Colorectal cancer (CRC) is broadly composed of three molecular subtypes – Chromosomal
Instability (CIN), Microsatellite Instability (MSI), and CpG Island Methylator Phenotype (CIMP).
The CIMP subtype distinctly differs from the other subtypes by way of its serrated precursor
lesions, occurrence in the proximal colon, a stable near-diploid genome, and aberrant gene
expression patterns that are not caused by mutations alone. The pathophysiology of this cancer
subtype remains ill-understood despite extensive research, and this inadequacy hampers the
development of effective treatment strategies. A crucial missing link in the numerous
mechanistic research efforts undertaken to date is the incorporation of a three-dimensional
(3D) spatiotemporal context that reflects mediations by the ambient microenvironment. To
address this limitation, I aim to investigate the structural and functional impact of 3D nuclear
architecture in CIMP CRC. The correlation between epigenetic modulation of gene expression
and alteration of 3D nuclear architecture is rapidly gaining recognition, but little is known of its
significance in CIMP CRC. I propose to address this limitation by using a combination of genome-wide sequencing and quantitative 3D microscopy studies on archived patient samples and immortalized cell lines that represent normal and CIMP CRC cells. The experiments outlined here are envisioned to establish a foundational framework to systemically understand CIMP CRC pathophysiology.