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

Sushil Kumar, Ajeya Nandi, Snahlata Singh, Rohan Regulapati, Ning Li, John W. Tobias, Christian W. Siebel, Mario Andres Blanco, Andres J. Klein-Szanto, Christopher Lengner, Alana L. Welm, Yibin Kang and Rumela Chakrabarti ()
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Sushil Kumar: University of Pennsylvania
Ajeya Nandi: University of Pennsylvania
Snahlata Singh: University of Pennsylvania
Rohan Regulapati: University of Pennsylvania
Ning Li: University of Pennsylvania
John W. Tobias: University of Pennsylvania
Christian W. Siebel: Genentech Inc.
Mario Andres Blanco: University of Pennsylvania
Andres J. Klein-Szanto: Fox Chase Cancer Center
Christopher Lengner: University of Pennsylvania
Alana L. Welm: University of Utah
Yibin Kang: Princeton University
Rumela Chakrabarti: University of Pennsylvania

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20664-5

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