Wesley Lewis, a senior computational biology major at the University of Rochester, utilized single nucleus RNA sequencing to investigate cellular heterogeneity in small cell lung cancer.
Small cell lung cancer (SCLC) is an aggressive and highly-recurrent cancer that originates from pulmonary neuroendocrine cells. Integrating my own values and passions with the unique biomedical institution of the Broad was a daunting prospect at first. But the unwavering support and guidance of my mentors soon put me at ease, wrapping me in an amazing working and learning environment. Every lab member and collaborator I had the pleasure of working with took a meaningful interest in my goals and aspirations, not only for the summer but for my future career in science.It is marked by a 5-year average survival rate of under 10%, due in part to frequent late stage diagnosis. SCLC biology has been characterized via extensive molecular and histologic approaches, in both patient-derived samples and mouse models. Recently, our lab developed single cell and single nucleus RNA sequencing (scRNA-seq and snRNA-seq), which allow for the characterization of single cell transcriptomes and the identification of cell types and states. Importantly, for cancer biology, these techniques enable us to identify malignant cell sub-populations and the molecular dysregulation driving their pathobiology. Here, we characterize the single-cell composition of SCLC in patient-derived xenografts (PDX) and surgical resections. We utilize snRNA-seq for its capability of sequencing frozen samples, which empowers us to collaborate across research sites and use banked tissues. We generate single-cell profiles from both PDX tumors and human SCLC data and develop a computational pipeline to analyze the single-cell composition of SCLC. Finally, we compare these SCLC profiles to healthy single cell references of the human lung, and identify potential large-scale amplification/deletion events. This data provides high resolution characterization of cellular populations that drive SCLC proliferation, and reveals key differentially expressed genes within these samples. Taken together, our results may inform novel targets for the treatment of SCLC and identify molecular markers for diagnosis in the early stages of cancer.
Project: Optimized single nuclei sequencing for frozen small-cell lung cancer samples
Mentors: Orr Ashenberg, Eugene Drokhlyansky, Nicholas Van Wittenberghe, Klarman Cell Observatory