Dll1+ quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway.
Sushil KumarAjeya NandiSnahlata SinghRohan RegulapatiNing LiJohn W TobiasChristian W SiebelMario Andres BlancoAndres J Klein-SzantoChristopher J LengnerAlana L WelmYibin KangRumela ChakrabartiPublished in: Nature communications (2021)
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.
Keyphrases
- rna seq
- stem cells
- signaling pathway
- single cell
- lps induced
- cell proliferation
- oxidative stress
- locally advanced
- crispr cas
- squamous cell carcinoma
- immune response
- cell therapy
- inflammatory response
- papillary thyroid
- cancer stem cells
- childhood cancer
- induced apoptosis
- electronic health record
- lymph node metastasis
- free survival
- data analysis
- toll like receptor
- artificial intelligence