# Research Topics Open all sections Close all sections ### Multiomic Characterization of Tumor Microenvironment in Breast Cancers expand\_more The overarching goal of this research is to improve the efficacy of precision cancer therapies, including chemotherapy and immunotherapy. This work is guided by two primary aims: (1) identifying biomarkers that predict responsiveness to specific therapies, and (2) elucidating mechanisms by which tumors develop therapeutic resistance. These challenges are addressed through integrative analyses combining single-cell transcriptomic data with high-dimensional spatial imaging. For imaging, Kenichi employs cyclic immunofluorescence (CyCIF), a technology developed in the LSP at Harvard Medical School. ### shinyDepMap, a Tool to Discover the Next Chemo Target expand\_more During his postdoctoral training, Kenichi pursued a project focused on cell death and therapeutic resistance in cancer cells using the Cancer Dependency Map (DepMap). DepMap systematically performs genome-wide CRISPR and shRNA genetic perturbation screens across hundreds of cancer cell lines to assess gene essentiality in a context-dependent manner. As part of this work, Kenichi developed shinyDepMap, an interactive, experimental biologist–friendly web tool designed to enable intuitive exploration of large-scale functional genomics datasets. A key contribution was the development of methods to normalize data across CRISPR and shRNA screens, yielding two interpretable metrics that quantify (i) the degree to which a gene is essential in the most sensitive cell lines (efficacy) and (ii) the extent to which a gene is selectively required in a subset of cell lines (selectivity) (Fig. 3A–C). Using this framework, 2,492 genes were identified as sufficiently essential. Clustering these essential genes based on their efficacy profiles across cell lines revealed hundreds of functional gene modules, many of which correspond to known molecular complexes (e.g., ribosomes) or biological pathways (e.g., ferroptosis) (Fig. 3D). This work has helped both academic groups and industry partners prioritize therapeutic targets, as genes with high selectivity represent particularly attractive candidates for anti-cancer drug development. ![fig3 depmap analysis](/sites/g/files/omnuum9236/files/styles/hwp_1_1__960x960_scale/public/kenichi_shimada/files/screen_shot_2022-01-14_at_3.51.43_pm.png?itok=2yHA8awq) Shimada K\*, Bachman JA, Muhlich JL, Mitchison TJ. shinyDepMap, a tool to identify targetable cancer genes and their functional connections from Cancer Dependency Map data. eLife. 2021 Feb 8;10:e57116. (\*correspondence) ### Organ-Level Response to Drugs – Common "Disease States" Induced by 160 Toxic Substances expand\_more During his postdoctoral training, Kenichi worked with Dr. Tim Mitchison at Harvard Medical School, where he leveraged large publicly available datasets to derive mechanistic insights into small-molecule drug action, disease processes, and therapeutic response. In one project, he expanded his interests into the chemical biology of organ systems by analyzing a large toxicogenomic resource, TG-GATEs. Toxicogenomics aims to improve the prediction of drug and chemical toxicity, and prior analyses of TG-GATEs primarily focused on this objective. Kenichi reanalyzed this extensively curated dataset—which profiles the effects of 160 small molecules on organ-specific transcriptomes, histopathology, and whole-body physiology in rats—to identify disease states and underlying causal pathways (Fig. 2A). While some inferred states corresponded to known liver, kidney, or gastrointestinal injuries, a particularly notable finding was the characterization of an adaptive liver response to chronic toxin exposure, marked by upregulation of xenobiotic metabolism and resistance to ferroptosis. This analysis also elucidated a mechanism underlying toxin-induced cachexia, a major indicator of drug toxicity in rats (Fig. 2B). This work was featured in [Harvard News](https://hms.harvard.edu/news/toxin-response).