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, Rumela Chakrabarti

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number432
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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