tumors, cellular heterogeneity, cancer stem cells, CSCs, cellular heterogeneity, cancer stem cells, CSC, tumor propagating cells, TPCs, Small Cell Lung Cancer, SCLC, genetic barcode lineage tracing
Biological Phenomena, Cell Phenomena, and Immunity | Medical Sciences
Tumors are often comprised of a multitude of cell types, a phenomenon called cellular heterogeneity, where a population of cancer stem cells (CSCs) or tumor propagating cells (TPCs, used hereafter) often mediate the differentiation of the entire tumor. These TPCs exhibit an enhanced plasticity, which allow for greater drug resistance since progeny may be more prone to evolve resistance to chemotherapy and growth in distal sites during metastasis. While tumor growth, metastasis, and chemoresistance are key to the basic biology behind cancer pathology, measuring cellular heterogeneity and plasticity in vivo has proven exceedingly difficult. One tumor that displays cellular plasticity is Small Cell Lung Cancer (SCLC), a devastating disease characterized by a low 5-year survival rate due to rapid metastasis and chemoresistance. The cellular heterogeneity contributes to the aggressive phenotype by imparting a subset(s) of cells with chemoresistance, tumor propagating potential, and propensity to metastasize, forming a highly plastic and heterogeneous tumor overall. Current approaches to understanding SCLC heterogeneity at a clonal level take a snapshot of the cells at an individual timepoint, which leads to the averaging of each individual clone's contribution to tumor dynamics and does not allow for causal relationships to be drawn and hampers the study of SCLC. I propose a method for xenograft-derived and in vivo cellular barcoding of SCLC, combined with single-cell transcriptome profiling to observe the contribution of individual cells on tumor growth, metastasis, and chemoresistance, with particular attention placed on the activity of the regulators of pluripotency. This will be tested in two aims. Aim 1 will investigate the contribution of individual cells towards tumor growth, metastasis, and chemoresistance using genetic barcode lineage tracing in xenografts. Aim 2 will use CRISPR/Cas9 genetic barcoding in vivo to trace the cells responsible for growth, metastasis, and resistance in a SCLC GEMM.
Basic Biomedical Sciences
Wollenzien, Hannah, "Tracing Intratumoral Cellular Heterogeneity in Small Cell Lung Cancer Using Genetic Barcode Lineage Tracing" (2020). IdeaFest. 21.