Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer.
Adam C MuellerMiles PiperAndrew GoodspeedShiv BhuvaneJason S WilliamsShilpa BhatiaAndy V PhanBenjamin Van CourtKathryn L ZolmanDaewon ParkAyman J OweidaSara ZakemCheryl MeguidMichael William KnitzLaurel DarraghThomas E BickettJacob GadwaLuisa MestroniMatthew R G TaylorKimberley R JordanPeter DempseyM Scott LuciaMartin D McCarterMarco Del ChiaroWells A MessersmithRichard D SchulickKaryn A GoodmanMichael J GoughCasey S GreeneJames C CostelloAntonio Galveo NetoDavid LagaresKirk C HansenAdrie Van BokhovenSana D KaramPublished in: Cancer research (2021)
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.
Keyphrases
- radiation therapy
- locally advanced
- extracellular matrix
- genome wide
- radiation induced
- poor prognosis
- neoadjuvant chemotherapy
- squamous cell carcinoma
- rectal cancer
- epithelial mesenchymal transition
- phase ii study
- cell surface
- bone marrow
- stem cells
- cancer therapy
- liver fibrosis
- copy number
- small cell lung cancer
- signaling pathway
- drug induced
- free survival
- study protocol
- binding protein
- transcription factor
- long non coding rna
- clinical trial
- cell migration
- single cell
- case report
- human health
- oxidative stress
- dna binding
- radiofrequency ablation