Research

Toward elucidation of cell-to-cell communication during liver pathogenesis.

I studied the mechanism of a non-apoptotic form of oxidative cell death, called ferroptosis, in the laboratory of Dr. Brent Stockwell for my thesis.

He received B.A. and M.A. from the University of Tokyo, Japan, where he studied molecular biology of Duchenne muscular dystrophy under Dr. Ryoichi Matsuda. After finishing my M.A. and before joining the Ph.D. program at Columbia, I served as a research assistant and bioinformatician at HuBit Genomix, Inc., a biotech venture engaged in SNP analysis of Japanese cohorts for half a year.

In my thesis work, I studied cell death and cancer pharmacology both experimentally and computationally. I discovered a mechanistically novel lethal compound, FIN56, that induces ferroptosis, a regulated form of non-apoptotic oxidative cell death. I characterized the mechanism of action of FIN56-induced cell death and performed chemoproteomic target identification to discover that the activity of mevalonate pathway regulates drug sensitivity to ferroptosis inducers (Shimada, et al., Nature Chemical Biology, 2016). I also established a systematic approach to discover biomarkers for drug sensitivity through drug sensitivity of > 6,000 compounds and transcritpome data analysis across 60 cancer cell line panel (known as the NCI60 project) and discovered that endogenous NADPH content is a strong predictor for drug sensitivity to FIN56 and other ferroptosis inducers (Shimada, et al., Cell Chemical Biology, 2016).

In my postdoc, I have been working on elucidating drug-induced liver-injury. Continuing to use both experimental and computational approaches, I have been tackling this problem from various aspects, ranging from analysis of publicly avaialble datasets to experimental approaches at single cell level in vivo (mouse) and in vitro (mouse and human).

Kenichi was originally trained as a molecular biologist. He received his PhD in the laboratory of Dr. Brent Stockwell at Columbia University. Dr. Stockwell had recently discovered ferroptosis, a non-apoptotic oxidative cell death pathway induced by certain lethal small molecules. Since it’s discovery, ferroptosis has been shown to be involved in multiple diseases. Its potential in cancer therapy has also been suggested by many groups. To discover a novel regulatory mechanism of ferroptosis, he performed a chemical library screen and determined structure-activity relationships to find a new ferroptosis inducer, FIN56. Using target identification and cell biology techniques, Kenichi discovered that FIN56 induces ferroptosis by enhancing lipid peroxidation via two orthogonal mechanisms (Fig. 1A)¹. During PhD, Kenichi started to incorporate chemo- and bio-informatics in his research. He also explored to measure the similarities and differences between cell death pathways induced by different chemicals, utilizing the NCI-60 drug testing dataset, containing drug sensitivity data against thousands of lethal molecules as well as basal transcriptomes of a panel of 59 cancer cell lines. Through the analysis, he discovered that lethal drug sensitivity profiles of small molecules were clustered primarily based on their targets (eg, DNA, mitochondria, tyrosine kinases) or cell death phenotypes (e.g., apoptosis, ferroptosis), and that sensitivity to ferroptosis is largely determined by the endogenous level of NADPH (Fig. 1B)².

1. Shimada K, et al., Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016 Jul;12(7):497-503.
2. Shimada K**, et al., Cell-line selectivity improves the predictive power of pharmacogenomic analyses and helps identify NADPH as biomarker for ferroptosis sensitivity. Cell Chem Biol. 2016 Feb 18; 23(2):225-235. (**co-correspondence)

Research

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