Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer.
ADAM10 Protein
/ antagonists & inhibitors
Amyloid Precursor Protein Secretases
/ antagonists & inhibitors
Animals
Antifibrotic Agents
/ therapeutic use
Apoptosis
Carcinoma, Pancreatic Ductal
/ pathology
Cell Movement
Cell Proliferation
Ephrin-B2
/ blood
Epithelial-Mesenchymal Transition
Female
Fibrosis
/ drug therapy
Gamma Rays
/ adverse effects
Humans
Membrane Proteins
/ antagonists & inhibitors
Mice
Mice, Inbred C57BL
Pancreatic Neoplasms
/ pathology
Prognosis
Radiation Injuries
/ drug therapy
Survival Rate
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 06 2021
15 06 2021
Historique:
received:
19
11
2020
revised:
18
12
2020
accepted:
27
01
2021
pubmed:
3
2
2021
medline:
15
12
2021
entrez:
2
2
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33526513
pii: 0008-5472.CAN-20-3892
doi: 10.1158/0008-5472.CAN-20-3892
pmc: PMC8260469
mid: NIHMS1670703
doi:
Substances chimiques
Antifibrotic Agents
0
EFNB2 protein, human
0
Ephrin-B2
0
Membrane Proteins
0
Amyloid Precursor Protein Secretases
EC 3.4.-
ADAM10 Protein
EC 3.4.24.81
ADAM10 protein, human
EC 3.4.24.81
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3255-3269Subventions
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028282
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147059
Pays : United States
Organisme : NHLBI NIH HHS
ID : K25 HL148386
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028529
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2021 American Association for Cancer Research.
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