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This conference will focus on three major areas: First, it will present new approaches to generate precise and complex genetic alterations in mice and other animals to better “humanize” models and allow for in vivo studies of cancer gene function. Second, it will highlight studies to investigate fundamental mechanisms of cancer initiation and progression, including the cell of origin of tumors, their evolution, their metabolism, and their interactions with the immune system. Finally, the meeting will explore how genetically engineered animal models can help evaluate the efficacy of novel therapeutic approaches and to decipher mechanisms of therapeutic resistance.