Integrin-Linked Kinase in Papillary Thyroid Cancer-Associated Fibroblasts and the Tumor Microenvironment

Ohio State University, Columbus OH

Investigators

Abstract

Papillary thyroid cancer (PTC) is the most common cause of thyroid cancer-related death. For PTCs resistant to traditional therapies, including surgery and radioactive iodine ablation, there are no curative treatments. Moreover, many patients with indolent PTC often are over-treated due to a lack of informative biomarkers that can distinguish between these cancers and more aggressive variants. Efforts to identify useful biomarkers and develop therapies have focused largely on tumor-cell autonomous drivers. Unfortunately, none have satisfactorily met clinical needs. Therefore, investigations of potential therapeutic targets and potential biomarkers beyond those derived from the tumor cell itself are critical. In other cancer types, cancer-associated fibroblasts are cells of the tumor microenvironment known to promote cancer progression by creating fibrosis through collagen secretion and by communicating with tumor cells as well as immune cells that can facilitate evasion from immune surveillance. The role of fibroblasts in PTC is understudied, representing a critical knowledge gap in this disease. Our long-term goal is to improve our understanding of the function of thyroid fibroblasts in PTC in order to uncover novel diagnostic and therapeutic strategies. Our overall objective is to determine molecular mechanisms of PTC-fibroblast communication, beginning with the study of the serine threonine kinase integrin-linked kinase (ILK), a protein critical in facilitating fibroblast communication. Our laboratory has generated data implicating fibroblasts in progression of PTCs and suggesting a function for ILK in this process, specifically in PTCs with the BRAFV600E mutation. Thus, we hypothesize that ILK functions at a focal point of communication between thyroid fibroblasts, BRAF-positive PTC cells, and immune cells of the tumor microenvironment. Our first Aim is to define mechanisms by which PTC cells activate fibroblasts. Our working hypothesis is that signaling from BRAF-positive PTC cells leads to increased expression of ILK in thyroid fibroblasts. Using cell culture and transgenic mouse models, we will investigate mechanisms leading to increased fibroblast ILK expression and how ILK facilitates fibroblast collagen production and cytokine secretion. Our second Aim is to determine how signaling from thyroid fibroblasts facilitates PTC progression. Our working hypothesis is that inhibition of ILK signaling pathways in thyroid fibroblasts will decrease signaling to both cancer cells and tumorigenic immune cells. We propose to investigate how ILK in fibroblasts affects this communication via either secreted factors, direct cell-cell communication, or both. After completion of our proposed Aims, we will have an improved understanding of how, via ILK signaling, PTC activates fibroblasts, and how these activated fibroblasts in turn facilitate PTC growth and alter the tumor microenvironment. Knowledge gained by these studies has the potential to uncover biomarkers to more precisely treat patients as well as uncover proteins that can provide novel treatment targets to be used in either isolation or in combination with current therapies.