👤 Dai Kusumoto

In the tumor microenvironment, hypoxia and stromal interactions contribute to enhanced malignant behavior in cancer cells. This study aimed to assess whether pancreatic cancer cells with higher malignancy display stronger responses to hypoxia and stromal cells than their less malignant parental cells, and evaluated the underlying mechanisms, focusing on lysophosphatidic acid (LPA) receptor signaling linked to the acquisition of malignant traits. Highly invasive PANC-M10 cells, derived from the parental pancreatic cancer PANC-1 cells, were cultured at 1% O Show less

Lysophosphatidic acid (LPA) receptor-mediated signaling contributes to the pathogenesis of cancer. The tumor microenvironment (TME), composed of cancer cells and surrounding stromal cells, plays a key role in promoting malignant traits, including resistance to anticancer drugs. In this study, we investigated the roles of LPA receptor-1 (LPA Show less

Hypoxia plays a crucial role in driving tumor progression by altering cellular signaling pathways. Lysophosphatidic acid (LPA) receptor signaling regulates malignant properties in cancer cells, including motility and chemoresistance. This study aimed to compare the cellular functions of gastric cancer AGS cells under cobalt chloride (CoCl Show less

In solid tumors, cancer cells adapt to hypoxic and nutrient deprived environments to support malignant progression. This study examined whether hypoxic and low glucose conditions enhance malignant behaviors more strongly in highly migratory MG63-R10 cells, which are derived from osteosarcoma MG-63 cells, compared to parental MG-63 cells, and further investigated whether lysophosphatidic acid (LPA) receptor signaling regulates this adaptation. MG63-R10 and MG-63 cells were cultured under hypoxic (1% O Under 1% O These results suggest that, compared to parental MG-63 cells, highly migratory osteosarcoma MG63-R10 cells adapt their malignant cellular functions to hypoxic and low-glucose conditions through LPA receptor signaling, highlighting this pathway as a potential therapeutic target in aggressive osteosarcomas. The online version contains supplementary material available at 10.1007/s12195-025-00873-y. Show less

Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM. We generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high-speed video imaging. The differences between control and HCM iPSC-derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease-promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy-promoting factors. Interestingly, endothelin-1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC-derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous Mybpc3-targeted knock in mice. High-speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC-derived cardiomyocytes, which revealed that self-beating HCM iPSC-derived single cardiomyocytes stimulated by endothelin-1 showed variable contractile directions. Interactions between the patient's genetic backgrounds and the environmental factor endothelin-1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC-derived cardiomyocytes. Show less

Mutations in vacuolar protein sorting 13A (VPS13A) gene are responsible for chorea-acanthocytosis (ChAc). We previously determined the full-length sequence and exon-intron structure of mouse VPS13A and generated a ChAc model mouse by using the gene targeting technique. In the process, we found diverse 5' and 3' transcript variants. Since ChAc is a rare neurodegenerative disorder, the mouse model should be useful for investigation of ChAc molecular pathogenesis, and the model's brain specific variants of VPS13A will be indispensable in these investigations. In the present study, we investigated mouse VPS13A transcript variants. We found brain-specific variants of mouse VPS13A, which may be involved in the brain-specific pathology of ChAc. In addition, we identified for the first time mouse VPS13C cDNA sequences and brain-specific variants of VPS13C. Show less