DLL3 regulates Notch signaling in small cell lung cancer

Jun W Kim; Julie H Ko; Julien Sage

doi:10.1016/j.isci.2022.105603

DLL3 regulates Notch signaling in small cell lung cancer

iScience. 2022 Nov 16;25(12):105603. doi: 10.1016/j.isci.2022.105603. eCollection 2022 Dec 22.

Authors

Jun W Kim^{1

2}, Julie H Ko^{1

2}, Julien Sage^{1

2}

Affiliations

¹ Department of Pediatrics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA, USA.
² Department of Genetics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA, USA.

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.

Keywords: Cancer; In silico biology; Molecular biology.

Abstract

Grants and funding