Reinvigorating the overdominant model of tumor suppression

Stanford University, Stanford CA

Investigators

Abstract

Reinvigorating the overdominant model of tumor suppression Tumor suppressor genes (TSGs) play essential roles in cancer pathogenesis, from cancer initiation to progression and therapy responses. More than 50 years after Knudson proposed the “two-hit” model of tumor suppression, this paradigm remains fundamental to the field of cancer biology and was later complemented by the “one-hit” or haploinsufficiency model of tumor suppression. In contrast, a third mode of tumor suppression posits a non-monotonic relationship between TSG dosage and tumor fitness, where inactivation of one gene copy is beneficial, but the loss of both is less beneficial or even detrimental—a phenomenon due to genetic overdominance. Utilizing CRISPR/Cas9-based somatic genome editing and tumor barcode sequencing (Tuba- seqUltra), combined with gRNA cutting efficiency information, I identified seven candidate overdominant TSGs in the oncogenic KRAS-driven lung adenocarcinoma, notably including Suz12 and Eed from the polycomb repressive complex 2 (PRC2). In this proposed study, I hypothesize that overdominance is a significant factor shaping the functionality of many TSGs and that overdominant TSGs are enriched in chromatin regulators. First, I will refine the Tuba-seqUltra platform to systematically measure the overdominant effect of TSGs in vivo and explore the interplay between different oncogenic backgrounds and overdominant tumor suppression (Aim 1). To gain insight into the molecular mechanism of overdominant tumor suppression, I will investigate the phenotypic consequences of heterozygous and homozygous deletion of the key PRC2 members Eed using single-cell RNA-Seq and single-cell ATAC-Seq (Aim 2). Finally, to study the extent of overdominant tumor suppression in lung adenocarcinoma, I will use machine learning methods to quantify the overdominance of 200 known and putative TSG. This will determine the prevalence of overdominance in tumor suppression and assess whether overdominant TSGs are enriched in dosage-sensitive pathways like those involving chromatin regulators (Aim 3). This study will establish robust methodologies for researching overdominant TSGs in cancer, evaluating their prevalence, and deciphering the underlying molecular mechanisms. This could profoundly impact our understanding of cancer biology and influence future therapeutic strategies.