Decades of cancer research have led to major breakthroughs in understanding cancer gene function and to important advances in diagnosis and treatment of these complex diseases. Despite this progress, most advanced cancers in adults are ultimately refractory to treatment, and cures for these common conditions remain out of reach. The difficulty in treating advanced cancers relates to many variables, including an incomplete understanding of how cancer initiates, the complexity of the alterations in cancer, heterogeneity in tumors and only a partial understanding of the molecular underpinnings of central cancer pathways. My research program over the next seven years seeks to address important aspects of these fundamental roadblocks. I will address the target cell populations from which cancers emerge - the cell-of-origin - and determine how these early beginnings are linked to one of the most fundamental properties of cancer cells, the acquisition of immortal proliferative properties. I will identify new telomerase-expressing stem cell populations in divers tissues and determine how they relate to cancer cells-of-origin. I will probe the mechanisms by which immortality is acquired by telomerase upregulation and reveal the means by which highly recurrent mutations in the TERT promoter promote tumorigenesis. I will devise methods for disrupting maintenance of the immortal phenotype, ultimately rendering cancer cells incapable of long-term proliferation or survival. Together, this program will lead to fundamental new insights into the origins of cancer, reveal how aspiring cancers circumvent critical bottlenecks they encounter during carcinogenesis and lead to new therapies with potential to treat many of the most refractory human cancers.