Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer

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

High local failure rates despite high margin‐negative resection rates in a cohort of borderline resectable and locally advanced pancreatic cancer patients treated with stereotactic body radiation therapy following multi‐agent chemotherapy

“…[39][40] In addition, combined modality approaches that may help address pathways of therapeutic resistance to radiation should also be explored. 41 Limitations inherent to our study include its retrospective, single-arm, and single-institution nature. Furthermore, with respect to surgical margins, it remains a matter of debate how specimens are processed and analyzed, and it remains unclear what constitutes a truly positive margin especially in a population that has received neoadjuvant therapy.…”

The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth

“…A recent study described the role of stromal fibrosis in activating pro-survival and epithelial-to-mesenchymal transition (EMT) pathways in PDAC. The group identified two cell-surface proteins, a disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after radiation therapy (RT) and suggested that activation by ephrinB2 drives fibroblasts toward a myofibroblast differentiation, thereby driving cancer invasion ( Mueller et al, 2021 ). Unfortunately, there are few studies that include data on fibroblast heterogeneity and/or phenotype with respect to resistance to RT and most studies focus more on the mechanisms underpinning RT resistance in general; as such, this section will be a more general viewpoint on the role of CAFs in mediating/alleviating radioresistance in PDAC.…”

The Dynamic Entropy of Tumor Immune Infiltrates: The Impact of Recirculation, Antigen-Specific Interactions, and Retention on T Cells in Tumors

“…In this way chemokine receptors that are induced by activation are likely to be enriched on the antigenspecific populations in the tumor environment, akin to the activation markers CD69 and CD39. It may also be important that CXCL16 is an unusual chemokine in that it is membrane bound, until cleaved by proteases that are regulated under inflammatory conditions and during cancer treatment (84)(85)(86)(87). Therefore, CXCR6 may generate a retentive niche for antigenreactive cells in close contact with epithelial cells, or recruitment from systemic circulation under inflammatory conditions.…”