Eavesdropping on Cancer: Developing Blood-Based Exosome Diagnostics

Project Overview

Although advances in therapies and the reduction of risk factors have contributed to a decline in the occurrence and death rates associated with lung cancer, our understanding of early lung cancer behavior remains limited. This limitation is primarily due to challenges in obtaining samples and the availability of sensitive biological tools to detect cancer behavior at its initial stages. Furthermore, the tumor microenvironment surrounding cancer cells has been identified as a crucial factor in various tumor processes essential for cancer progression. it serves as a potential source for the development of next-generation therapeutic options.

This research incorporated cutting-edge 'omics' technologies to comprehensively characterize all genes and proteins expressed by cancer cells throughout the progression of the disease with 2 genetically engineered mouse models (GEMM) for lung cancer. In the initial phase of this project, targeted mutations were introduced into the DNA of normal cells to precisely induce cancer formation in a controlled and temporally regulated manner. This effort resulted in the creation of two novel GEMMs, namely Sftpc-KPM and Scgb1a1-KPM. To characterize the tumor microenvironment of these mice, we employed various techniques such as single-cell RNA sequencing, miRNA profiling of secreted exosomes, and proteomic analysis at high resolution. Additionally, cancer cell lines derived from these mice have been isolated and thoroughly characterized, allowing for in vitro experiments on these mouse lung cancer cells. This comprehensive approach provides an unprecedented level of detail regarding the complexity of cancer biology and enables the discovery of novel therapeutic targets to combat the progression of cancer.

Mission Impact

This project leverages the multi-disciplinary expertise unique to Lawrence Livermore National Laboratory (LLNL) (animal models and ex vivo models of infection, single-cell omics, and bioinformatics) to understand the characteristics of lung cancer initiation and progression. The success of this research has yielded increased capabilities in in vitro and in vivo pulmonary systems and molecular biology profiling of mammalian responses to disease which has a broad impact by driving innovation across the Mission Focus Areas/Core Competencies at LLNL: Bio Resilience and Bioscience and Bioengineering.

Publications, Presentations, and Patents

Hum NR, Sebastian A, Martin KA, Rios-Arce ND, Gilmore SF, Gravano DM, et al. IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer. Front Oncol. 2022;12:928474. LLNL-JRNL- 830154

M.D. Sewavi, N.F. Leon, N.R. Hum, "Unraveling The Role of Exosomal miRNA In Breast Cancer Diagnostics" (Poster Presentation, GEM Annual Board Meeting & Conference, Philadelphia, PA, September 2023). LLNL-POST-854112

Leon, N.F., Baliu-Rodriguez, D., Murugesh, D.K., Sebastian, A, Loots, G.G., Hum N.R.; Abstract 9: Histological characterization of two genetically engineered mouse models of non-small cell lung cancer. Cancer Res 1 April 2023; 83 (7_Supplement): 9. AACR Annual Meeting Orlando, FL April 2023. https://doi.org/10.1158/1538-7445.AM2023-9 LLNL-POST-846593

N.R. Hum, C. Morfin, S.P. Wilson, D.K. Murugesh, A. Sebastian, G.G. Loots, "Defining cellular complexity of mesenchymal lineage-derived cells in the adult murine long bones using single-cell transcriptional profiling and bone-targeted Cre-based lineage tracing" (Poster Presentation, ASBMR Annual Meeting Austin, TX, October 2022). LLNL-POST-839155

Hum N.R., Leon N.F., Sebastian A., Martin K.A., Loots G.G.; Abstract 3136: Molecular characterization of the effects of cancer-derived exosomes on murine lung cancer tumors. Cancer Res 15 June 2022; 82 (12_Supplement): 3136. AACR Annual Meeting New Orleans, LA April 2022. https://doi.org/10.1158/1538-7445.AM2022-3136 LLNL-POST-832973