Characterizing and Targeting the Chromatin Determinants of Cancer Cell Identity: Cancer's Addiction to its Originating Cellular Lineage

Abstract

Cancer is a complex disease that is initiated by genetic perturbations in normal cells leading to uncontrollable cellular division. The ensuing tumor mass, at both primary and distant metastatic sites, hinders the normal functioning of essential organs and causes death. With the advent of modern multi-omics technologies, we have generated comprehensive molecular portraits of human cancers; however, the biological mechanisms that underlie the common genetic alterations in cancer remain largely uncharacterized and understudied. This has markedly impeded the clinical translation of extensive genomic information acquired from human malignancies. As a young scientist, a feature of cancer genomic profiles that intrigues me the most is that somatic alterations across cancer types show a tissue-specific pattern of recurrence and distribution. This implies that the originating/precursor cell lineage gene programs persist in cancer cells (albeit aberrantly) and dictate the set of oncogenes that are competent to drive transformation and/or progression. As articulated in detail in this following thesis, systematic interrogation of driver lineage-oncogene associations can uncover novel molecular dependencies that can be co-targeted to inhibit cancer cell growth and survival—a concept herein termed as “targeting the cancer cell identity.” These lineage-targeted therapies are most likely to be synergistic with existing therapies that target oncogene-addiction, potentially leading to more durable therapeutic benefits in patients with advanced incurable cancers. Given the remarkable technological advances that allow us to read, write, and edit the chemical letters that make up our DNA, and our ability to acquire single-cell or even single-molecule level information, I believe we are stepping into another golden age for molecular biology. Particularly, the view of cancer genomes as natural CRISPR screens can help elucidate not only the pathogenic roles of driver proteins, but also specific functions of key constituent residues and regulatory protein domains in normal physiology. I eagerly anticipate and look forward to the discoveries in this research discipline in the years to come.