The inhibition of pancreatic cancer progression by K-Ras-overexpressing mesenchymal stem cell-derived secretomes

• Published in: Scientific reports Vol. 13; no. 1; pp. 15036 - 14
• Main Authors: Huo, Qingji, Li, Kexin, Sun, Xun, Zhuang, Adam, Minami, Kazumasa, Tamari, Keisuke, Ogawa, Kazuhiko, Fishel, Melissa L, Li, Bai-Yan, Yokota, Hiroki
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 12.09.2023; Nature Publishing Group UK; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; Animals; Carcinoma, Pancreatic Ductal - drug therapy; CD44 antigen; Cell migration; Cell proliferation; Culture Media, Conditioned - pharmacology; Gemcitabine; Humans; K-Ras protein; Leukocytes, Mononuclear; Mesenchymal stem cells; Mice; Moesin; Neoplastic Processes; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - therapy; Peripheral blood mononuclear cells; Phosphatidylinositol 3-Kinases; Secretome; Stem cells; Tumor cells; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-41835-6

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival. To explore an uncharted function of K-Ras proto-oncogene, K-Ras was activated in mesenchymal stem cells (MSCs) and the effects of MSC conditioned medium (CM) on PDAC were examined. Overexpression of K-Ras elevated PI3K signaling in MSCs, and K-Ras/PI3K-activated MSC-derived CM reduced the proliferation and migration of tumor cells, as well as the growth of ex vivo freshly isolated human PDAC cultures. CM's anti-tumor capability was additive with Gemcitabine, a commonly used chemotherapeutic drug in the treatment of PDAC. The systemic administration of CM in a mouse model suppressed the colonization of PDAC in the lung. MSC CM was enriched with Moesin (MSN), which acted as an extracellular tumor-suppressing protein by interacting with CD44. Tumor-suppressive CM was also generated by PKA-activated peripheral blood mononuclear cells. Collectively, this study demonstrated that MSC CM can be engineered to act as a tumor-suppressive agent by activating K-Ras and PI3K, and the MSN-CD44 regulatory axis is in part responsible for this potential unconventional option in the treatment of PDAC.