Annual Report 2021

Tsuruoka Metabolomics Laboratory (Team Makinoshima)

Hideki MAKINOSHIMA

Introduction

 During carcinogenesis and cancer progression, homeostasis, which maintains a constant biological state, breaks down. Beyond the homeostatic mechanism, metabolites that induce carcinogenesis and metabolic systems specific to cancer cells are overproduced or decreased within individuals, and the metabolites themselves contribute to the development and malignant transformation of cancer. We are analyzing cancer cells, tumor tissues and blood samples from the viewpoint of cancer metabolism.

The Team and What We Do

 In FY2021, we also aimed to identify metabolites and metabolic pathways specific to cancer and to discover new drugs targeting them. In collaborative research between the Institute for Advanced Biosciences, Keio University and the National Cancer Center, we collected samples from patient-derived samples, cancer cell lines, cancer stromal cells, and mouse models, and analyzed the metabolome of cancer. In drug discovery research targeting metabolic pathways characteristic to cancer, we studied the regulatory mechanisms of nucleic acid biosynthetic pathways. Furthermore, we proposed the possibility of a new therapeutic method that inhibits the new biosynthetic pathway of purine nucleic acids with antifolates and the recycling pathway with new drugs. We elucidated the regulation mechanism of nucleic acid metabolism in small cell lung cancer, elucidated the regulation mechanism of deoxyribonucleotide biosynthesis in small cell lung cancer, analyzed cholesterol metabolites associated with breast cancer metastasis, elucidated the regulation mechanism of nucleic acid biosynthesis in breast cancer, and elucidated the mechanism of drug resistance to antifolates in malignant pleural mesothelioma.

Research activities

 As a result of the above research activities, some papers were published. Antifolates are used in the treatment of malignant pleural mesothelioma, and we conducted research on drug resistance to antifolates and published a paper on it (paper 1). We clarified the regulatory mechanism of the DNA biosynthetic pathway in proliferating small cell lung cancer cells and analyzed its function in tumor progression (paper 2). Using small cell lung cancer, breast cancer, and malignant pleural mesothelioma as research materials, we established a cell line in which the gene for HPRT1, an enzyme important in the purine nucleic acid recycling pathway, was knocked out, and investigated its sensitivity to antifolate drugs. We continued to explore the potential for combination therapy with inhibitors of synthesis and salvage pathways. Furthermore, through joint research with Gunma University, we analyzed changes in metabolites in cancer cells caused by heavy ion beams and published the results in a paper (paper 3).

1. Upregulation of Thymidylate Synthase Induces Pemetrexed Resistance in Malignant Pleural Mesothelioma.
Sato Y, Tomita M, Soga T, Ochiai A, Makinoshima H.
Front Pharmacol. 2021 Sep 27;12:718675.

2. De novo deoxyribonucleotide biosynthesis regulates cell growth and tumor progression in small-cell lung carcinoma.
Maruyama A, Sato Y, Nakayama J, Murai J, Ishikawa T, Soga T, Makinoshima H.
Sci Rep. 2021 Jun 29;11(1):13474.

3. Metabolic Alteration in Cancer Cells by Therapeutic Carbon Ions.
Osu N, Makinoshima H, Oike T, Ohno T.
Anticancer Res. 2021 Dec;41(12):6023-6029.

Education

Yuzo Sato (Keio University Institute for Advanced Biosciences, Graduate Student)

Chihiro Homma (Keio University Institute for Advanced Biosciences, Special Research Student)

Future Prospects

 In FY2022, we will continue the characterization of HPRT1-deficient cells and antifolate-resistant cells to elucidate the nucleic acid biosynthesis control mechanism. At the same time, we are studying the control mechanism of nucleic acid metabolic pathways using animal models, and we plan to continue to verify it from next year onward.