Functional characterization of the lineage plasticity landscape of cholangiocarcinoma

As a tumor evolves, its cells can take on distinct identities that distort the lineage expression programs of their normal counterparts. In cholangiocarcinoma (CCA), a highly lethal and treatment-resistant cancer of the bile ducts, we show for the first time that ongoing lineage plasticity occurs in patient samples and is functionally connected to tumor aggressiveness phenotypes. These novel insights open the opportunity for exploiting lineage plasticity as a new source of biomarker and therapeutic discovery. To do so, we propose a comprehensive and systematic creation of a functional landscape of CCA lineage plasticity, dissecting both its regulators and its impacts on malignancy and drug response. The base blueprint of this landscape will come from extensive RNA and chromatin data generation, upon which will be layered mechanistic, drug vulnerability, and in vivo tumor data. Our long-term goal is for our landscape to serve as a foundational roadmap for future CCA research efforts to project their data onto and gain clinically-relevant guidance. Specifically, our aims will 1) dissect the proximal regulators of lineage plasticity, by perturbing lineage-specifying transcription factors and by conducting cutting-edge spatial epigenomics of patient samples; 2) leverage our newly-discovered roles of the tumor suppressor genes ARID1A and BAP1 in regulating lineage plasticity to more deeply understand their mechanisms of action, therapeutic vulnerabilities, and in vivo impacts in new mouse models; and 3) harness the collected data and innovative bioinformatics to construct a lineage plasticity landscape that interconnects dense sequencing data with functional wet lab assays and mouse modeling data. In sum, our deliverables include new drug targets and mouse models, deep patient sample data, chromatin regulatory mechanisms, and a unified view of how the subversion of normal developmental programs in cancer can be exploited to advance translational oncology. Project Number: 1R01CA299653-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Lawrence Kwong | Institution: UNIVERSITY OF TX MD ANDERSON CAN CTR, HOUSTON, TX | Award Amount: $510,671 | Activity Code: R01 | Study Section: Gene Regulation in Cancer Study Section[GRIC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11288960