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

S. Kumar; A. Nandi; Snahlata Singh; R. Regulapati; Ning Li; J. W. Tobias; C. W. Siebel; M. A. Blanco; Andrés J.P. Klein-Szanto; Christopher J. Lengner; A. L. Welm; Yibin Kang; R. Chakrabarti

doi:10.1038/s41467-020-20664-5

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

S. Kumar, A. Nandi, Snahlata Singh, R. Regulapati, Ning Li, J. W. Tobias, C. W. Siebel, M. A. Blanco, Andrés J.P. Klein-Szanto, Christopher J. Lengner, A. L. Welm, Yibin Kang, R. Chakrabarti

Research output: Contribution to journal › Article › peer-review

46 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-kappaB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-kappaB pathway completely sensitizes Dll1(+) tumors to chemotherapy, highlighting therapeutic avenues for chemotherapy resistant breast cancer patients in the near future.

Original language	American English
Article number	432
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20664-5
State	Published - 2021
Externally published	Yes

Keywords

Animals Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use Benzamides/pharmacology/therapeutic use Breast/pathology Breast Neoplasms/*drug therapy/genetics/pathology Calcium-Binding Proteins/antagonists & inhibitors/genetics/*metabolism Cell Line, Tumor Cell Proliferation/drug effects/genetics Cell Survival/drug effects/genetics Datasets as Topic Disease Models, Animal Doxorubicin/pharmacology/therapeutic use Drug Resistance, Neoplasm/drug effects/*genetics Female Gene Expression Regulation, Neoplastic Humans Membrane Proteins/*metabolism Mice Mice, Knockout NF-kappa B p50 Subunit/antagonists & inhibitors/*metabolism Neoplastic Stem Cells/drug effects/metabolism RNA-Seq Receptors, Notch/metabolism Signal Transduction/drug effects/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-20664-5

https://www.ncbi.nlm.nih.gov/pubmed/33462238

Cite this

Kumar, S., Nandi, A., Singh, S., Regulapati, R., Li, N., Tobias, J. W., Siebel, C. W., Blanco, M. A., Klein-Szanto, A. J. P., Lengner, C. J., Welm, A. L., Kang, Y., & Chakrabarti, R. (2021). Dll1(+) quiescent tumor stem cells drive chemoresistance in breast cancer through NF-kappaB survival pathway. Nature Communications, 12(1), Article 432. https://doi.org/10.1038/s41467-020-20664-5

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title = "Dll1(+) quiescent tumor stem cells drive chemoresistance in breast cancer through NF-kappaB survival pathway",

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-kappaB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-kappaB pathway completely sensitizes Dll1(+) tumors to chemotherapy, highlighting therapeutic avenues for chemotherapy resistant breast cancer patients in the near future.",

keywords = "Animals Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use Benzamides/pharmacology/therapeutic use Breast/pathology Breast Neoplasms/*drug therapy/genetics/pathology Calcium-Binding Proteins/antagonists & inhibitors/genetics/*metabolism Cell Line, Tumor Cell Proliferation/drug effects/genetics Cell Survival/drug effects/genetics Datasets as Topic Disease Models, Animal Doxorubicin/pharmacology/therapeutic use Drug Resistance, Neoplasm/drug effects/*genetics Female Gene Expression Regulation, Neoplastic Humans Membrane Proteins/*metabolism Mice Mice, Knockout NF-kappa B p50 Subunit/antagonists & inhibitors/*metabolism Neoplastic Stem Cells/drug effects/metabolism RNA-Seq Receptors, Notch/metabolism Signal Transduction/drug effects/genetics",

author = "S. Kumar and A. Nandi and Snahlata Singh and R. Regulapati and Ning Li and Tobias, {J. W.} and Siebel, {C. W.} and Blanco, {M. A.} and Klein-Szanto, {Andr{\'e}s J.P.} and Lengner, {Christopher J.} and Welm, {A. L.} and Yibin Kang and R. Chakrabarti",

note = "Kumar, Sushil Nandi, Ajeya Singh, Snahlata Regulapati, Rohan Li, Ning Tobias, John W Siebel, Christian W Blanco, Mario Andres Klein-Szanto, Andres J Lengner, Christopher Welm, Alana L Kang, Yibin Chakrabarti, Rumela eng K22 CA193661/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England 2021/01/20 Nat Commun. 2021 Jan 18;12(1):432. doi: 10.1038/s41467-020-20664-5.",

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doi = "10.1038/s41467-020-20664-5",

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AU - Nandi, A.

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AU - Regulapati, R.

AU - Li, Ning

AU - Tobias, J. W.

AU - Siebel, C. W.

AU - Blanco, M. A.

AU - Klein-Szanto, Andrés J.P.

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AU - Welm, A. L.

AU - Kang, Yibin

AU - Chakrabarti, R.

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AB - 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-kappaB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-kappaB pathway completely sensitizes Dll1(+) tumors to chemotherapy, highlighting therapeutic avenues for chemotherapy resistant breast cancer patients in the near future.

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ER -

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

Abstract

Keywords

UN SDGs

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Histopathology Facility

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

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Histopathology Facility

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