1: Molecular Understanding of Lung Cancer Heterogeneity and Identification of Novel Therapeutic Targets Using Patient-Derived Lung Cancer Organoid Libraries / 2: Design of Immune Cell Therapy with Fewer Side Effects Using Mathematical Models

An organoid library unveils subtype-specific IGF-1 dependency via a YAP-AP1 axis in human small cell lung cancer

Nature Cancer.

2025 May;6(5):874-891. doi: 10.1038/s43018-025-00945-y.

Fukushima T, Togasaki K, Hamamoto J, Emoto K, Ebisudani T, Mitsuishi A, Sugihara K, Shinozaki T, Okada M, Saito A, Takaoka H, Ito F, Shigematsu L, Ohta, Y, Takahashi S, Matano M, Kurebayashi Y, Ohgino K, Sato T, Kawada I, Asakura K, Hishida T, Asamura H, Ikemura S, Terai H, Soejima K, Oda M, Fujii M, Fukunaga K, Yasuda H, Sato T.

Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma

Nature Communications.

2025 May 11;16(1):4369. doi: 10.1038/s41467-025-59623-3.

Shinozaki T, Togasaki K, Hamamoto J, Mitsuishi A, Fukushima T, Sugihara K, Ebisudani T, Okada M, Saito A, Shigematsu L, Takaoka H, Ito F, Ohgino K, Ishioka, K, Watanabe K, Hishima T, Kurebayashi Y, Emoto K, Terai H, Ikemura S, Kawada I, Asakura K, Hishida T, Asamura H, Ohta Y, Takahashi S, Oda M, Saito M, Matano M, Soejima K, Fujii M, Fukunaga K, Yasuda H, Sato T.

Lung cancer is a heterogeneous disease, containing many subgroups with different pathological and genetic characteristics. The Department of Pulmonary Medicine and the Department of Biochemistry (Professor Toshiro Sato) have established a close collaborative research system and built a research infrastructure using patient-derived lung cancer organoids to understand lung cancer heterogeneity at the molecular level. Based on this infrastructure, we have now published findings leading to new treatments for lung cancer in Nature Cancer and Nature Communications. The first paper concerns small cell lung cancer. Small cell lung cancer is a refractory disease with an extremely poor prognosis, but we have identified a therapeutic agent (IGF1R inhibitor) effective for non-neuroendocrine type small cell lung cancer. Based on this finding, development toward personalized medicine using IGF1R inhibitors in small cell lung cancer is expected. The second paper concerns EGFR mutation-positive lung adenocarcinoma. In this field, "acquired resistance," where molecular targeted drugs targeting EGFR stop working during the course of treatment, is a major problem. We have newly clarified the mechanism of acquired resistance observed in approximately 30% of cases and identified a drug (CDK4/6 inhibitor) that can overcome this resistance. Through this, we proposed a new therapeutic strategy effective for lung cancer after resistance acquisition. Both papers have the potential to contribute significantly to the future development of lung cancer treatment, and clinical application is expected.

(Hiroyuki Yasuda, Associate Professor, Department of Pulmonary Medicine)

Cell.

2025 May 1;188(9):2372-2389.e35.

Taisuke Kondo, François X.P. Bourassa, Sooraj Achar, Justyn DuSold, Pablo F. Céspedes, Makoto Ando, Alka Dwivedi, Josquin Moraly, Christopher Chien, Saliha Majdoul, Adam L. Kenet, Madison Wahlsten, Audun Kvalvaag, Edward Jenkins, Sanghyun P. Kim, Catherine M. Ade, Zhiya Yu, Guillaume Gaud, Marco Davila, Paul Love, James C. Yang, Michael L. Dustin, Grégoire Altan-Bonnet, Paul François, Naomi Taylor

While CAR T-cell therapy, a type of cancer immunotherapy, shows remarkable therapeutic effects against blood cancers, side effects on normal tissues are a major challenge for solid tumors. We have now developed a new technology that dramatically improves the accuracy of distinguishing between cancer cells and normal cells by incorporating an artificial T-cell receptor (TCR) into CAR T-cells. Specifically, we clarified through both mathematical models and experiments the phenomenon where the activity of the CAR is suppressed when the TCR reacts to a weak antigen in situations where the TCR and CAR are activated simultaneously. Based on this finding, we designed a new control mechanism where weak antigens in normal tissues apply a "brake" to CAR T-cells, while strong tumor antigens apply an "accelerator." In fact, these TCR/CAR T-cells successfully attacked only tumor cells selectively in humanized mice, minimizing damage to normal lung tissue cells. Furthermore, we are working to predict CAR T-cell behavior with mathematical models to improve experimental efficiency and reproducibility. This achievement is expected to contribute significantly to the development of safer and more effective cancer immunotherapies by integrating TCR-based identification mechanisms into CAR T-cells. The first author, Taisuke Kondo, engaged in this research while studying abroad at the National Cancer Institute (NCI) after completing the Doctoral Programs at the Keio University School of Medicine, and has now returned to the Division of Cancer Immunotherapy, Institute for Advanced Medical Research (Professor Yuki Kagoya).

(Taisuke Kondo, Division of Cancer Immunotherapy, Institute for Advanced Medical Research)

Circ Res,

Jun. 26, 2025. doi: 10.1161/CIRCRESAHA.124.326030.

Ko S, Liu X, Taniguchi Y, Ichihara G, Komuro J, Yamakawa H, Shirakawa K, Hashimoto H, Katsumata Y, Endo J, Hattori M, Minato N, Sano M, Anzai A†, Ieda M.

Eur J Heart Fail.

2025 Jul 4. doi: 10.1002/ejhf.3755.

Toshikazu D Tanaka, Yasuyuki Shiraishi, Ryeonshi Kang, Takashi Kohno, Satoshi Shoji, Toraaki Okuyama, Yuhei Oi, Ayumi Goda, Ryo Nakamaru, Yuji Nagatomo, Mitsunobu Kitamura, Munehisa Sakamoto, Michiru Nomoto, Atsushi Mizuno, Tomohisa Nagoshi, Shun Kohsaka, Tsutomu Yoshikawa

Nat Commun.

2025 Jul 1;16(1):5475. doi: 10.1038/s41467-025-60515-9.

Takayuki Morikawa, Shinya Fujita, Yuki Sugiura, Shinpei Tamaki, Miho Haraguchi, Kohei Shiroshita, Shintaro Watanuki, Hiroshi Kobayashi, Hikari Kanai-Sudo, Yoshiko Naito, Noriyo Hayakawa, Tomomi Matsuura, Takako Hishiki, Minoru Matsui, Masato Tsutsui, Makoto Suematsu & Keiyo Takubo