Heimsoeth, A. | Search bioRxiv

bioRxiv2026

MYC-MIZ1 Complexes at Enhancers Tune Neuroendocrine Identity of Small Cell Lung Cancer

MYC family members have been extensively studied as undruggable transcription factors regulating oncogenic signaling in highly aggressive tumors such as small cell lung cancer (SCLC), via promoter binding. Here, leveraging the previously described Myc-driven SCLC mouse model (RPM), we generated RPM-Miz1{Delta}POZ (RPMM) mice to uncover a Myc-dependent regulation of neuroendocrine (NE) differentiation, via enhancers. Our functional and genomic analyses reveal that Miz1 facilitates Myc binding to low-affinity E-boxes at distal chromosomal regions, thereby enabling Myc occupancy at sites with otherwise limited intrinsic affinity. We further show that SCLC patients and cellular models share an enrichment of low-affinity E-Box Myc binding motifs at enhancer regions that loop to genes of classic neuroendocrine differentiation. Integrated epigenetic and genomic analyses with AI-modeling implicate Myc/Miz1 binding at enhancers as the determinant for the expression of bona-fide neuroendocrine genes. In RPMM tumors, the suppression of neuroendocrine identity is paralleled by a redistribution of Myc protein towards promoter-proximal regions, hyper-activation of Myc transcriptional programs, apoptotic priming and enhanced sensitivity to etoposide. Together, these findings uncover Miz1/Myc-engaged enhancers as a central hub for neuroendocrine lineage programs and provide a mechanistic basis for a targeted inhibition of Miz1 to boost chemosensitivity in SCLC.

cancer biology↗

bioRxiv2023

Functional synapses between small cell lung cancer and glutamatergic neurons

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, clinical recurrence and high rate of mortality. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified a strong and consistent signal for neuronal, synaptic, and glutamatergic signaling gene sets in murine and human SCLC. We show that SCLC cells have the ability to develop intimate contacts with neuronal glutamatergic terminals in vitro, in autochthonous primary lung tumors and in brain-engrafted tumors. These contacts can develop into bona fide synapses, allowing SCLC cells to receive glutamatergic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we show that SCLC cells derive a robust proliferation advantage when co-cultured with neurons. Moreover, the repression of glutamate release and the stimulation of the inhibitory glutamate receptor GRM8 displayed therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells appear to hijack glutamatergic signaling to sustain tumor growth, thereby exposing a novel entry route for therapeutic intervention.

cancer biology↗