William Hwang

Research in the Hwang Laboratory is anchored on the immense phenotypic, temporal and spatial heterogeneity of tumor ecosystems and the many insights that can only be gleaned by studying these systems at the level of their individual components—single molecules or cells. Hence, our research is focused on the high-resolution study of tumor-stroma interactions through the development and application of experimental and computational techniques in single-cell and spatial biology, neuroscience, advanced microscopy, and functional genetic screens to patient-derived specimens, three-dimensional tumoroid co-cultures, and genetically-engineered mouse models to answer critical questions in cancer neurobiology and therapeutic resistance. We aim to study general oncological mechanisms but have a particular interest in pancreatic and other gastrointestinal cancers.   Intratumoral nerves play a critical role in the pathophysiology and morbidity of many malignancies but remain poorly understood. To address this gap in knowledge, we are identifying cell-type specific mediators of nerve recruitment and perineural invasion, as well as dissecting dynamic mechanisms of collaboration between tumor cells and the peripheral nervous system including biochemical, metabolic, physical, and electrical interactions using approaches such as spatial proteotranscriptomics, high-resolution and super-resolution microscopy, tumoroid co-culture, functional neuroscience, optogenetics, and in vivo models. We anticipate that these pioneering studies will uncover fundamental new biology in the burgeoning field of cancer neuroscience while identifying new opportunities for therapeutic intervention.   Furthermore, we are investigating the genetic, epigenetic, and phenotypic factors including cell state plasticity and microenvironmental context that mediate therapeutic resistance. Our team is assessing the roles of plasticity versus selection of malignant cell states under cytotoxic stress using barcode-based lineage tracing approaches. We are also interested in identifying the key regulator(s), context dependence, mechanisms of immune evasion, and therapeutic vulnerabilities specific to treatment-enriched malignant phenotypes. Given the increasingly recognized importance of the tumor microenvironment, we are innovating new methods to discover mechanisms of therapeutic resistance at the tumor-stromal interface using single-cell spatial transcriptomics and stromal tumoroids.