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Published on: January 12, 2020
DLL3 regulates Notch signaling in small cell lung cancer
Jun W Kim1,2, Julie H Ko1,2, Julien Sage1,2
1Department of Pediatrics, 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.
Insights
High DLL3 expression in small-cell lung cancer (SCLC) drives tumor heterogeneity by expanding cells with reduced neuroendocrine markers. This finding impacts DLL3-targeting therapy strategies for SCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Tumor heterogeneity is a key factor in cancer progression and treatment resistance.
- In small-cell lung cancer (SCLC), the Notch signaling pathway contributes to heterogeneity by altering neuroendocrine cell states.
- DLL3, an atypical Notch ligand, is implicated in SCLC and may serve as a biomarker and regulator of cell interactions.
Purpose of the Study:
- To investigate DLL3 as a biomarker for the neuroendocrine state in SCLC.
- To understand DLL3's role in regulating cell-cell interactions and tumor heterogeneity in SCLC.
- To develop and validate a model predicting DLL3's impact on SCLC cell populations.
Main Methods:
- Mathematical modeling to predict DLL3 expression effects on SCLC cell populations.
- Development of a single-chain variable fragment (scFv) for in vivo DLL3 tracking.
- Creation of a novel mouse model with inducible DLL3 expression in SCLC tumors.
Main Results:
- High DLL3 levels were found to promote the expansion of SCLC cell populations.
- This expansion was characterized by lower expression of both neuroendocrine and non-neuroendocrine markers.
- The study provides in vivo validation of DLL3's role in modulating SCLC cell states.
Conclusions:
- DLL3 plays a significant role in driving tumor heterogeneity in SCLC.
- DLL3 influences the balance between neuroendocrine and non-neuroendocrine cell populations within SCLC.
- These findings may inform the clinical application of DLL3-targeting therapies in SCLC treatment.
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