Annual Report 2024

Division of Innovative Pathology and Laboratory Medicine (Kashiwa Campus)

Genichiro Ishii, Miyuu Ibe, Sora Nakamaru, Jun Suzuki

Introduction

 Some members are from the Department of Pathology and Clinical Laboratories and Department of Clinical Laboratories in the National Cancer Center Hospital East (NCCHE).

The Team and What We Do

 We aspire to lay the scientific groundwork for next-generation cancer therapies by illuminating the pivotal role of the tumor microenvironment, focusing especially on cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), which constitute the predominant stromal elements of neoplastic tissue.

Research Activities

 The following are the major research results of this year.

1. In EGFR-mutated lung adenocarcinoma, solid-predominant histology and high podoplanin expression in cancer-associated fibroblasts (CAFs) emerged as independent predictors of resistance to osimertinib and poor prognosis. These findings suggest their potential utility as indicators for selecting patients who may benefit from more intensive therapeutic strategies.

2. In stage I EGFR-mutated lung adenocarcinoma, histological grading according to the IASLC system was strongly correlated with prognosis. High-grade tumors were characterized by greater infiltration of tumor-promoting CAFs and TAMs, suggesting that the unfavorable outcomes observed in this group may, at least in part, be driven by such stromal interactions.

3. In resected lung squamous cell carcinoma, stromal micronests were demonstrated to be an independent predictor of poor prognosis, showing significant associations with both recurrence and overall survival. Evaluation of micronests thus holds promise as a novel pathological risk marker.

Education

 Our department offers specialized lectures to clinical residents pursuing doctoral programs at Juntendo University Graduate School, in formal affiliation with the National Cancer Center. Several of our staff members also serve as adjunct faculty at the Graduate School of Frontier Sciences, The University of Tokyo, where they contribute to both research supervision and academic instruction. In parallel, we are actively engaged in providing research training and scholarly guidance to clinical residents of the National Cancer Center Hospital East.

Future Prospects

1. We have established a novel in vitro model that faithfully recapitulates the human tumor microenvironment, incorporating three essential cellular components: cancer cells, cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs). Using this system, we aim to elucidate the distinct and cooperative roles of CAFs and TAMs in promoting cancer cell invasion.

2. Characterizing the tumor microenvironment following chemotherapy is of paramount importance for the development of more effective therapeutic strategies. Using the same methodology, we have successfully generated cisplatin-resistant cancer cells as well as cisplatin-resistant CAFs. Moving forward, our objective is to delineate how cisplatin-resistant CAFs contribute to the establishment of the “reprogression niche,” a microenvironment in which residual cancer cells regain proliferative and invasive capacity after treatment. Of note, RNA sequencing and single-cell RNA sequencing analyses of both resistant cancer cells and resistant CAFs have already been completed and thoroughly evaluated.

List of papers published in 2024

Journal

1. Kojima N, Nishino S, Sasahara Y, Taki T, Imada H, Miyoshi T, Watanabe SI, Ishii G, Yatabe Y, Mori T, Yoshida A. Inflammatory spindle cell PEComa of the lung with YAP1::TFE3 fusion: a report of two cases and a potential relationship with clear cell stromal tumour. Histopathology, 86:365-372, 2025

2. Umemura S, Udagawa H, Ikeda T, Murakami H, Daga H, Toyozawa R, Kozuki T, Sakakibara-Konishi J, Ohe Y, Morise M, Kato T, Shingyoji M, Hara S, Furuya N, Teranishi S, Takata S, Miyamoto S, Nakachi I, Wakabayashi M, Nomura S, Sato A, Ishii G, Tsuchihara K, Sugiyama E, Kirita K, Sakai T, Shibata Y, Izumi H, Nosaki K, Zenke Y, Matsumoto S, Yoh K, Niho S, Goto K. Clinical Significance of a Prospective Large Genomic Screening for SCLC: The Genetic Classification and a Biomarker-Driven Phase 2 Trial of Gedatolisib. Journal of thoracic oncology, 20:177-193, 2025

