Tumor Pathology/Molecular Pathology

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Email	enomoto.atsushi.d3◎f.mail.nagoya-u.ac.jp(Please send a message after replacing "◎" mark with "@" mark. )
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OUTLINE

The Laboratory of Tumor Pathology/Molecular Pathology aims to train board-certified pathologists and pathology researchers while promoting the development of original, innovative research in pathology. At the undergraduate level, we are responsible for pathology lectures, practical training, and supervision of CPC (Clinicopathological Conference) presentations for medical students. For the training of pathologists, we receive extensive support from faculty members of the Department of Pathology at Nagoya University Hospital and affiliated hospitals. In addition to fostering pathologists who can contribute to regional healthcare, we place strong emphasis on nurturing specialists with defined subspecialty expertise. Through research activities in the graduate program, we aim to cultivate pathologists and pathology researchers who can independently formulate morphology-based research questions. Our research approach centers on molecular functional analysis combined with meticulous morphological evaluation, and is carried out by members with diverse academic backgrounds. We are deeply grateful for the support of numerous collaborators both within and outside Nagoya University. Those interested in our laboratory are warmly encouraged to contact us.

RESEARCH PROJECTS

Research Theme 1
Stromal Biology: Roles of Fibroblasts in Cancer and Fibrotic Diseases

The tumor stroma (non-epithelial components) is enriched with cancer-associated fibroblasts (CAFs), a phenomenon particularly prominent in highly aggressive cancers such as pancreatic cancer. In addition, age-related functional decline, tissue injury and repair, and chronic inflammation in many organs are closely associated with increased fibroblast populations and excessive extracellular matrix deposition, leading to fibrosis.
Recent studies have revealed significant functional heterogeneity among stromal fibroblasts (Kobayashi et al., Nat Rev Gastroenterol Hepatol, 2019; Miyai et al., Cancer Sci, 2020; Shiraki et al., Nagoya J Med Sci, 2022, among others). We identified the GPI-anchored membrane protein Meflin and its related molecules as markers of fibroblasts that play important roles in tumor suppression, tissue repair after injury, and suppression of fibrosis, and have been analyzing their functions (Maeda et al., Sci Rep, 2016; Ichihara et al., Pathol Int, 2022, among others).
We have demonstrated that Meflin expressed in CAFs suppresses tumor progression and/or enhances antitumor immune responses (Mizutani et al., Cancer Res, 2019; Miyai et al., Cancer Sci, 2020; Kobayashi et al., Gastroenterology, 2021; Miyai et al., Life Sci Alliance, 2022, among others). Furthermore, Meflin is essential for tissue repair following injuries such as myocardial ischemia and lung damage (Hara et al., Circ Res, 2019; Nakahara et al., Eur Respir J, 2021). Induction of heart failure in Meflin-deficient mice results in a form of heart failure characterized by cardiac stiffening, known as HFpEF (heart failure with preserved ejection fraction) (Hara et al., Circ Res, 2019).
More recently, through collaboration with a group at Columbia University in the United States, we have been involved in studies highlighting the importance of fibroblast–neuron interactions (Kobayashi et al., Cancer Discov, 2025; Kobayashi et al., Cancer Res, 2025). In addition, together with numerous collaborators, we are developing therapeutic strategies aimed at converting fibroblasts from tumor-promoting to tumor-suppressive phenotypes (Iida et al., Oncogene, 2022; Owaki et al., Br J Cancer, 2024, among others).
In the future, we aim to further elucidate the diversity and significance of fibroblasts across various pathological conditions by focusing on additional related molecules, and to advance research toward the development of novel therapeutic approaches.

Research Theme 2
Molecular Mechanisms Regulating Fibroblast Activation and Resolution

Fibroblasts are essential for maintaining tissue structure, and recent studies have demonstrated their roles as niches for tissue stem cells and their indispensable contributions to physiological functions in various organs. Fibroblasts are mainly localized around blood vessels and play critical roles in vascular function and regeneration. When tissues are damaged by physical stress, inflammation, or cancer, fibroblasts rapidly become activated and proliferate, inducing wound-healing responses in cooperation with inflammatory cells such as macrophages. Accumulating evidence indicates that both insufficient and prolonged wound-healing responses can contribute to the progression and exacerbation of diseases, including cancer. Our studies have also reported findings supporting this concept (Mizutani et al., Cancer Res, 2019; Hara et al., Circ Res, 2019; Nakahara et al., Eur Respir J, 2021; ; Ando et al., J Pathol, 2024). These observations highlight the importance of appropriately regulating fibroblast activity for the development of therapies for cancer, inflammatory diseases, and fibrotic disorders.
However, the molecular mechanisms governing fibroblast activation and resolution remain largely unknown, particularly those responsible for resolution. We are currently focusing on the ability of human fetuses and specific animal models to achieve scarless wound healing after tissue injury, and are investigating the molecular mechanisms that appropriately regulate fibroblast activation and resolution. In addition, we are studying how fibroblast aging influences fibroblast dynamics as well as the physiological functions of various organs and tissues.

Research Theme 3
Development of Antibody–Drug Conjugates Based on the Characteristics of Stromal Cells

Meflin, a molecule specific to fibroblasts and mesenchymal stromal cells (mesenchymal stem cells), is also expressed in a subset of mesenchymal tumors derived from these cells (Esaki et al., Oncogene, 2025; Shiraki et al., Brain Pathology, 2025). We have demonstrated that Meflin is involved in drug resistance and recurrence of osteosarcoma, and reported that an antibody–drug conjugate (ADC) consisting of an anti-Meflin antibody linked to an anticancer agent can serve as a potential therapeutic option for refractory osteosarcoma (Esaki et al., Oncogene, 2025). We also envision that this ADC may be applicable to other cancers, including refractory tumors accompanied by prominent stromal reactions. To promote the clinical translation of this therapy, we have established a startup company (BFACT Inc.) and are actively engaged in research and development aimed at its implementation in society.

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