GSE149444 MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [WGS data]

Contributors : Abbie S Ireland ; Yi Qiao ; Xiaomeng Huang ; Szabolcs Tarapcsak ; Gabor Marth ; Trudy G OliverSeries Type : OtherOrganism : Mus musculusDistinct SCLC molecular subtypes have been defined based on expression of lineage-related transcription factors: ASCL1, NEUROD1, POU2F3 or YAP1, but their origins remain unknown. To study transcriptional dynamics of MYC-driven tumor evolution and compare transcriptional states to human SCLC tumors, we performed bulk and single-cell RNA-sequencing on various timepoints of Rb1/Trp53/MycT58A (RPM) tumor cells (from Ad-Cgrp-Cre infected mice) as they progress in culture, and on RPM bulk tumors. Here, to complement these analyses we performed ~30X whole-genome sequencing (WGS) of early (day 4) and late (day 23) time-point RPM tumor cells from culture, along with a matching normal blood control to confirm complete loss of expected regions of Rb1 and Trp53. WGS analyses revealed no detectable copy number variations (CNVs), and SNV analysis suggests that minimal clonal and subclonal evolution occurs in vitro. Together, these data ultimately reveal that MYC drives the dynamic evolution of SCLC subtypes. We find that MYC promotes a temporal shift from an ASCL1-to-NEUROD1-to-YAP1+ state from a neuroendocrine cell of origin. MYC activates Notch signaling to dedifferentiate tumor cells to non-neuroendocrine fates. These findings support our overall conclusions that genetics, cell of origin, and tumor cell plasticity determine SCLC subty...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Mus musculus Source Type: research