Induction of ADAM10 by RT drives fibrosis, resistance, and EMT in pancreatic cancer.
oregon; portland; chiles
Stromal fibrosis activates pro-survival and pro-epithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell surface proteins, A disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after RT. RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with EphrinB2 FC-protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after radiation therapy and identifies a targetable pathway to enhance RT efficacy.
Pathology & Laboratory Medicine
Earle A. Chiles Research Institute
Mueller, Adam C; Piper, Miles; Goodspeed, Andrew; Bhuvane, Shiv; Williams, Jason S; Bhatia, Shilpa; Phan, Andy V; Van Court, Benjamin; Zolman, Kathryn L; Peña, Brisa; Oweida, Ayman J; Zakem, Sara; Meguid, Cheryl; Knitz, Michael W; Darragh, Laurel; Bickett, Thomas E; Gadwa, Jacob; Mestroni, Luisa; Taylor, Matthew R G; Jordan, Kimberly R; Dempsey, Peter; Lucia, M Scott; McCarter, Martin D; Del Chiaro, Marco; Messersmith, Wells A; Schulick, Richard D; Goodman, Karyn A; Gough, Michael J.; Greene, Casey S; Costello, James C; Galvao Neto, Antonio; Lagares, David; Hansen, Kirk C; Van Bokhoven, Adrie; and Karam, Sana D, "Induction of ADAM10 by RT drives fibrosis, resistance, and EMT in pancreatic cancer." (2021). Articles, Abstracts, and Reports. 4478.