Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer
- 1 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (12), 3255-3269
- https://doi.org/10.1158/0008-5472.can-20-3892
Abstract
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.Keywords
Funding Information
- Cancer Center Support (P30CA046934)
- Cancer Center Support (R01-DE028282)
- Cancer Center Support (R01-DE028529)
- NIH (R01 HL147059-01)
This publication has 64 references indexed in Scilit:
- The Matrisome: In Silico Definition and In Vivo Characterization by Proteomics of Normal and Tumor Extracellular MatricesMolecular & Cellular Proteomics, 2012
- PEGylation Potentiates the Effectiveness of an Antagonistic Peptide That Targets the EphB4 Receptor with Nanomolar AffinityPLOS ONE, 2011
- Overview of the Matrisome--An Inventory of Extracellular Matrix Constituents and FunctionsCold Spring Harbor Perspectives in Biology, 2011
- Molecular signatures database (MSigDB) 3.0Bioinformatics, 2011
- NG2+ CNS Glial Progenitors Remain Committed to the Oligodendrocyte Lineage in Postnatal Life and following NeurodegenerationNeuron, 2010
- Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10PLoS Biology, 2009
- Eph-Ephrin Bidirectional Signaling in Physiology and DiseaseCell, 2008
- Expression of L1-CAM and ADAM10 in Human Colon Cancer Cells Induces MetastasisCancer Research, 2007
- Phase I Trial of the Matrix Metalloproteinase Inhibitor Marimastat Combined with Carboplatin and Paclitaxel in Patients with Advanced Non–Small Cell Lung CancerClinical Cancer Research, 2005
- LETTERS TO THE EDITORAnnals of Surgery, 2002