A Systems Biology Approach to Identifying a Master Regulator That Can Transform the Fast Growing Cellular State to a Slowly Growing One in Early Colorectal Cancer Development Model.

Jihye Choi,Jeong-Ryeol Gong,Soobeom Lee,Chang Young Joung,Kwang-Hyun Cho,Chae Young Hwang

doi:10.3389/fgene.2020.570546

Jihye Choi, Jeong-Ryeol Gong + Show 4 more

Open Access

https://doi.org/10.3389/fgene.2020.570546

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Abstract

Colorectal cancer (CRC) has been most extensively studied for characterizing genetic mutations along its development. However, we still have a poor understanding of CRC initiation due to limited measures of its observation and analysis. If we can unveil CRC initiation events, we might identify novel prognostic markers and therapeutic targets for early cancer detection and prevention. To tackle this problem, we establish the early CRC development model and perform transcriptome analysis of its single cell RNA-sequencing data. Interestingly, we find two subtypes, fast growing vs. slowly growing populations of distinct growth rate and gene signatures, and identify CCDC85B as a master regulator that can transform the cellular state of fast growing subtype cells into that of slowly growing subtype cells. We further validate this by in vitro experiments and suggest CCDC85B as a novel potential therapeutic target that may prevent malignant CRC development by suppressing stemness and uncontrolled cell proliferation.

Highlights

Colorectal cancer (CRC) has been most extensively studied for characterizing genetic mutations along its development
In order to investigate complex events occurring during the cancer initiation, we establish an early CRC development model, perform scRNA-seq, and analyze the scRNA-seq dataset (Figure 1). scRNA-seq is conducted at 3- and 7-days after transduction of shRNA targeting APC (shAPC) or shScr on human colon epithelial cells (HCEC)-1CT (1CT) cells
We find that SG has a higher apoptosis signature and a lower stemness signature than fast growth subpopulations (FG) (Figure 3A and Supplementary Figure S4), implying that SG has a fate to go through apoptosis without developing further malignancy

Summary

Introduction

Colorectal cancer (CRC) has been most extensively studied for characterizing genetic mutations along its development. Loss of adenomatous polyposis coli (APC) is considered as the first step of CRC development, which is followed by mutations of other driver genes such as KRAS and TP53 (Fearon and Vogelstein, 1990; Powell et al, 1992). Our understanding of CRC progression has been advanced over last few decades, but we still do not know much about its initiation process starting from APC deficiency. This is because there are limited measures for observation and analysis of cancer initiation events. If we unveil CRC initiation events, we might be able to identify novel prognostic markers and therapeutic targets for early cancer detection and prevention (Kaufman et al, 2016)

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