Annual Report 2024

Laboratory of Molecular Genetics

Haruna Takeda, Kotomi Sato

Introduction

 Our laboratory aims to elucidate the mechanisms underlying colorectal cancer progression and to identify novel therapeutic targets. To this end, we utilize unique forward-genetic in vivo models, organoids, and cancer cell lines. In particular, we are investigating how environmental factors such as obesity and chronic inflammation influence the selection of oncogenic mutations. Given the global increase in obesity, clarifying the link between obesity and colorectal tumorigenesis represents an important medical challenge.

 To identify therapeutic targets, we focus on the activation of the Wnt pathway, which is frequently observed in colorectal cancer. By performing genome-wide CRISPR-based screening, we aim to identify genes essential for the survival of Wnt-activated cells and to further characterize their functions.

Research Activities

 In obese mice fed a high-fat diet, an increased number of intestinal tumors was observed. Single-cell transcriptomic analyses suggested that this phenomenon may result from enhanced fatty acid metabolism in tumor cells, which in turn promotes cell proliferation. Furthermore, adipokines were implicated in diet-dependent tumor formation, indicating the potential involvement of a novel molecular mechanism that we plan to investigate in detail.

 Through therapeutic target screening, we identified a gene involved in energy metabolism and conducted functional validation. Suppression of this candidate gene in multiple colorectal cancer cell lines led to growth inhibition in a subset of cell lines, thereby providing in vitro proof-of-concept evidence for its therapeutic relevance.

Education

 We trained five students from Kitasato University, Hoshi University, and the Institute of Science Tokyo.

Future Prospects

 We will continue to study using our newly developed obesity-associated colorectal tumor models to perform detailed analyses, focusing on fatty acid metabolism and adipokine-mediated regulation. We will also investigate the involvement of stromal and immune cells, aiming to clarify how tumor-stromal interactions contribute to cancer progression. These analyses will serve as the basis for establishing preventive strategies against obesity-associated colorectal cancer.

 With regard to therapeutic target discovery, we plan to advance in vivo proof-of-concept studies while further dissecting the functional interactions between Wnt pathway activation and candidate genes. Through these efforts, we aim to lay the foundation for the development of new therapeutic strategies for colorectal cancer.