Alexander Pertsemlidis, PhD

The COVID-19 pandemic has impacted our work in several ways. First, supply chain disruptions have made it more difficult to obtain materials, reagents, and services. Second, cancellation or postponement of many conferences and symposia have made it more difficult to disseminate results. Third, an increase in manuscript submissions to journals, a decrease in available reviewers, and a change in editorial focus towards COVID-19 research and away from other fields, have made it more difficult to publish results. We have been able to overcome these obstacles and continue our work by deepening our development of experimental models, using virtual meeting platforms, and expanding our network of collaborators. These approaches have provided broader access to materials, reagents, and expertise and sparked new ideas and complementary directions for investigation. Our approach of using biosynthetic labeling to identify miRNAs that are exported from lung tumors to peripheral blood, discover miRNAs that are biomarkers of lung cancer metastasis, characterize their contributions to metastasis, and confirm their value as therapeutic targets by which metastasis can be controlled will need to be developed in several directions before the findings can be translated into clinical practice. These directions include developing platforms for delivery of miRNA mimics or inhibitors to the desired tissues, identifying miRNA combinations with synergistic on-target and fewer off-target effects, and identifying vulnerabilities of the tumor microenvironment that are exploited by cancer cells to influence progression and metastasis. We have expanded our network of collaborators to include Greg Aune at UTHSCSA, with whom we are developing a novel drug delivery vehicle designed to effectively eliminate both tumor cells and toxicities to key normal tissues, Nicholas Peppas at UT Austin, with whom we are developing hydrogels capable of delivering payloads specifically to cancer cells, Luiz Penalva at UTHSCSA, with whom we are identifying miRNA combinations that achieve specific phenotypic changes in cancer cells, like driving them towards differentiation (and away from malignant transformation), and Rolf Brekken at UT Southwestern, with whom we are studying miRNA regulation of the AXL receptor, a key facilitator of immune escape by cancer cells, which leads to aggressive and metastatic cancers.

Update: We are implementing an RNA labeling approach in lung cancer models based on cells that differ in their ability to metastasize. Labeling RNA by cell and tissue of origin allows us to (1) identify specific miRNAs in serum and tissue that are secreted by tumor cells, and (2) exploit those miRNAs as therapeutic targets to control metastasis. We used a set of genes for which expression correlates with extremes of cell migration and patient outcomes to identify 8 lung adenocarcinoma cell lines, 4 derived from metastatic sites which express high levels of these metastatic prognostic factors, and 4 derived from primary tumors which express low levels of these factors. To date, we have integrated RNA labeling into 3 such models, and are currently building an additional 5 models which are growing under selection. These modified cell lines will be further developed by isolation of single cells to grow genetically homogenous subclones (a process which we have completed for 1 model already). These monoclonal models will then be implanted into immunocompromised mice to identify small RNA species differentially secreted by metastatic- and non-metastatic-prone lung cancers.