Roeland Roel Nusse

Roel Nusse was born in Amsterdam, The Netherlands. He received his PhD from the Netherlands Cancer Institute and the University of Amsterdam in 1980. He completed postdoctoral studies at the University of California, San Francisco in 1982 working with Dr. Harold Varmus. After several years as head of the molecular biology department at the Netherlands Cancer Institute, he returned to the Bay Area and joined the Stanford faculty in 1990 as a Professor of Developmental Biology. He has been a Howard Hughes Medical Institute Investigator since 1990.  In 1999 he was appointed as chair of the department of Developmental Biology at Stanford, a position he still holds.  Currently, he is the Virginia and Daniel K. Ludwig Professor of Cancer Research. In 2010, he was elected as a member of the National Academy of Sciences. Roel Nusse is also a fellow of the American Academy of Arts and Sciences and a member of the Royal Dutch Academy of Sciences. In 2016, he received the Breakthrough Prize in Life Sciences. He has made major discoveries in developmental biology and adult stem cell research.  His pioneering research has elucidated the mechanism and role of Wnt signaling, one of the paradigms for the fundamental connections between normal development and cancer.


Gene signatures and stemness in the liver controlled by local Wnt signals

Wnt signaling is widely implicated in stem cell control, as a mechanism to regulate the number of stem cells in tissues. Using various cell labeling and lineage tracing methods, we have described novel populations of stem cells in various tissues, including in the liver. In that tissue, we found that hepatocytes that reside in the pericentral domain of the liver demonstrate stem cell behavior. Although these cells are functional hepatocytes, they are diploid and thus differ from the mostly polyploid mature hepatocyte population. They are active in homeostatic cell replacement and therefore distinct from oval cells, which require injury for their induction. Through transcriptional gene profiling, we have identified a molecular mechanism that maintains the stem cells in a diploid state, involving a transcriptional repressor, Tbx3, a Wnt target gene. Based on additional gene expression data, we propose that Tbx3 defines a state of stemness in the liver. It is noteworthy that liver cancer is often characterized by loss of function mutations in negative components of the Wnt pathway, including Axin and APC. Human liver cancer cells (HCC) often express Tbx3 as well.  We suggest that peri-central hepatocyte stem cells, normally controlled by a paracrine Wnt signal, are precursors to liver cancer. Ongoing research includes developing methods to expand mouse and human hepatocytes in culture, based on hepatocyte growth promoting factors we have identified in vivo.