Abstract Metastasis in breast cancer is a major challenge for prognosis and effective treatment, primarily because cancer cells can create an immune-suppressive microenvironment that supports their progression and spread. The physical properties of cancer cells significantly influence their metastatic potential and their interaction with the environment. Identifying targets that impact both the physical characteristics of cancer cells, and their microenvironment is crucial for tackling metastatic disease. Interferon-stimulated gene 15 (ISG15), a ubiquitin-like protein, is often overexpressed in breast cancer tissues and is associated with poor prognosis, higher tumor grade, and increased invasiveness. Despite these associations, the precise role of ISG15 and its post-translational modification, ISGylation, in cancer cell behavior and interactions with their microenvironment remains unclear. To explore this, we interrogated the biophysical role of ISG15 by using mouse modeling and in vitro loss of function approaches. We utilized whole- body ISG15-deficient mice and conducted a series of experiments to assess the impact of ISG15 on cancer cell properties and their surrounding environment. Our preliminary results indicate that cells lacking ISG15 exhibit altered physical traits, such as increased stiffness and size, which may influence their metastatic behavior. Additionally, targeting ISG15 or disrupting ISGylation enhances the susceptibility of cancer cells to immune cell-mediated destruction. In ISG15- deficient mice, we observed significantly reduced tumor growth and metastasis compared to wild-type controls. These findings suggest that ISG15 modulates critical aspects of cancer cell behavior and their interactions with the microenvironment, contributing to immune evasion and metastatic spread. Our research highlights ISG15 as a promising therapeutic target and provides a foundation for developing new strategies to prevent and treat metastatic cancer Citation Format: Mohamed Haloul, Priya Shah, Vinay Pai, Faruk Hossen, James James Lee, Ekrem Emrah Er. ISG15 modulate cancer cell mechanics and metastasis in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B027.
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