Novel tools for the mechanistic dissection of mutation-specific carcinogenesis
Embargo Date
2025-07-19
OA Version
Citation
Abstract
Recent large-scale genome sequencing projects have identified a number of common and recurring somatic mutations thought to play a role in the progression of cancer. Mapping each genomic change to functional and behavioral alterations in cellular behavior is critical to developing tailored therapies for patients harboring these genomic changes. In this work, I outline two novel tools that enable mechanistic investigation of the consequences of common somatic mutations, which will help lay a foundational understanding for development of targeted precision drug therapies. In the first project outlined here, focusing on the role of PI3K axis dysfunction in breast cancer, we describe an engineered optogenetic PI3K platform that enables orthogonal control over PI3K activity in the cell. We explore the effects of distinct PI3K axis lesions on PI3K signaling dynamics and demonstrate that the altered signaling dynamics alone underscore many of the altered behaviors observed in the mutants. In the second project outlined here, we describe the development of a novel lung-on-chip device that enables the coculture of iPS-derived alveolar type 2 epithelial cells with engineered vasculature. Using this on-chip model, we explore the role of a common lung adenocarcinoma driver mutation, KRAS G12D, on epithelial morphology and angiogenic signaling to the adjacent vasculature. We demonstrate that this mutation drives a hyperproliferative phenotype within the epithelium and an angiogenic response in the nearby vasculature. This angiogenic response was found to be mediated by increased section of the angiogenic factor soluble urokinase-type plasminogen activator receptor (suPAR), providing a novel target to limit KRAS G12D mediated angiogenesis in lung adenocarcinoma. Collectively, this work provides novel insight into the mechanisms of mutation-specific carcinogenesis in both breast and lung cancer and lays the foundation for future work in mapping the functional consequences of mutations to identify therapeutic vulnerabilities.