Annual Report 2024
Laboratory of Cancer Pathophysiology
Yasuyuki Nagumo, Michiko Narita, Minoru Narita, Mitsuaki Yamazaki, Hiroshi Nagase, Fumimasa Amaya, Naoko Kuzumaki, Yusuke Hamada, Yukari Suda, Kanako Miyano, Hironori Sato
Introduction
Recent advances in cancer therapy have led to a steady increase in the population of cancer survivors, underscoring the importance of maintaining and improving the quality of life (QOL) for patients living with cancer. In this context, the present study focuses on comprehensive investigations of cancer pathophysiology, with the overarching goal of establishing next-generation supportive and palliative care strategies. In line with the Fourth Basic Plan for Cancer Control in Japan, the study pursues an integrated approach encompassing both cancer treatment and survivorship. The progression and clinical manifestations of cancer are influenced not only by tumor genomic alterations but also by co-existing conditions, persistent pain, and psychological stress. A comprehensive understanding of these multifactorial determinants is considered essential for the advancement of high-quality supportive care. Furthermore, the study has emphasized the roles of the nervous and immune systems in cancer pathophysiology, and has established a framework to elucidate neuro–immune–tumor interactions, particularly focusing on the effects of nociceptive signaling and neural responses on the tumor microenvironment.
Research Activities
1) Analysis of sensory neuron–cancer cell–immune cell interactions
To investigate intercellular interactions in humans, sensory neurons were differentiated from human induced pluripotent stem (iPS) cells and co-cultured with human cancer cells (e.g., lung and breast cancer) and immune cells under in vitro conditions. Within this co-culture system, sensory neurons were selectively activated, and phenotypic alterations in cancer cells and other cell types were examined. In addition, reciprocal changes in sensory neurons induced by cancer cells were analyzed to explore bidirectional intercellular interactions. Furthermore, using transgenic mice bearing orthotopic tumor transplants, the interplay between sensory neuronal stimulation and tumor progression was also evaluated.
2) Predictive analyses using human disease databases to evaluate the influence of pain relief on cancer pathophysiology
In collaboration with the Department of Palliative Medicine at the National Cancer Center Hospital, a retrospective cohort study of patients with cancer-related pain was conducted, revealing that residual pain may influence overall survival and the duration of pharmacological treatment. In addition, based on the cohort study, serum analyses were performed using blood samples obtained from patients with cancer-related pain.
3) Translational research for the development of novel non-narcotic analgesics
Through rational drug design, novel non-narcotic opioid analgesics were generated, and analyses were conducted using cancer pain model mice and patient-derived xenograft (PDX) models to obtain non-clinical proof of concept. In addition, under in vitro conditions, the ligand properties of these compounds were characterized, and their effects on iPS cell-derived sensory neurons, as well as on cancer cells, were evaluated.
Education
We accepted 26 individuals from collaborating universities (Hoshi University, Tokyo University of Science, etc.) as partnering graduate students and trainees, and provided them with research and education opportunities through paper publication and research presentation.
Future Prospects
Overcoming the complexity of cancer pathophysiology requires not only a comprehensive understanding of neuro–immune–tumor interactions but also the establishment of analytical platforms capable of capturing their temporal and spatial dynamics at high resolution. Future directions will involve the application of advanced methodologies, such as spatial transcriptomics, to systematically delineate dynamic networks among neural, tumor, and immune cells within the tumor microenvironment. Simultaneously, strengthening collaborative research frameworks and advancing translational approaches that integrate clinical data with experimental findings in a bidirectional manner will be critical. These efforts are expected to yield mechanistic insights that facilitate the development of novel analgesics and contribute to the refinement of supportive and palliative care.
List of papers published in 2024
Journal
1. Suda Y, Nakamura K, Matsuyama F, Hamada Y, Makabe H, Narita M, Nagumo Y, Mori T, Kuzumaki N, Narita M. Peripheral-central network analysis of cancer cachexia status accompanied by the polarization of hypothalamic microglia with low expression of inhibitory immune checkpoint receptors. Molecular Brain, 17:20, 2024
2. Tamura H, Miyazaki A, Kawamura T, Gotoh H, Yamamoto N, Narita M. Chronic ingestion of soy peptide supplementation reduces aggressive behavior and abnormal fear memory caused by juvenile social isolation. Scientific Reports, 14:11557, 2024