3. Oi H, Taki T, Kuroe T, Sakamoto N, Sakashita S, Kojima M, Sugiyama E, Umemura S, Sakai T, Izumi H, Zenke Y, Matsumoto S, Yoh K, Ishii M, Tsuboi M, Goto K, Ishii G. NETosis in pulmonary pleomorphic carcinoma. Cancer science, 116:524-532, 2025

4. Urabe A, Adachi M, Sakamoto N, Kojima M, Ishikawa S, Ishii G, Yano T, Sakashita S. Deep learning detected histological differences between invasive and non-invasive areas of early esophageal cancer. Cancer science, 116:824-834, 2025

5. Nagata H, Kinoshita T, Sakashita S, Kojima M, Taki T, Kuwata T, Yura M, Shitara K, Ishii G, Sakamoto N. Area of Residual Tumor Measurement After Preoperative Chemotherapy as an Objective and Quantitative Method for Predicting the Prognosis of Gastric Cancer: A Single-Center Retrospective Study. World journal of surgery, 49:717-726, 2025

6. Sasaki T, Oda S, Kuno H, Hiyama T, Taki T, Takahashi S, Ishii G, Tsuboi M, Kobayashi T. Potential of spectral imaging generated by contrast-enhanced dual-energy CT for lung cancer histopathological classification - A preliminary study. European journal of radiology open, 14:100628, 2025

7. Uehara Y, Izumi H, Taki T, Sakai T, Udagawa H, Sugiyama E, Umemura S, Zenke Y, Matsumoto S, Yoh K, Kubota S, Aokage K, Sakamoto N, Sakashita S, Kojima M, Nagamine M, Hosomi Y, Tsuboi M, Goto K, Ishii G. Solid Predominant Histology and High Podoplanin Expression in Cancer-Associated Fibroblast Predict Primary Resistance to Osimertinib in EGFR-Mutated Lung Adenocarcinoma. JTO clinical and research reports, 6:100779, 2025

8. Niimi T, Samejima J, Wakabayashi M, Miyoshi T, Tane K, Aokage K, Taki T, Nakai T, Ishii G, Kikuchi A, Yoshioka E, Yokose T, Ito H, Tsuboi M. Ten-year follow-up outcomes of limited resection trial for radiologically less-invasive lung cancer. Japanese journal of clinical oncology, 54:479-488, 2024

9. Nagasaki Y, Taki T, Nomura K, Tane K, Miyoshi T, Samejima J, Aokage K, Ohtani-Kim SJ, Kojima M, Sakashita S, Sakamoto N, Ishikawa S, Suzuki K, Tsuboi M, Ishii G. Spatial intratumor heterogeneity of programmed death-ligand 1 expression predicts poor prognosis in resected non-small cell lung cancer. Journal of the National Cancer Institute, 116:1158-1168, 2024

10. Goto E, Taki T, Nomura K, Miyakami Y, Miyoshi T, Tane K, Samejima J, Aokage K, Nagamine M, Sakashita S, Sakamoto N, Kojima M, Suzuki K, Tsuboi M, Ishii G. Clinicopathological differences between EGFR mutated and EGFR wild-type lung adenocarcinoma with papillary predominant pattern. Lung cancer (Amsterdam, Netherlands), 192:107830, 2024

11. Tsushima T, Sato N, Guo YM, Nakamura H, Kunisada K, Chi SG, Akie K, Takahashi Y, Nakamura S, Shimada K, Ishii G, Minami Y, Yuda J. Richter transformation acquiring PLCG2 mutation during Bruton tyrosine kinase inhibitors treatment. EJHaem, 5:642-645, 2024

12. Kaminuma Y, Nakai T, Aokage K, Taki T, Miyoshi T, Tane K, Samejima J, Miyazaki S, Sakamoto N, Sakashita S, Kojima M, Watanabe R, Tsuboi M, Ishii G. Prognostic significance of micronest in cancer stroma in resected lung squamous cell carcinoma. Human pathology, 150:20-28, 2024

