Title | Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Mueller AC, Piper M, Goodspeed A, Bhuvane S, Williams JS, Bhatia S, Phan AV, Van Court B, Zolman KL, Peña B, Oweida AJ, Zakem S, Meguid C, Knitz MW, Darragh L, Bickett TE, Gadwa J, Mestroni L, Taylor MRG, Jordan KR, Dempsey P, M Lucia S, McCarter MD, Del Chiaro M, Messersmith WA, Schulick RD, Goodman KA, Gough MJ, Greene CS, Costello JC, Neto AGalveo, Lagares D, Hansen KC, Van Bokhoven A, Karam SD |
Journal | Cancer Res |
Volume | 81 |
Issue | 12 |
Pagination | 3255-3269 |
Date Published | 2021 Jun 15 |
ISSN | 1538-7445 |
Keywords | ADAM10 Protein, Amyloid Precursor Protein Secretases, Animals, Antifibrotic Agents, Apoptosis, Carcinoma, Pancreatic Ductal, Cell Movement, Cell Proliferation, Ephrin-B2, Epithelial-Mesenchymal Transition, Female, Fibrosis, Gamma Rays, Humans, Membrane Proteins, Mice, Mice, Inbred C57BL, Pancreatic Neoplasms, Prognosis, Radiation Injuries, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays |
Abstract | Stromal fibrosis activates prosurvival and proepithelial-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 radiation therapy (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 RT and identifies a targetable pathway to enhance RT efficacy. SIGNIFICANCE: Targeting a previously unidentified adaptive resistance mechanism to radiation therapy in PDAC tumors in combination with radiation therapy could increase survival of the 40% of PDAC patients with locally advanced disease.See related commentary by Garcia Garcia et al., p. 3158 GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3255/F1.large.jpg. |
DOI | 10.1158/0008-5472.CAN-20-3892 |
Alternate Journal | Cancer Res |
PubMed ID | 33526513 |
PubMed Central ID | PMC8260469 |
Grant List | P30 CA046934 / CA / NCI NIH HHS / United States R01 DE028282 / DE / NIDCR NIH HHS / United States R01 HL147059 / HL / NHLBI NIH HHS / United States K25 HL148386 / HL / NHLBI NIH HHS / United States R01 DE028529 / DE / NIDCR NIH HHS / United States |
Related Faculty:
Andy Phan, M.D.