2023 Grantee: William L. Hwang, MD, PhD
Massachusetts General Hospital
Research Project: Mechanisms of Cancer-Nerve Dynamics in Pancreatic Cancer
Award: 2023 Pancreatic Cancer Action Network Career Development Award funded by Rick Star in Memory of Janet Ranta Star
Award Period: July 1, 2023 – June 30, 2025
Dr. William Hwang is a principal investigator and physician-scientist at the Center for Systems Biology, Center for Cancer Research, and Department of Radiation Oncology at Massachusetts General Hospital and Harvard Medical School where he leads the Laboratory for Spatial and Systems Oncology, cares for patients with gastrointestinal malignancies and serves as associate director of the Radiation Biology & Research Program.
Dr. Hwang has a long-standing interest in the immense temporal and spatial heterogeneity of biological systems and the many insights that can only be gleaned by studying systems at the level of their individual components – single molecules or cells. His laboratory studies tumor-stromal interactions through the development and application of novel techniques in advanced microscopy, single-cell and spatial biology, and genetic engineering to patient-derived specimens, stromal tumoroids and mouse models. Current project areas include mechanisms of therapeutic resistance mediated by cell state plasticity, and tumor-nerve interactions, which are remarkably important in the pathogenesis of many cancers but poorly understood. His work has been honored with a Rhodes Scholarship, ASCO/CCF Young Investigator Award, AACR NextGen Star Award, and 40 under 40 in Cancer Award – Rising Stars and Emerging Leaders.
Emerging evidence indicates that the active recruitment of nerve fibers into tumors and subsequent cancer cell invasion (known as perineural invasion) play an important role in cancer development, metastasis, therapeutic resistance, recurrence, pain, and death across many cancer types. One of the hallmarks of pancreatic cancer is an exceptionally high frequency of perineural invasion. The diverse molecular mechanisms underlying this tumor-nerve dialogue remain largely unknown, and this has hindered the development of therapies targeting this key pathological process.
The overarching goal of Dr. Hwang’s project is to dissect the molecular mechanisms underlying the dynamic interactions between cancer cells and the peripheral nervous system, which will serve as a guide for therapeutic development in this underexplored area of tumor biology. In their prior work, his research team discovered a cancer cell subtype that exhibits features of neurodevelopment and is associated with therapeutic resistance and poor clinical outcomes. Based on a spatial analysis of patient tumors and complementary nerve growth assays performed in their lab, they now hypothesize that the mechanisms enabling cancer cells to recruit nerves into the tumor microenvironment may be at least partially distinct from those facilitating invasion of cancer cells into nerves. This distinction is an important consideration for therapeutic targeting.
In this PanCAN Career Development Award project, generously funded by Rick Star in Memory of Janet Ranta Star, Dr. Hwang and his team will dissect the molecular mechanisms underlying nerve recruitment by pancreatic cancer and the invasion of cancer cells into intra-tumoral nerves. They have developed a new, three-dimensional method of growing cancer cells and nerves together within an extracellular matrix that mimics the tumor microenvironment. The Hwang lab will use this platform – along with advanced spatial biology and genetic engineering tools – to study the dynamics of cancer cell-nerve interactions, including the formation of synapse-like structures, the presence of electrical activity, and the migration of cancer cells along neuronal processes. The investigators anticipate that this study will transform the understanding of how pancreatic cancer cells and the peripheral nervous system collaborate to promote tumor growth, survival, and dissemination, as well as guide prioritization for therapeutic intervention in the burgeoning cancer neuroscience field.