Date of Award

January 2023

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Sajid Khan

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related death both in the United States and worldwide, making it an urgent area of investigation for the oncology community. The inferior survival of patients with right-sided colon cancer (RCC) compared to left (LCC), particularly in metastatic disease, as well as the resistance of RCC to certain targeted systemic therapies, represent clinically important features relevant to the development of improved targeted therapies for CRC. Given the high probability that there is a biological component underpinning the differing clinical behaviors of CRC across anatomic laterality, we conducted a multi-omic analysis on frozen liver metastasis tissue samples from patients with metastatic CRC. Our results from overlapping metabolomic and transcriptomic analyses implicate differences in glucuronidation, proteoglycan metabolism, immunomodulation, ferroptosis, reactive oxygen species generation, bile acid abundance, fatty acid oxidation, collagen and extracellular matrix modulation. Pro-tumorigenic signaling of two canonical cancer pathways, MEK-ERK and PI3K-AKT, both of which are downstream of the Epidermal Growth Factor Receptor (EGFR) are further implicated. By integrating the findings of the two analyses, as well as those from the literature, we propose several candidates for relevant biological differences underlying the inferior survival of metastatic RCC, as well as its resistance to EGFR-inhibitor therapy. Notably, increased Transcription Growth Factor Beta signaling in RCC is implicated as a core candidate mechanism tying together many of the observed findings.

Comments

This is an Open Access Thesis.

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