Dll1+ quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway

Sushil Kumar,Yibin Kang,Snahlata Singh,Andres J Klein-Szanto,Alana L Welm,Christian W Siebel,Rohan Regulapati,Christopher Lengner,John W Tobias,Rumela Chakrabarti,Ning Li,Mario Andres Blanco,Ajeya Nandi

doi:10.1038/s41467-020-20664-5

Abstract

Development of chemoresistance in breast cancer patients greatly increases mortality. Thus, understanding mechanisms underlying breast cancer resistance to chemotherapy is of paramount importance to overcome this clinical challenge. Although activated Notch receptors have been associated with chemoresistance in cancer, the specific Notch ligands and their molecular mechanisms leading to chemoresistance in breast cancer remain elusive. Using conditional knockout and reporter mouse models, we demonstrate that tumor cells expressing the Notch ligand Dll1 is important for tumor growth and metastasis and bear similarities to tumor-initiating cancer cells (TICs) in breast cancer. RNA-seq and ATAC-seq using reporter models and patient data demonstrated that NF-κB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-κB pathway completely sensitizes Dll1+ tumors to chemotherapy, highlighting therapeutic avenues for chemotherapy resistant breast cancer patients in the near future.

Highlights

Development of chemoresistance in breast cancer patients greatly increases mortality
We found that loss of Dll[1] led to a dramatic reduction in hyperplasia in PyMT-Dll1 conditional-knockout (Dll1cKO) compared to PyMTDll1WT mammary glands at 8 weeks (Fig. 1c), suggesting that loss of Dll[1] affects early events in tumorigenesis, potentially by impacting tumor-initiating populations
We could not determine if Dll1+ cells themselves had tumor-initiating cancer cells (TICs)/cancer stem cells (CSCs) properties due to the lack of appropriate mouse models

Summary

Introduction

Development of chemoresistance in breast cancer patients greatly increases mortality. As specific ligandbased therapies are likely to provide a better safety profile than global Notch signaling inhibitors, determining the role of Dll[1] in TIC generation/function and Notch-mediated chemotherapeutic resistance, may aid in the identification of effective and bettertolerated therapeutics for breast cancer patients. Pharmacological blocking of Dll[1] or NF-κB pathway sensitizes tumor cells to chemotherapy and significantly abolishes tumor growth and metastasis in tumor initiation and progression study. These data suggest that quiescent Dll1+ TICs are an important regulator of breast tumor progression and metastasis and are responsible for chemoresistance. As such, targeting Dll[1] in combination with chemotherapy and NF-κB may be a promising therapeutic strategy for breast cancer patients who are resistant to chemotherapy

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Results

Conclusion