Gastric cancer is the fourth most common malignancy and the second leading cause of cancer death amongst men and women worldwide. Both genetic and environmental factors are proposed to contribute to gastric tumorigenesis. For example, germline E-cadherin mutations result in Hereditary Diffuse Gastric Cancer, an inherited cancer predisposition syndrome. Meanwhile, environmental acquisition of H. pylori infection is a major cause of sporadic intestinal-type gastric cancer. The study of gastric cancer has been hampered by the lack of adequate model systems, an incomplete investigation of the somatic mutations that contribute to gastric cancer, and an insufficient evaluation of the gastric stem cell compartment's role in tumorigenesis. In my preliminary efforts I have developed a robust primary gastric explant culture system that enables the long-term propagation and multi-lineage differentiation of gastric epithelium that can further undergo successful oncogenic transformation, thus representing the first-ever development of invasive carcinoma from primary gastric epithelium in the in vitro setting. The project and experiments I propose in this project encompass an integrated and collaborative approach aimed at 1) developing a robust in vitro gastric cancer model, 2) validating a novel oncogene amplification (FGFR2) in human gastric cancer and assessing the prevalence of this finding in sporadic and familial gastric cancers, and 3) confirming the roles of the gastric stem cell compartment in the development of gastric cancer. This project integrates cell biology, human genetics and mouse knockout approaches to gain insight into gastric cancer tumorigenesis and specifically, E-cadherin-dependent tumorigenesis. As a Medical Oncologist with PhD training in molecular biology and oncological science, I have a deep and long-standing interest in the molecular pathogenesis of solid tumors including gastric cancer. I propose to pursue mentored research in the laboratory of Dr. Calvin Kuo at the Stanford University Medical School in order to develop the required skills and ability to become a successful, independent investigator. In addition to scientific mentoring by Dr. Kuo, I will receive guidance by Dr. James Ford and a supervisory committee with expertise in genomics, cancer biology and translational research. I believe this project will lead to the identification o new gastric cancer oncogenes that will become immediate targets for novel therapeutics and for application of previously-developed small molecule inhibitors. I intend to devote 90% of my effort to this project in the laboratory under the mentorship of Dr. Kuo. The remainder of my time will be spent working with Dr. James Ford, my co-mentor, in the GI Oncology Clinic at the Stanford Cancer Center where I will continue to see gastric cancer patients in addition to pursuing didactic training, attending national meetings and preparing presentations and manuscripts describing my work. My goal remains to obtain an appointment in a Division of Medical Oncology as a tenure-track academic physician scientist who pursues innovative research capable of bringing novel therapeutic options to the clinic.
Gastric cancer is a major worldwide health concern that has been historically underfunded and scientifically under-investigated. This project seeks to investigate the causes of gastric cancer by identifying and validating novel cancer-causing genes which could then be exploited to develop novel treatments for this disease. This proposal describes the recent development of a unique in vitro method for studying gastric cancer and seeks to leverage this advancement to functionally validate both newly identified cancer-causing genes, and the contribution of stem cells to the development of gastric cancer.
|Nadauld, Lincoln D; Garcia, Sarah; Natsoulis, Georges et al. (2014) Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer. Genome Biol 15:428|
|Li, Xingnan; Nadauld, Lincoln; Ootani, Akifumi et al. (2014) Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. Nat Med 20:769-77|
|Nadauld, Lincoln D; Ford, James M (2013) Molecular profiling of gastric cancer: toward personalized cancer medicine. J Clin Oncol 31:838-9|