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bioRxiv · 10.1101/2022.07.08.499386

DLL3 REGULATES NOTCH SIGNALING IN SCLC

Kim, J. W.·Ko, J. H.·Sage, J.
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Abstract

Tumor heterogeneity plays a critical role in tumor development and response to treatment. In small-cell lung cancer (SCLC), intratumoral heterogeneity is driven in part by the Notch signaling pathway, which reprograms neuroendocrine cancer cells to a less/non-neuroendocrine state. Here we investigated the atypical Notch ligand DLL3 as a biomarker of the neuroendocrine state and a regulator of cell-cell interactions in SCLC. We first built a mathematical model to predict the impact of DLL3 expression on SCLC cell populations. We next tested this model using a single-chain variable fragment (scFv) to track DLL3 expression in vivo and a new mouse model of SCLC with inducible expression of DLL3 in SCLC tumors. We found that high levels of DLL3 promote the expansion of a SCLC cell population with lower expression levels of both neuroendocrine and non-neuroendocrine markers. This work may influence how DLL3-targeting therapies are used in SCLC patients.

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Kim, J. W., Ko, J. H., Sage, J.. 2022-07-10. DLL3 REGULATES NOTCH SIGNALING IN SCLC. https://doi.org/10.1101/2022.07.08.499386

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