PROJECT SUMMARY: Cancer Biology Research Program Melissa Wong, Ph.D., and Mara Sherman, Ph.D., Program Co-Leaders The Cancer Biology Program (CB) is the unified discovery engine of the Knight Cancer Institute (KCI). Its focus is on discovering novel therapeutic mechanisms and targets for cancer therapy, through integrative investigation of genetic, molecular and cellular processes underlying cancer initiation and progression. CB members drive the basic and basic-to-translational research innovation that is foundational to advances in Precision Early Detection and Precision Oncology, in alignment with the KCI Strategic Plan. Scientific research within the program spans the continuum from cancer initiation through progression, with emphasis on how cell signaling and the crosstalk between cells within the tumor microenvironment influence tumorigenesis and the response to therapy. To accomplish these goals, the program is organized into three research themes: Tumorigenesis & Genetic Instability (examining cell-intrinsic and -extrinsic mechanisms that predispose to cancer, including regulation of cell cycle checkpoint control, DNA damage and repair, and genetic and epigenetic alterations); Signal Transduction (focused on cellular signaling mechanisms relevant to homeostatic and neoplastic cell proliferation); and the Tumor Microenvironment (investigating mesenchymal support, immune, and vascular cell interactions with neoplastic cells). Program co-Leader Melissa Wong, Ph.D. is an expert in stem cell biology, particularly in colorectal, lung and pancreatic cancer. Co-Leader Mara Sherman, Ph.D. is an expert in micro- environmental regulation of solid tumorigenesis, with a focus on pancreatic cancer. The 38 members of CB are drawn from five basic science departments, five clinical departments or divisions in the OHSU School of Medicine, and four institutes within OHSU. Total direct cost funding as of December 31, 2020 was $9,955,528 with peer-reviewed funding of $9,120,686 of which $4,436,923 or 49% was from the NCI. The discoveries made in this program have resulted in 323 publications during the funding period, of which 20% are intra-programmatic collaborations, 48% are inter-programmatic, and 44% are inter-institutional collaborations; 24% of these publications are in journals with an impact factor greater than 10. CB members made numerous impactful scientific discoveries, including the development of new genetically-engineered mouse models for breast cancer and pancreatic cancer that faithfully recapitulate the inter-tumoral heterogeneity seen in patients; a novel, hierarchical relationship between myeloid enhancer mutations and oncogene activation in the initiation and progression of acute myeloid leukemia; and continued insights into micro-environmental contributions to tumor development, progression, and therapeutic resistance. These investigations align with and directly support the KCI Strategic Plan’s foundations of Precision Early Detection an...