13. Niimi T, Samejima J, Koike Y, Miyoshi T, Tane K, Aokage K, Taki T, Ishii G, Tsuboi M. A case of lung metastasis from gastric cancer presenting as ground-glass opacity dominant nodules. Journal of cardiothoracic surgery, 19:365, 2024

14. Ishii G. New insights into cancer pathology learned from the dynamics of cancer-associated fibroblasts. Pathology international, 74:493-507, 2024

15. Kubota S, Taki T, Miyoshi T, Tane K, Samejima J, Aokage K, Wakabayashi M, Nomura K, Nagamine M, Kojima M, Sakashita S, Sakamoto N, Tsuboi M, Ishii G. Prognostic value of the international association for the study of lung cancer grading system and its association with the tumor microenvironment in stage I EGFR-muted lung adenocarcinoma. European journal of cancer (Oxford, England : 1990), 207:114184, 2024

16. Hashimoto T, Nakamura Y, Fujisawa T, Imai M, Shibuki T, Iida N, Ozaki H, Nonomura N, Morizane C, Iwata H, Okano S, Yamagami W, Yamazaki N, Kadowaki S, Taniguchi H, Ueno M, Boku S, Oki E, Komatsu Y, Yuki S, Makiyama A, Otsuka T, Hara H, Okano N, Nishina T, Sakamoto Y, Miki I, Kobayashi S, Yuda J, Kageyama SI, Nagamine M, Sakashita S, Sakamoto N, Yamashita R, Koga Y, Bando H, Ishii G, Kuwata T, Park WY, Ohtsu A, Yoshino T. The SCRUM-MONSTAR Cancer-Omics Ecosystem: Striving for a Quantum Leap in Precision Medicine. Cancer discovery, 14:2243-2261, 2024

17. Adachi M, Taki T, Kojima M, Sakamoto N, Matsuura K, Hayashi R, Tabuchi K, Ishikawa S, Ishii G, Sakashita S. Predicting lymph node recurrence in cT1-2N0 tongue squamous cell carcinoma: collaboration between artificial intelligence and pathologists. The journal of pathology. Clinical research, 10:e12392, 2024

18. Kitaoka T, Harada K, Sakashita S, Kojima M, Taki T, Kuwata T, Kinoshita T, Futakuchi M, Ishii G, Sakamoto N. Quantification of Gremlin 1 throughout the tumor stroma using whole slide imaging and its clinicopathological significance in gastric cancer. Virchows Archiv, 485:1107-1116, 2024

19. Taki T, Koike Y, Adachi M, Sakashita S, Sakamoto N, Kojima M, Aokage K, Ishikawa S, Tsuboi M, Ishii G. A novel histopathological feature of spatial tumor-stroma distribution predicts lung squamous cell carcinoma prognosis. Cancer science, 115:3804-3816, 2024

20. Aokage K, Koyama S, Kumagai S, Nomura K, Shimada Y, Yoh K, Wakabayashi M, Fukutani M, Furuya H, Miyoshi T, Tane K, Samejima J, Taki T, Hayashi T, Matsubayashi J, Ishii G, Nishikawa H, Ikeda N, Tsuboi M. Efficacy, Safety, and Influence on the Tumor Microenvironment of Neoadjuvant Pembrolizumab plus Ramucirumab for PD-L1-Positive NSCLC: A Phase II Trial (EAST ENERGY). Clinical cancer research, 30:5584-5592, 2024

21. Takano Y, Suzuki J, Nomura K, Fujii G, Zenkoh J, Kawai H, Kuze Y, Kashima Y, Nagasawa S, Nakamura Y, Kojima M, Tsuchihara K, Seki M, Kanai A, Matsubara D, Kohno T, Noguchi M, Nakaya A, Tsuboi M, Ishii G, Suzuki Y, Suzuki A. Spatially resolved gene expression profiling of tumor microenvironment reveals key steps of lung adenocarcinoma development. Nature communications, 15:10637, 2024