Abstract LB273: An emerging paradigm of heterogeneous midkine expression in thyroid cancer

Abstract

Abstract Midkine (MDK) is a pleiotropic heparin-binding growth factor, contributing to both normal tissue homeostasis and disease development. MDK expression is gradually increased during carcinogenesis, acting as a mediator for the acquisition of cancer hallmarks, such as invasion/metastasis, and immunosuppression. Tissue-wide gene expression analysis using publicly available databases reveal that MDK is significantly upregulated in most human carcinomas. In the thyroid, MDK has been associated with increased metastatic potential in the context of papillary thyroid cancer, which is an otherwise relatively non-aggressive thyroid tumor. We thus theorized that more aggressive types of thyroid cancers may be linked to increased MDK expression/function from an earlier onset. To gain such insights, we developed a digital pathology infrastructure to investigate MDK expression in a characterized mouse model of Anaplastic Thyroid Carcinoma (ATC), the most aggressive and lethal type of thyroid cancer with low but increased prevalence in the human population, and an intrinsic resistance to available therapeutic options. Mice with conditional ablation of tumor suppressors, Pten and p53, in thyrocytes [Pten, p53]thyr-/− develop thyroid carcinomas with mixed follicular and anaplastic components, and histological hallmarks of high aggressiveness, including giant cells, bone metaplasia, and muscular/tracheal invasion, which are all recapitulated in human disease. MDK was more highly expressed in anaplastic, when compared to follicular components of the same animal tumors. When the above hallmarks were topographically and microanatomically demarcated within the anaplastic component, it was found that MDK expression was higher near and around giant cell islets, as well as within the anaplastic lesions invading beyond the cartilaginous rings of tracheal mucosal epithelium. Based on recent evidence that MDK does not solely function in the extracellular space, but can also be endocytosed within tumor cells, whereby it exerts tumor-promoting functions, we further quantified the intra/extranuclear MDK fraction using intensity thresholding immunofluorescence. Of interest, MDK+ follicular lesions, were primarily characterized by nuclear MDK expression, whereas MDK was mostly found secreted in the extracellular space of anaplastic lesions, thus implying different modes of MDK trafficking, secretion, and possibly function in them. The take home message is to work towards establishing and developing gain- and loss-of-function experiments, to elucidate mechanistic underpinnings on the role of MDK in the development of aggressive ATC lesions. Citation Format: Dimitra P. Anastasiadou, Antonio Di Cristofano, George S. Karagiannis. An emerging paradigm of heterogeneous midkine expression in thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB273.