Tuesday, April 1, 2025
4/1/2025
NEUROD1 function in SCLC fate and plasticity - Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung tumor responsible for > 30,000 deaths annually in the US. SCLC has a two-year survival rate of ~6% with no approved targeted therapies beyond recently-approved immunotherapy. SCLC is initially highly responsive to chemotherapy, but rapidly develops resistance leading to mortality in ~12 months. A major unmet need for SCLC treatment is the identification of new therapeutic targets and treatment strategies. SCLC has historically been treated as a single disease without patient stratification based on molecular information. We and others recently identified distinct SCLC molecular subtypes based on expression of lineage-related oncogenic transcription factors: ASCL1, NEUROD1, POU2F3 and more controversially, YAP1. MYCL oncogene is associated with the most common ASCL1 group (~70% of SCLC), while MYC is overexpressed in the NEUROD1/POU2F3/YAP1 subtypes (~30% of SCLC). Importantly, we and others found that MYC-driven SCLC has unique therapeutic vulnerabilities compared to MYCL-driven SCLC. MYC has the capacity to drive SCLC subtype plasticity, promoting ASCL1+ tumors to a NEUROD1+ and then a YAP1+ state. MYC-induced Notch pathway activation is critical for SCLC subtype plasticity. While ASCL1 has been frequently studied, much less is known about the 2nd-most common NEUROD1+-subtype. We hypothesize that NEUROD1 expression denotes a neuronal transcriptional state of SCLC, that NEUROD1- mediated repression of Notch signaling is critical for this tumor cell state, and that the NEUROD1+ state has unique therapeutic vulnerabilities. We further predict that NEUROD1 inhibition will shift tumors to developmentally predictable non-neuroendocrine cell fates. Our objective is to determine the function of NEUROD1 in the NEUROD1+ subtype of SCLC, to identify mechanisms that regulate subtype plasticity, and uncover the relationship between NEUROD1 and Notch signaling. Toward this end, we created the first mouse model of NEUROD1+ SCLC and generated mice with conditional Neurod1 loss to study its function in vivo. Preliminary data have identified highly conserved NEUROD1 target genes. Large-scale CRISPR-based genetic screens have identified predicted dependencies that have the potential for therapeutic targeting. Our hypotheses will be tested in two specific aims: 1) Determine the function of NEUROD1 in MYC-driven SCLC cell fate. 2) Determine the mechanistic relationship between NEUROD1 and Notch signaling in SCLC subtype plasticity. Our approach is innovative because we will employ novel immune-competent GEMMs of MYC-driven SCLC, ~17 new human PDX, and single cell data from primary human SCLC. We will use state-of-the-art technologies in single cell RNA-seq and lineage tracing in new organoid models coupled with our ChIP-seq data to comprehensively determine the role of NEUROD1 in SCLC. This research is significant because these findings will lead to a better understanding of SCLC molecular subtypes and ultimately facilitate tailored SCLC treatment.
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