Abstract 2106: Importance of alveolar epithelial cell type 2 populations in non-small cell lung cancer progression from localized to metastatic disease

Abstract

Abstract Introduction: Non-small cell lung cancer (NSCLC) is by far the leading cancer killer. Identifying personalized treatment strategies to prevent and treat metastases remains an unmet clinical need. Alveolar epithelial type II (AT2) cells are self-renewing epithelial stem cells that have been identified to initiate a majority NSCLCs. Previously, we have reported the presence of multiple AT2 cell types in micrometastatic circulating tumor cell-derived xenograft (CDX) models and patient metastatic tumors. These findings provide a rationale to further study whether and how AT2 cells contribute to metastatic progression. Hypothesis: We hypothesize that AT2 cell types have a functional role in metastasis tumorigenicity of NSCLC. Methods: A library of NSCLC patient-derived circulating tumor cell (CTC) lines, xenograft (PDX) models, and publicly available data sets of patients’ NSCLC tumor tissues were subjected to single cell/bulk RNA sequencing and analysis to determine the frequencies and expression patterns of AT2 subclones. Using magnetic bead sorting AT2 cells were enriched and AT2-associated tumorigenicity, migratory and invasion capacity determined using 3D culture and PDX models. The effects of AT2 depletion on PDX tumor characteristics were evaluated histologically. Frequencies of AT2 phenotypes in primary and metastatic tumors were validated in human tissue microarrays and patient CTCs. Results: An additional AT2 population was identified in NSCLC brain metastases and primary lung tumors that had metastasized already. However, this additional AT2 cell population was absent in primary lung tumors of patients that had not metastasized and in patients with lymph node, pleural and liver metastases. AT2-depleted NSCLC cell lines had reduced tumorigenicity in PDX models in comparison to tumors derived from whole cell populations. In addition, tumors derived from AT2 depleted cell lines were highly necrotic. AT2-depleted cell lines showed decreased migratory and invasion capacity in 3D models. Further, AT2 phenotypes were identified at high rates in NSCLC patients’ metastases and CTCs. Conclusion: Findings indicate an important role of AT2 cells in metastatic progression, beyond their known role in NSCLC initiation. The role of AT2 in metastasis migration, invasion and growth offers unique opportunities to identify novel therapeutic targets. Expansion of translational findings on AT2 cells has high potential for clinical impact to prevent or treat metastatic disease in NSCLC patients. Citation Format: Kanve Nagaraj Suvilesh. Importance of alveolar epithelial cell type 2 populations in non-small cell lung cancer progression from localized to metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2106.