Understanding Lineage Plasticity in Non-Small Cell Lung Cancers Using Monoclonal Populations of Cells
Abstract
Lung cancer diagnoses account for roughly 1.6 million deaths worldwide. It is the leading cause of cancer deaths in the US for men and the second leading cause for women. Due to late detection lung cancers have a high mortality rate, with survival rates of less than twenty percent after 5 years. While the introduction of targeted treatments has impacted survival for subgroups of lung cancer patients, especially those affected by Non-Small Cell Lung Cancer (NSCLS), the effect of these anti-cancer drugs is often temporary, and resistance is routinely acquired through different mechanisms. Lineage plasticity or the ability a tumor cell has to undergo transformation from one histology type to another is emerging as a potential mechanism of a resistance to treatment. For example, tumors of epithelial origin, like lung adenocarcinomas, can transform into neuroendocrine tumors and even acquire histological characteristics of Small Cell Lung Cancers (SCLC). However, understanding the molecular events associated with this transformation still remains an unmet need in oncology. Using a commercially available lung cancer model, this work aimed at identifying morphological and molecular traits associated with neuroendocrine transdifferentiation in lung cancer. We use single cell cloning and expansion techniques to establish monoclonal populations of cells from a heterogeneous cell line model. A total of 61 clones were established and successfully expanded and observed over time to capture morphological characteristics, signal transduction events, and assess level of expression of neuroendocrine markers. Lastly, using previously established protocols, for selected clones we assessed their ability to undergo lineage change after perturbation of their growth conditions. While clonal evolution drives acquired resistance in cancer, the establishment of monoclonal population of cells from heterogenous models may provide novel insights on the mechanisms of resistance to anti-cancer treatments and for understanding lineage plasticity in cancer.
Description
This thesis has been embargoed for 5 years. It will not be available until December 2026 at the earliest.
Keywords
Lung cancer, Lineage plasticity, NSCLC, Cloning, NE-TD, Neuroendocrine