The Lung Tumor Microenvironment: Role of Resident Pulmonary Vascular Progenitor Cells in Cancer Progression and Metastasis

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ABSTRACT Lung cancer remains the leading cause of cancer-related deaths worldwide. While targeted therapies against oncogenic drivers and immunotherapy approaches have shown promise in reducing the incidence, resistance to targeted therapies often leads to relapse and progression of disease. In addition, only a relatively small portion of unselected non-small cell lung cancer (NSCLC) patients respond to mono-immunotherapy. Therefore, novel therapeutic approaches are urgently needed. Developing new therapeutic strategies requires a better understanding of the complex interactions between cancer cells and cells within the tumor microenvironment (TME). The TME is a complex niche of multiple cell types, including immune cells of the innate and adaptive immune system, cancer-associated fibroblasts, vascular cells, and extracellular matrix (ECM). Defining the critical cell types and mechanisms whereby cells of the TME regulate cancer progression remains a challenge. Recently an abundance of studies related to recruited immune cells have emerged. Also, while tumor angiogenesis is a hallmark of cancer, anti-angiogenic therapy has had limited success for the treatment of lung cancer, and thus a better understanding of how the vasculature contributes to disease progression is required. Finally, while the role of cancer stem cells to cancer progression has been well established, the role of stromal progenitor/stem cells contributing to the TME and cancer progression and metastasis is a completely understudied area of research. Serendipitous observations made by us through the use of fate-mapping systems to track vascular smooth muscle cells (SMCs) in the setting of vascular disease demonstrated that mature SMCs migrate into the outer adventitial layer of the blood vessel and are genetically reprogrammed into a subpopulation of resident adventitial progenitor cells termed AdvSca1-SM cells. AdvSca1-SM cells are a select subpopulation of authentic vascular progenitor cells that exhibit multiple fate decisions. AdvSca1-SM cells reside in multiple vascular beds (e.g. aorta, carotid and femoral arteries, and the pulmonary and coronary arterial vasculature). Reprogramming is dependent on SMC induction of the transcription factor, Klf4, and AdvSca1-SM cells are the predominant cell type responding to vessel wall dysfunction, which is dependent on loss of Klf4. Our recent findings demonstrate that lung AdvSca1-SM cells expand in number, adopt a myofibroblast phenotype, and are major contributors to lung cancer progression and metastasis. We propose here that cancer cell-mediated activation of AdvSca1-SM cells results in their differentiation into essential cells of the TME that promote tumor progression and metastasis. Ablation will blunt, but loss of Klf4 expression will exacerbate tumor growth and metastasis. Two Aims will test our hypotheses. Aim One will use innovative in vivo fate mapping and in vitro conditioned media approaches to define the fate of AdvSca1-SM cells and the role of cancer cells in AdvSca1- SM cell activation in the setting of lung cancer progression and metastasis. Aim Two will define the role of AdvSca1-SM cell ablation or AdvSca1-SM-specific deletion of Klf4 on lung cancer progression and metastasis.