Genome imbalances and tumorigenesis
Human cancers exhibit a diverse array of genomic gains and losses that alter the dosage of hundreds of genes at once. Approximately 90% of solid tumors display whole-chromosome aneuploidy, while many tumors with diploid karyotypes nonetheless harbor segmental or arm-length aneuploidies that also result in significant gene copy number alterations. The prevalence of aneuploidy in cancer – first noted more than 100 years ago – has led to a widespread belief that genomic imbalances play a crucial role in tumor development. Indeed, in the early 20th century, Theodor Boveri speculated that abnormal karyotypes altered the balance between pro- and anti-proliferative cellular signals, and were therefore sufficient to induce transformation. “Boveri’s hypothesis” has motivated nearly a century of research into the origins and consequences of aneuploidy, but the precise relationship between abnormal karyotypes and tumorigenesis remains unclear. We are developing novel mouse models that harbor germ-line aneuploidies to explore the impact of genome dosage alterations on tumor development and progression.
While aneuploidy is a ubiquitous feature of human tumors, it occurs rarely in somatic cells. Thus, differences between aneuploid and euploid cells may represent crucial therapeutic vulnerabilities in cancer. By identifying phenotypes that are shared among tumors with different aneuploidies, we hope to discover pathways that can be manipulated to selectively eliminate aneuploid cells or to block aneuploidy’s non-cell autonomous effects. Drugs that target these pathways may have broad utility against a wide range of aneuploid cancers, while exhibiting minimal toxicity in euploid tissue.
Discovery and characterization of genes affecting survival time in cancer
Certain tumors can be cured by surgery alone. Other tumors derived from the same tissue and classified at the same pathological stage will inevitably recur after surgery and often prove to be fatal. For instance, stage II colorectal cancer is typically treated by surgical resection with curative intent. However, about 20% of these tumors will recur following surgery, and patients with recurrent disease have a 5 year survival rate of only 30%. While adjuvant chemotherapy can lower the risk of colorectal cancer relapse, the difficulty in identifying patients who would benefit from additional treatment, coupled with its debilitating side effects, has limited its use. In general, many clinical decisions are constrained by the poor understanding of the molecular features that differentiate potentially fatal and non-fatal human tumors. A greater understanding of the genes and biological pathways that drive tumor aggressiveness would improve patient risk stratification and allow for more accurate treatment decisions.
In order to uncover new cancer genes and to increase our understanding of the molecular differences between fatal and non-fatal tumors, we are analyzing data derived from cancer survival studies. In these studies, investigators profile tissue from tumors surgically excised from patients, and then link that data with clinical information on the patient’s tumor, treatment regime, and the length of time until death and/or another adverse event occurred. Tumors included in these studies are typically matched for stage, grade, and treatment, and only pure samples that yield high-quality RNA (or other biological molecules) are analyzed. Genes whose expression consistently correlates with increased or decreased survival time in cancer may represent novel oncogenes, tumor suppressors, or mediators of the metastatic state. We will therefore deploy CRISPR technology to modulate the expression of these genes in primary cells and in cancer cells in order to establish molecular links between these genes and cancer prognosis. FOXM1 (shown at left) is one such gene that is almost always over-expressed specifically in deadly tumors.