Abstract 1391: The role of lysosomal membrane permeabilization in ECM-detached cancer cells

Abstract The progression of metastatic cancer invariably leads to a lower 5-year survival rate compared to patients diagnosed with primary tumors alone, so the elimination of metastasizing cells is crucial to improve patient outcomes. A barrier to cancer metastasis is anoikis, an apoptotic form of cell death induced when a cell loses attachment to the extracellular matrix (ECM). However, cells that do successfully metastasize develop anoikis resistance and are able to survive in ECM-detachment. The survival of ECM-detached metastatic cancer cells can result from a variety of changes including elevated antioxidant activity and altered metabolism. Many of these adaptive changes rely on lysosomes, which are acidic, membrane-bound organelles that are responsible for degradation of materials. Therefore, we hypothesize that lysosomal dynamics contribute to anoikis resistance. We have found that lysosomes in non-cancerous mammary epithelial cells grown in ECM-detached conditions exhibit signs of lysosomal membrane permeabilization (LMP) and dysfunction, suggesting that LMP is caused by ECM-detachment and contributes to anoikis. In support of our hypothesis, we have found that some breast cancer cell lines and oncogenically transformed cells are able to maintain intact, functional lysosomes during ECM-detachment. Preliminary data also demonstrate that the downstream effects of LMP, specifically the release of lysosomal protease cathepsin B into the cytosol, may contribute to anoikis signaling. Ongoing work aims to elucidate the mechanism(s) by which ECM-detachment causes LMP in normal cells and understand the changes in this mechanism that confer LMP resistance in cancer cells. In a translational setting, this information could lead to a therapy that prevents metastasis by sensitizing resistant cancer cells to LMP-mediated cell death, thus improving patient outcomes. Citation Format: Hannah M. Tanczos, Lauren Young, Paulina Harnisch, Isabella Gomez, Jianping He, Jordan Cockfield-Iratishe, Zachary T. Schafer. The role of lysosomal membrane permeabilization in ECM-detached cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1391.