2026 Theses Doctoral

Uncovering aneuploidy drivers and vulnerabilities in cancer

Zhakula-Kostadinova, Nadja

Aneuploidy, defined as gains or losses of whole chromosomes or chromosome arms, is among the most pervasive genomic alterations in human cancer. Although recurrent patterns of chromosome arm gain and loss occur across tumor types, the mechanisms through which these alterations contribute to tumor development, cancer cell fitness, and therapeutic response remain incompletely understood. Increasing evidence suggests that recurrent aneuploidies are not merely passenger alterations, but functional determinants of cancer cell state that reshape signaling pathways, metabolic programs, and lineage-specific dependencies.

This dissertation investigates the downstream consequences of recurrent chromosome arm aneuploidies in cancer, with a particular focus on squamous cancers. Chapter 1 provides a comprehensive overview of recurrent aneuploidy patterns across cancers and their effects on proliferation, DNA damage response, metabolism, immune signaling, differentiation, and therapeutic sensitivity. This chapter additionally examines sterol regulatory element-binding protein 1 (SREBP1) signaling and the mevalonate pathway as emerging metabolic vulnerabilities in genomically altered cancers. Chapter 2 describes Breakpoint Identification of Significant Cancer Undetected Targets (BISCUT), a computational framework developed to identify candidate drivers of recurrent chromosome arm aneuploidy in cancer.

This work demonstrated that recurrent chromosome arm alterations are shaped primarily by their effects on tumor fitness and identified dosage-sensitive candidate drivers underlying recurrent arm-level gains and losses across tumor types. Chapter 3 investigates how recurrent chromosome 3q-gain, a defining feature of squamous cancers, creates a selective vulnerability to inhibition of the SREBP-mevalonate pathway axis. Using isogenic epithelial models, genome-wide CRISPR interference screening, pharmacologic perturbation, transcriptomic and lipidomic profiling, and in vivo xenograft studies, this work identifies an aneuploidy-driven dependency on SREBP signaling and HMGCR activity in 3q-gain cells. Mechanistically, 3q-gain cells exhibit altered lipid homeostasis and impaired SREBP1 activation in response to sterol depletion, resulting in heightened sensitivity to mevalonate pathway inhibition. These findings establish a mechanistic link between lineage-defining aneuploidy and metabolic therapeutic vulnerability in squamous cancers.

Together, the studies presented in this dissertation demonstrate that recurrent chromosome arm aneuploidies shape signaling, metabolism, and therapeutic response in cancer. These findings support the broader concept that lineage-specific aneuploidies may represent an underappreciated class of precision oncology targets and provide a framework for identifying aneuploidy-driven therapeutic vulnerabilities across cancer types.