, please visit us at our DLDRC webpage here.