Cell types in healthy tissues only take on a finite number of states, since they are generated following a strict developmental program. Cancer cells, however, carry genetic alterations that may remove such constraints, leading to a fundamental challenge: the potential co-existence of genetically distinct clones, each supporting multiple stable cancer cell states.
To understand the effect of subclonal variation in cancer, we have developed a set of single-cell multiomics methods, such as DNTR-seq for joint WGS/mRNA-seq (see: Zachariadis et al. Mol. Cell 2020, Andrews et al. Nat. Methods 2021, Enge et al. Cell 2017). In this project, we are applying the methods to leukemias and solid tumors with a high level of subclonal genetic heterogeneity to understand the general rules of how gene dosage affects expression, as well as longitudinally during treatment to better understand genetic and epigenetic features of treatment persistence.