Sunday, May 18, 2025
5/18/2025
Interrogating a novel axis of tumor suppression in small cell lung cancer - SUMMARY Small cell lung cancer (SCLC) is an aggressive cancer type with no targeted therapies available. It is critical that we gain a better understanding of the genes that drive SCLC and that we model key SCLC subsets. Employing genetically engineered mouse (GEM) models is central to this effort. To identify candidate tumor suppressive and biologically important pathways, we applied genome-scale functional screens to a cellular model of early- stage SCLC. We identified a stress activated protein kinase (SAPK) pathway, as tumor suppressive in SCLC cellular model systems. Map2k4, Map2k7 and Jun were particularly strong screen hits. The SAPK/AP-1 pathway is a target of deletions and mutations in human SCLC, with targeted sequencing revealing MAP2K4 deletion or mutation in ~3% of SCLC. In human datasets, AP-1 transcriptional activity is associated with ASCL1 target gene expression, linking this pathway to the SCLC-A subtype. Moreover, our preliminary data confirms potent acceleration of SCLC tumorigenesis with Map2k7 deletion in a sensitized Rb/p53-deleted mouse model. In this proposal we explore the biological roles for this SAPK axis in SCLC tumorigenesis. We will leverage study of cellular models of SCLC, in vivo genetically engineered mouse models, and human tumor datasets to define roles for the SAPK pathway in SCLC tumor suppression. We will generate and characterize GEM models of SCLC with deletion in Rb/p53 along with either Map2k7 or Map2k4 to elucidate effects of SAPK suppression on tumor initiation and progression. We will employ cellular models to interrogate the impact of SAPK perturbation on early stage and late-stage SCLC cells. We will perform RNA-seq analyses to identify transcriptional programs consistently regulated by a MAP2K4/MAP2K7 axis upstream of c-JUN/AP-1. These analyses will use SCLC tumor tissue from mouse models along with isogenic SCLC cell lines with SAPK pathway perturbations. We will also perform CUT&RUN occupancy studies to determine the impact of SAPK perturbation on genomic binding of JUN and FOS and ATAC-seq to examine chromatin accessibility. Integrative analyses will then identify candidate direct transcriptional targets of AP-1 relevant to tumor suppression for functional perturbation studies. There is increasing appreciation that SCLC exhibits different subtypes based on transcriptional features. Our preliminary data support the notion that SCLC differs in the level of SAPK/AP-1 activation, likely via both genetic and via transcriptional suppression of pathway components. Changes in this pathway may also be linked to neuroendocrine features and transcriptional subtype of SCLC. This proposal will elucidate an unappreciated tumor suppressor axis in SCLC and will also help us understand factors that govern SCLC transcriptional state and SCLC subtype.
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