Colorectal cancer (CRC) is the third most common and third deadliest cancer worldwide with rising incidence rates attributed to environmental risk factors like diet. Investigating how these factors impact carcinogenesis requires an understanding of how transcriptional events evolve with respect to neoplastic progression. We employed meta-transcriptomics and latent trajectory modeling to establish a compendium of profiled healthy, adenoma, and CRC samples scored by their position along a pseudotemporal axis. By interpolating a continuous scale from cross-sectional data, dynamic processes occurring throughout disease progression can be analyzed more accurately. For example, smaller pseudotimes represented pre-malignant dysplasia and was characterized by cellular hyperproliferation downstream of genomic stress. Larger pseudotimes represented post-malignant progression and was characterized by a prominent stromal and inflammatory response. As dysregulated bile acid (BA) metabolism is intrinsically linked with diet and CRC development, we next assessed how neoplastic progression modulated colonic BA-related pathways. Pseudotemporal analysis delineated a role and clinical utility of the FGFR4-KLB-FGF19 pathway in disease progression. FGFR4 was an early CRC oncogene and the only FGFR that could be directly associated with tumorigenesis, suggesting that targeted inhibition may be a novel therapeutic modality. KLB's expression and prognostic profile was inverse to FGFR4, indicating a tumor suppressor role in early CRC. In particular, predictive informatics ascribed a functional role for KLB in opposing FGFR4-mediated dysplastic processes, which was validated using cellular models of differentiation as well as transgenic and morphological studies. FGF19 was also identified as an oncogene and putative blood-based CRC biomarker due to its endocrine properties. Immunodeficient mice transplanted with FGF19-expressing cells demonstrated supraphysiologic levels of circulating FGF19 that exerted potent endocrine effects targeting hepatic metabolism and enterohepatic recirculation of BAs. Collectively, the data provide clear evidence for the importance of the FGFR4-KLB-FGF19 complex in modulating CRC oncogenesis as well as its potential translational applicability for screening/diagnostic purposes.
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Doctor of Philosophy (Ph.D.)
College of Medicine
Burnett School of Biomedical Sciences
Biomedical Sciences; MD/PhD Track
Length of Campus-only Access
Doctoral Dissertation (Open Access)
Rohr, Michael, "Deciphering the Role and Clinical Application of the FGFR4-KLB-FGF19 Axis in Colorectal Neoplastic Progression" (2022). Electronic Theses and Dissertations, 2020-. 1485.