( ![fig2 tox](/sites/g/files/omnuum9236/files/styles/hwp_1_1__960x960_scale/public/kenichi_shimada/files/screen_shot_2022-01-13_at_7.09.26_pm.png?itok=APMN9ibb) ### Mechanism of Ferroptosis expand\_more Kenichi was originally trained as a molecular biologist and received his PhD in the laboratory of Dr. Brent Stockwell at Columbia University. During his doctoral training, Kenichi contributed to the early discovery and mechanistic characterization of ferroptosis, a non-apoptotic, oxidative form of cell death induced by specific lethal small molecules. Since its identification, ferroptosis has been implicated in a wide range of diseases, and its potential relevance to cancer therapy has been widely explored. To identify novel regulatory mechanisms of ferroptosis, Kenichi performed a chemical library screen coupled with structure–activity relationship analyses, leading to the discovery of a new ferroptosis inducer, FIN56. Using a combination of target identification and cell biological approaches, he demonstrated that FIN56 induces ferroptosis by promoting lipid peroxidation through two orthogonal mechanisms (Fig. 1A)1. During his PhD training, Kenichi also began integrating chemo- and bioinformatics approaches into his research. He investigated similarities and differences among cell death pathways induced by diverse small molecules using the NCI-60 drug testing dataset, which includes drug sensitivity profiles for thousands of compounds alongside baseline transcriptomes from 59 cancer cell lines. This analysis revealed that lethal drug sensitivity profiles cluster primarily by molecular targets (e.g., DNA, mitochondria, tyrosine kinases) or cell death phenotypes (e.g., apoptosis, ferroptosis), and further showed that sensitivity to ferroptosis is largely determined by endogenous NADPH levels (Fig. 1B)2. ![fig1 ferroptosis](/sites/g/files/omnuum9236/files/styles/hwp_1_1__960x960_scale/public/kenichi_shimada/files/screen_shot_2022-01-13_at_7.35.59_pm.png?itok=vYypFPSO) 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) ## Recent Publications Download 6 citations download- [BibTeX](/bibcite/export?pager_style=no_pager&number_of_items=6&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=bibtex) - [EndNote X3 XML](/bibcite/export?pager_style=no_pager&number_of_items=6&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=endnote8) - [EndNote 7 XML](/bibcite/export?pager_style=no_pager&number_of_items=6&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=endnote7) - [Endnote tagged](/bibcite/export?pager_style=no_pager&number_of_items=6&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=tagged) - [Marc](/bibcite/export?pager_style=no_pager&number_of_items=6&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=marc) - [PubMedId](/bibcite/export?pager_style=no_pager&number_of_items=6&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=pubmed_id) - [RIS](/bibcite/export?pager_style=no_pager&number_of_items=6&sort_field=bibcite_year--desc&taxonomy_filters=&&&format=ris) ### 2025 Wanderley CWS, Michaud DE, Shimada K, Nelson A, Fu J, Schnitt SJ, Tolaney SM, Mittendorf EA, Barroso-Sousa R, Waks A, et al. [APOE+ Tumor-Associated Macrophages and CD4-DOCK4 T Cells Reveal Distinct Microenvironmental Features in HER2-Low and HER2-0 Hormone Receptor-Positive Breast Cancer](https://doi.org/10.1101/2025.09.04.674072). bioRxiv. 2025. Wanderley CWS, Michaud DE, Shimada K, Nelson A, Fu J, Schnitt SJ, Tolaney SM, Mittendorf EA, Barroso-Sousa R, Waks A, et al. [APOE+ Tumor-Associated Macrophages and CD4-DOCK4 T Cells Reveal Distinct Microenvironmental Features in HER2-Low and HER2-0 Hormone Receptor-Positive Breast Cancer](https://doi.org/10.1101/2025.09.04.674072). bioRxiv. 2025. - add\_circle do\_not\_disturb\_on Abstract Novel anti-HER2 antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), have shown efficacy in tumors with varying HER2 expression, including HER2-low and even tumors with minimal HER2 presence. This has sparked interest in the biology... ### 2024 Guerriero JL, Lin J-R, Pastorello R, Du Z, Chen Y-A, Townsend MG, Shimada K, Hughes ME, Ren S, Tayob N, et al. [Qualification of a multiplexed tissue imaging assay and detection of novel patterns of HER2 heterogeneity in breast cancer](https://www.nature.com/articles/s41523-023-00605-3). NPJ Breast Cancer. 