Human stem and progenitor-based models of lung adenocarcinoma - PROJECT SUMMARY/ABSTRACT Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide. Lung adenocarcinoma (LUAD) is the most common subtype of NSCLC. Genetically engineered mouse models (GEMMs) in which expression of mutant oncogenes and/or deletion of tumor suppressors leads to the formation of autochthonous tumors are the most commonly used models in lung adenocarcinoma research. Although the lesions generated in these models histopathologically resemble human tumors, they differ in their molecular characteristics. Unlike human tumors, murine ones lack high mutational burden. Our preliminary evidence highlights that the anatomical region from which lung adenocarcinoma arises is significantly different in murine and human lungs. Further, the epithelial stem and progenitor composition and their lineage trajectories are distinct in mice and people. Notably, previous studies have shown that GEMMs are non-responsive to single ICI therapies. All these reasons point towards the need to develop novel human-relevant lung adenocarcinoma models. As an alternative model to GEMMs, patient-derived organoids (PDO) and patient-derived xenografts (PDX) in mice have been proposed to evaluate tumors. Although well suited for personalized therapy, PDO and PDX models are limited in availability, lose their original characteristics with passaging, and are not easily controlled for the mutations and tumor stage being studied. These technical limitations have made it difficult to dissect the mechanisms influencing human lung tumor cell plasticity. To overcome these limitations, we seek to model tumors by genome editing primary human lung cells and culture them as tumor organoids or orthotopically xenograft them into mice. In Aim 1, we seek to introduce oncogenic mutations into two primary human lung stem and progenitor populations and generate organoid models. These models are amenable for high throughput drug testing in the future. Further, in Aim 2, we will xenograft the mutated stem/progenitor populations into lungs of immunodeficient mice to develop an in vivo model. We will perform histopathological analysis to compare the resulting tumors to primary human lung adenocarcinoma. We will further perform single cell transcriptomics to characterize the tumor cell states and dissect the role of cell of origin in determining histopathology of tumors and tumor cell states. In brief, we seek to develop novel lung adenocarcinoma models that better capture the initiation, progression and composition of primary human LUAD tumors, and characterize the cell of origin dependent effects on the resulting tumors.
