Your Donations in Action: Adam Mueller, MD, PhD
Investigating drivers of fibrosis and tumor progression in pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with minimal improvement in outcomes despite advances in surgical technique, chemotherapy and radiation therapy delivery.
In PDAC tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), there is upregulation of fibrosis, extracellular matrix (ECM) and EMT gene signatures, which can drive therapeutic resistance and tumor invasion.
With his 2019 RSNA Research Resident Grant, “Investigating the Role of Crosstalk Between ADAM10 and EphrinB2/EPHB4 in Mediating Radiation Induced Fibrosis, Invasion and Metastasis in Pancreatic Cancer,” Adam Mueller, MD, PhD, assistant professor of radiation oncology in the Sidney Kimmel Cancer Center at Thomas Jefferson University, and colleagues conducted molecular, functional and translational analysis in mouse models that 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 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. “These findings represent a model of PDAC adaptation that explains resistance and metastasis after RT and identifies a targetable pathway to enhance RT efficacy,” Dr. Mueller said.
“The RSNA R&E Foundation Research Resident grant, was instrumental in funding this project, which resulted in publication in Cancer Research, and no doubt played a role in my hiring as a physician scientist at Thomas Jefferson University,” Dr. Mueller said. “I have continued to pursue this work, now funded by an RSNA Research Scholar Grant, and thanks to this support have also secured funding from the Kim Foster Foundation and Viewray Corporation. I have also received high scores for the NCI K08 and ACS Clinician Scientist Development grant, which is currently awaiting final funding decision.”
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