2024;10(1). Guerriero JL, Lin J-R, Pastorello R, Du Z, Chen Y-A, Townsend MG, Shimada K, Hughes ME, Ren S, Tayob N, et al. [Qualification of a multiplexed tissue imaging assay and detection of novel patterns of HER2 heterogeneity in breast cancer](https://www.nature.com/articles/s41523-023-00605-3). NPJ Breast Cancer. 2024;10(1). - add\_circle do\_not\_disturb\_on Abstract Emerging data suggests that HER2 intratumoral heterogeneity (ITH) is associated with therapy resistance, highlighting the need for new strategies to assess HER2 ITH. A promising approach is leveraging multiplexed tissue analysis techniques such as cyclic... Shimada K, Michaud DE, Cui YX, Zheng K, Goldberg J, Ju Z, Schnitt SJ, Pastorello R, Kania LD, Hoffer J, et al. [An estrogen receptor signaling transcriptional program linked to immune evasion in human hormone receptor-positive breast cancer](https://www.biorxiv.org/content/10.1101/2024.11.23.619172v1). bioRxiv. 2024. Shimada K, Michaud DE, Cui YX, Zheng K, Goldberg J, Ju Z, Schnitt SJ, Pastorello R, Kania LD, Hoffer J, et al. [An estrogen receptor signaling transcriptional program linked to immune evasion in human hormone receptor-positive breast cancer](https://www.biorxiv.org/content/10.1101/2024.11.23.619172v1). bioRxiv. 2024. - add\_circle do\_not\_disturb\_on Abstract T cells are generally sparse in hormone receptor-positive (HR+) breast cancer, potentially due to limited antigen presentation, but the driving mechanisms of low T cell abundance remains unclear. Therefore, we defined and investigated programs (‘gene... ### 2021 Weng J-H, Koch PD, Luan H, Tu H-C, Shimada K, Ngan I, Ventura R, Jiang R, Mitchison T. [Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation](https://www.nature.com/articles/s42255-021-00366-y). Nat Metab. 2021;3(4):513–522. doi:10.1038/s42255-021-00366-y Weng J-H, Koch PD, Luan H, Tu H-C, Shimada K, Ngan I, Ventura R, Jiang R, Mitchison T. [Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation](https://www.nature.com/articles/s42255-021-00366-y). Nat Metab. 2021;3(4):513–522. doi:10.1038/s42255-021-00366-y - add\_circle do\_not\_disturb\_on Abstract Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell... Shimada K, Bachman J, Muhlich J, Mitchison T. [shinyDepMap, a tool to identify targetable cancer genes and their functional connections from Cancer Dependency Map data](https://elifesciences.org/articles/57116). Elife. 2021;10. doi:10.7554/eLife.57116 Shimada K, Bachman J, Muhlich J, Mitchison T. [shinyDepMap, a tool to identify targetable cancer genes and their functional connections from Cancer Dependency Map data](https://elifesciences.org/articles/57116). Elife. 2021;10. doi:10.7554/eLife.57116 - add\_circle do\_not\_disturb\_on Abstract Individual cancers rely on distinct essential genes for their survival. The Cancer Dependency Map (DepMap) is an ongoing project to uncover these gene dependencies in hundreds of cancer cell lines. To make this drug discovery resource more accessible to... ### 2020 Stokes M, Small JC, Vasciaveo A, Shimada K, Hirschhorn T, Califano A, Stockwell B. [Mesenchymal subtype neuroblastomas are addicted to TGF-βR2/HMGCR-driven protein geranylgeranylation](https://www.nature.com/articles/s41598-020-67310-0). Sci Rep. 2020;10(1):10748. doi:10.1038/s41598-020-67310-0 Stokes M, Small JC, Vasciaveo A, Shimada K, Hirschhorn T, Califano A, Stockwell B. [Mesenchymal subtype neuroblastomas are addicted to TGF-βR2/HMGCR-driven protein geranylgeranylation](https://www.nature.com/articles/s41598-020-67310-0). Sci Rep. 2020;10(1):10748. doi:10.1038/s41598-020-67310-0 - add\_circle do\_not\_disturb\_on Abstract The identification of targeted agents with high therapeutic index is a major challenge for cancer drug discovery. We found that screening chemical libraries across neuroblastoma (NBL) tumor subtypes for selectively-lethal compounds revealed metabolic... [ More arrow\_circle\_right ](/publications)