Grants We Funded

Abstract

Project Summary: Capsular fibrosis is an excessive fibrotic response of the cells surrounding breast implants that results in pain, deformity and rupture. Post-mastectomy radiation (PMRT) has been shown to increase the risk for capsular fibrosis after implant-based breast reconstruction by 4-times. Effective pharmacological treatment options that can treat or prevent capsular fibrosis have not been developed so far. Fibrosis of the skin after dermal injury has been shown to be related to elevated mechanical forces that trigger cellular mechanotransduction pathways, such as the focal adhesion kinase (FAK) pathway, which promotes excessive scar formation. Using small and large animal models, our group has demonstrated that pharmacological inhibition of the FAK pathway significantly reduces fibrosis, while promoting regenerative fibroblast subpopulations that induce healing of deep dermal injuries. The FAK pathway has also been shown to induce cellular adhesion in response to radiation, hence it is likely that mechanical signaling pathways also play a critical role in radiation-induced periprosthetic capsular fibrosis. Our understanding of how radiation affects capsular fibrosis on the molecular level still remains largely incomplete; hence there is an urgent need for more in-depth investigations of signaling pathways and specific cell populations that are drivers of radiation-induced fibrosis and sustain the profibrotic effects of radiation within the tissue long-term. This proposal aims to investigate the molecular mechanisms and changes in cellular subpopulations that underly radiation-induced fibrosis around biomedical implants and are the drivers behind increased complication rates in the setting of implant-based breast reconstruction. To achieve Aim 1, we will analyze irradiated and non-irradiated human breast capsule specimens using single-cell RNA sequencing (scRNASeq) to uncover transcriptional changes at the single-cell level that are induced by radiation. For Aim 2 we plan to investigate whether inhibition of cellular mechanotransduction using FAK-I is effective to mitigate radiation-induced fibrosis around silicone implants using a translational mouse model of foreign body response. Together, the proposed work will comprehensively define the molecular impact of radiation on periprosthetic capsular fibrosis and will provide novel strategies for the development of effective therapeutics to reduce capsular fibrosis after PMRT.

Impact Statement: Millions of patients undergoing implant-based breast reconstruction and aesthetic breast surgery are affected by capsular contracture, which is an excessive fibrotic response the body generates around breast implants. Capsular fibrosis can lead to pain, asymmetry and implant rupture, and effective treatment approaches for this condition have not been developed so far. Pre- and post-mastectomy radiation increases the rate of capsular contracture even further. The goal of this proposal is to comprehensively characterize how radiation affects the cells around breast implants to identify new targets that can lead to the development of pharmacological therapies, which can prevent this condition in patients undergoing radiation therapy for breast cancer.

Biography
I was born in 1989 in Idar-Oberstein, Germany. Before entering medical school in 2007, I had aspired to become a professional piano player, winning a medal of excellence at an international contest in Paris. I studied medicine at Freiburg University as a scholar of the German National Academic Foundation and received a magna cum laude degree for my doctoral thesis at the Dept. of Thoracic and Cardiovascular Surgery at Saarland University, investigating gene expression in the aortic wall of patients with aortic valve malformations. Working on basic science research projects during medical school allowed me to gain hands-on experience in molecular genetic techniques. After graduating from Freiburg University in 2014 (overall grade: 1.0 – outstanding), I entered the integrated Plastic Surgery residency program at Heidelberg University (Chairman: Ulrich Kneser, MD) and continued basic science research on gene and microRNA expression in small and large animal models as well as human patients. I passed the USMLE Steps 1 – 3 and received the ECFMG certificate. For the years 2019 and 2020, I received a research scholarship from the German Research Foundation, giving me the opportunity to join Dr. Geoffrey C. Gurtner’s laboratory at Stanford as a postdoc.