Enhancement of malignant potency through lysophosphatidic acid (LPA) receptor signaling in pancreatic cancer cells under hypoxic conditions

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% O₂ to mimic hypoxic conditions and co-cultured with lymphatic endothelial SVEC4-10 cells. Exposure to 1% O₂ increased <i>LPAR2</i> and <i>LPAR3</i> expression in PANC-M10 cells. Although cell proliferation in response to LPA treatment in 1% O₂ culture also increased in PANC-1 cells, the increase was more pronounced in PANC-M10 cells. PANC-M10 cells displayed markedly elevated invasive activity in 1% O₂ compared with PANC-1 cells. This hypoxia-induced invasion was reduced by AM966 (LPA₁ antagonist) and GRI-977,143 (LPA₂ agonist), while (2 S)-OMPT (LPA₃ agonist) further enhanced invasive capacity, indicating distinct receptor-dependent functions. Co-culture with SVEC4-10 cells at 1% O₂ amplified the invasive behavior of PANC-M10 cells beyond that observed under monoculture. In addition, the supernatant collected from PANC-M10 cells maintained at 1% O₂ more effectively stimulated SVEC4-10 tube formation than the supernatant from PANC-1 cells. These findings demonstrate that highly invasive pancreatic cancer cells undergo hypoxia-driven crosstalk with lymphatic endothelial cells, promoting tumor progression through LPA receptor-mediated signaling pathways.