Abstract 3092: Effect of cancer stem cell-specific progerin expression on metastatic potential

Metastasis signals the final and treatment-refractory stage of cancer disease. Formation of metastases is fueled by a small cell subpopulation within the tumor, the so-called cancer stem cells (CSCs), which have the ability to rejuvenate the heterogeneous tumor population and support self-renewal, survival and tumor cell heterogeneity. Stemness is a cell property rather than a distinct subpopulation of the tumor structure. In this respect, even if CSCs are specifically targeted to be killed, their surrounding cells dedifferentiate to replace assaulted CSCs. Herein, we sought to target CSCs with progerin, a truncated form of lamin A, which causes the Hutchinson-Gilford childhood progeria syndrome, a rare genetic disease of accelerated aging. We combined a promoter responsive to two stemness factors (Yamanaka factors) with the progerin gene and produced a lentiviral construct, where progerin is set under the transcriptional control of stemness cascades. Stable transduction of cancer cells with this construct establishes a dynamic gene modification of the tumor cell population, where all tumor cells carry the progerin gene, but only the ones where the levels of stemness factors are initially high or secondarily upregulated are able to express it. This way, stemness programs are transcriptionally linked with a gene that, when expressed in normal stem cells, causes premature exhaustion of adult stem cells, inhibits the regenerative capacity of tissues and accelerates senescence. We monitor the effects of CSC-specific progerin expression on the CSC reservoir and the tumor cell population dynamics over time, in comparison with CSC-specific expression of its wild-type laminA counterpart, as well as non CSC-specific progerin expression. We further examine how targeting the CSC turnover within the tumor population projects into metastasis-initiating processes, such as cell invasion, migration, epithelial-mesenchymal transition, and tumor metabolism. Our approach provides a model for addressing the potential crosstalk between stemness and senescence in the context of CSCs and holds promise to translate the findings into anti-metastatic therapeutic solutions. Funding: This project is funded by FORUN (889040) and P.M. has a scholarship from the German Cancer Aid (70114135). Citation Format: Philipp Morgenroth, Christoph Söhnchen, Alf Spitschak, Brigitte M. Puetzer, Stella Logotheti. Effect of cancer stem cell-specific progerin expression on metastatic potential [abstra