Fundamentally understanding cell proliferation will lead to novel approaches for cancer treatment and tissue repair

Cells divide during various stages in the human body, such as the development of an embryo or child, to maintain homeostasis, and to replace aging or dysfunctional cells and repair damages. However, in some diseases—most notably cancer—our cells have lost their ability to control their proliferation. Dr. Julien Sage, Professor of Pediatrics and Genetics at Stanford University, is interested in the fundamental mechanism driving the proliferation of cells. He uses novel genetic tools to understand the basic mechanisms of cancer initiation and progression, and explore how cells divide. By understanding the molecular basis of how cancers start and progress, he aims to find effective therapeutic targets and therapeutic strategies to prevent and treat metastasis, as well as enhance the proliferation of cells for tissue repair.

Dr. Sage’s work primarily focuses on the molecular machinery that decides whether a cell divides or not. Many of his experiments use stem cells, which often function as the source for other cells in the body during tissue repair and in cancer initiation. He is specifically working on a tumor suppressor named RB. The term “RB” is derived from a pediatric eye cancer called retinoblastoma. RB is expressed in all cells in the body, but children who have mutations in this gene develop tumors in their eyes or their bones; currently, it is not understood why this occurs. When RB is inactivated, cells tend to proliferate when they should not, which has been implicated in the development of cancer, initially in children, but also in adults. Dr. Sage’s cancer genetics lab, which comprises postdoctoral fellows, undergraduate and graduate students, research technicians, a master’s student, and an administrative assistant, covers both basic and applied research topics, including stem cells during embryogenesis, pediatric cancer, and adult tumors. They also focus on neuroendocrine cells and tumors, a field of biology that is currently not well-understood.

Together they closely collaborate with researchers in the U.S. and around the world. Their large network of collaborators worldwide provide reagents, clinical samples, and aid with specific technologies, which enables Dr. Sage and his team to apply the latest technologies to their research goals. They have developed innovative and accurate in vivo genetic mouse models for human cancers, which allow them and the scientific community to study the basic mechanisms of these tumors. A better understanding of how cell proliferation is regulated may lead to the identification of new approaches to enhance cell division for better tissue repair and to block proliferation in tumors. Currently, there have already been several clinical trials implemented in lung cancer patients based on Dr. Sage’s studies in preclinical models.

Current Research Includes:

Basic Understanding of the RB Pathway – The RB mutation acts as a cellular brake, normally limiting cell proliferation. Dr. Sage and his team are performing basic research on the RB pathway in order to fundamentally understand how it functions as a core machinery checkpoint that enables the cells to divide or not. They want to identify what controls its activity in normal cells, how exactly it slows or prevents proliferation, and what happens to cells when they lose RB function during the tumorigenic process. Dr. Sage and his team are interested in how this tumor suppressing molecule is able to inhibit cancer initiation and progression. After gaining a strong basic understanding of the RB pathway, they aim to extend this work and apply it to RB function in a number of different cancers.

Enhancing the Proliferation of Cells for Regeneration – In cancer, preventing the tumor mechanism from being disrupted (i.e. “breaks”) is critical. Clinicians want to prevent a break, or reactivate a break that occurs. However, in some other human diseases and disorders, a loosened break is ideal, as it helps with the regeneration process. Dr. Sage and his team want to gain a better understanding of how tumor suppressing mechanisms, such as the RB pathway, function. By carefully manipulating this pathway to continue dividing in a controlled setting, Dr. Sage aims to enhance the proliferation of stem cells, also known as repair mechanisms. This process has the potential to help the body increase the rate and efficiency to repair tissue and heal wounds.

Using Novel Models to Explore the Loss of RB Function in Neuroendocrine Tumors – Typically, tumors that have lost RB function have neuroendocrine features; they resemble both neurons and cells producing hormones. Based on this observation, Dr. Sage and his team are interested in furthering their understanding of neuroendocrine tumors, primarily those in the pancreas and lungs. Using their genetically-engineered mouse models, they can look at neuroendocrine tumors during loss of RB function, as well as other mutations in other cancer genes. These tumors have not been widely studied, and therapeutic options remain limited. They’re currently focusing on small cell lung cancer (SCLC)--the most lethal form of lung cancer--which is always mutant for RB. SCLC patients often are treated with chemotherapy or radiation therapy, but the effects are temporary. Dr. Sage and his team are modeling SCLC in mice to study its main clinical features, including rapid growth, resistance to chemotherapy, and high rate of metastasis. They also plan to explore other targets they have identified in neuroendocrine tumors. Their goal is to ultimately combine their basic analysis of RB and the RB pathway to preclinical and translational studies of neuroendocrine tumors.

Dr. Julien Sage grew up in a small town in France. None of his family members had ever gone beyond college, so he didn’t know what being a researcher entailed. Still, Dr. Sage enjoyed science, particularly biology, after having a high school class with a passionate biology teacher. He initially was interested in becoming a biology teacher, as several family members pursued teaching. However, while an undergraduate student at École Normale Supérieure in France, he had the opportunity to conduct research in a laboratory at Stanford University one summer. He worked side-by-side with extremely bright researchers from all over the world who were passionate about their work. He saw how valued basic research was there. Dr. Sage caught the bug and officially decided to pursue research. He went on to complete his postdoctoral studies at Massachusetts Institute of Technology (MIT), where he felt research in the US was exciting with much opportunity. A few years later, he became a faculty member at Stanford University. 

Initially, Dr. Sage was mainly driven to pursue research by fundamental questions in biology. Now,  he is more drawn to applied research and trying to translate his  work for the benefit of patients. His primary motivation is curiosity; the possibility to ask questions and, sometimes, to answer them. He is also motivated by the incredibly smart and driven people he works with. He enjoys each day at work, where he trains fantastic students, interacts with incredible colleagues, and is part of an ensemble that makes a difference. His research still entails both basic and applied goals; he and his team try to understand basic mechanisms underlying basic cellular processes, while never losing sight of the possibility that these discoveries may be translatable to patients with cancer.