2022 Lung Cancer Research Foundation Pilot Grant
Huanhuan Chen, PhD
The University of Chicago
Research Project:
A human pluripotent stem cell-based approach to metastasis of small cell lung cancer
Summary:
Small cell lung cancer (SCLC) is one of the most lethal human malignancies, which has remarkable metastatic propensity among all solid tumors. However, the biological principles of SCLC metastasis remain poorly understood. In this project, we will harness innovative methods and tools, the SCLC models derived from human pluripotent stem cells (hPSCs) that can be characterized at the single-cell level, to pursue the long-standing mysteries about SCLC metastasis. By interrogating the behaviors of the cells in the paired primary tumors and metastases in the hPSC-derived SCLC model, we are able to identify novel cellular, genetic, and molecular mechanisms counting for the highly metastatic potential of SCLC. Our findings are expected to generate new ideas about diagnosis or therapy for this recalcitrant cancer.
Final report:
The goal of this project was to try and develop a better understanding as to which cellular mechanisms promote metastases in small cell lung cancer (SCLC). The researcher has found that the expression level of CHD2 was higher in more advanced stages and when elevated represented a significant trend toward lower patient survival. By studying RUES2-derived RPM tumors the researcher was able to identify three distinct cell clusters, the most prominent of which had neuroendocrine differentiation. It was found that over expression of cMYC, a known marker in SCLC, produced a larger neuroendocrine component. By subclustering the neuroendocrine differentiation group ASCL-1 high and NEUROD-high compartments were identified. High expression of cMYC alters the transcriptional identity of the cells encouraging neuroendocrine differentiation and therefore contributing to the plasticity of SCLC.
Impact:
There are many things that are not understood about SCLC: reasons for its aggressive nature, development of refractory disease after initial treatment, etc. This grant is an attempt to understand the mechanisms that promote SCLC growth at the basic level. The importance of this work is the goal of understanding the biology of SCLC. This understanding could lead to the discovery of new targets and the development of novel treatment strategies.