Abstract LB041: Differential response to progranulin in proliferative and metastatic SW13 cell subtypes

Abstract

Abstract The SW13 human adrenocortical carcinoma line exists in proliferative SW13- and metastatic SW13+ subtypes which interconvert by epigenetic mechanisms in an epithelial to mesenchymal transition (EMT) process. This work investigates the contribution of progranulin to the maintenance of and conversion between the SW13 subtypes. A prognostic biomarker in cancer, progranulin is a pleotropic signaling molecule composed of 7 highly conserved granulin repeats. Each granulin unit has independent and sometimes opposing activity in the regulation of diverse cellular activities including proliferation, chemoresistance, lysosomal function, migration, wound healing, and inflammation. Thus, the ultimate biological activity of progranulin is context-dependent as it relies on the expression of diverse intracellular and extracellular proteases. Treatment with exogenous progranulin increases growth of SW13- cells but not SW13+ cells, a finding which suggests differential processing. As the metastatic SW13+ subtype produces more progranulin than the SW13- subtype, these data are consistent with an inability of SW13+ to process endogenous progranulin to the mitogenic granulin unit(s). Immunoblotting with antibodies specific for granulin repeats indicates that progranulin is processed differently in each subtype. In this work, we focused on lysosomes as a potential site for differential processing of progranulin for several reasons. First, lysosomes play a role in EMT. Second, lysosomal proteases have been shown to process progranulin and progranulin itself plays a role in lysosome maturation. Finally, preliminary data suggest that there are differences in lysosomal function and pH between the two subtypes. Ongoing experiments address the benefits of lysosomal acidification and the role that differential processing of progranulin may play on the maintenance and interconversion of the SW13 subtypes. Citation Format: Chika Okonya, McKale R. Montgomery, Agnes S. Pascual, Chandana Uppalapati, Kathryn J. Leyva, Elizabeth E. Hull. Differential response to progranulin in proliferative and metastatic SW13 cell subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB041.