http://repository.iitr.ac.in/handle/123456789/20277| Title: | Dll1+ quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway |
| Authors: | Kumar, Sushil Nandi A. Singh S. Regulapati R. Li N. Tobias J.W. Siebel C.W. Blanco M.A. Klein-Szanto A.J. Lengner C. Welm A.L. Kang Y. Chakrabarti R. |
| Published in: | Nature Communications |
| 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. © 2021, The Author(s). |
| Citation: | Nature Communications, 12(1) |
| URI: | https://doi.org/10.1038/s41467-020-20664-5 http://repository.iitr.ac.in/handle/123456789/20277 |
| Issue Date: | 2021 |
| Publisher: | Nature Research |
| Keywords: | blocking antibody doxorubicin immunoglobulin enhancer binding protein notch ligand dll1 Notch receptor unclassified drug Wnt1 protein antineoplastic agent benzamide derivative calcium binding protein DLK1 protein, human Dlk1 protein, mouse doxorubicin immunoglobulin enhancer binding protein membrane protein N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide NFKB1 protein, human Nfkb1 protein, mouse Notch receptor cancer chemotherapy disease treatment growth ligand protein tumor animal cell animal experiment animal model animal tissue Article breast cancer cancer stem cell cells controlled study drug resistance female flow cytometry lung metastasis lung nodule metastasis mouse nonhuman Notch signaling patient coding pharmacological blocking primary tumor RNA sequencing tumor growth animal breast breast tumor cancer stem cell cell proliferation cell survival disease model drug effect drug resistance gene expression regulation genetics human information processing knockout mouse metabolism pathology signal transduction tumor cell line Animals Antineoplastic Combined Chemotherapy Protocols Benzamides Breast Breast Neoplasms Calcium-Binding Proteins Cell Line, Tumor Cell Proliferation Cell Survival Datasets as Topic Disease Models, Animal Doxorubicin Drug Resistance, Neoplasm Female Gene Expression Regulation, Neoplastic Humans Membrane Proteins Mice Mice, Knockout Neoplastic Stem Cells NF-kappa B p50 Subunit Receptors, Notch RNA-Seq Signal Transduction |
| ISSN: | 20411723 |
| Author Scopus IDs: | 57213855617 57216244266 57189686345 57221772760 57226481884 7202182919 6701822709 56733790800 7102402798 57204892143 6602926951 7402784847 16149432900 |
| Author Affiliations: | Kumar, S., Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, United States Nandi, A., Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, United States Singh, S., Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, United States Regulapati, R., Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, United States Li, N., Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, United States Tobias, J.W., Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States Siebel, C.W., Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080, United States Blanco, M.A., Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, United States Klein-Szanto, A.J., Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA, United States Lengner, C., Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, United States Welm, A.L., Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, United States Kang, Y., Department of Molecular Biology, Princeton University, Princeton, NJ 08544, United States Chakrabarti, R., Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, United States |
| Funding Details: | We thank Dr. Leslie King (University of Pennsylvania, PA) for careful reading of the manuscript and helpful discussions. We thank Dr. Michael L. Atchison and Dr. Sar-mistha Banerjee for generously providing flow cytometry antibodies of marginal B-cells. We thank the animal facility located in Hill Pavilion building for housing and maintenance of all mouse models. We thank the Center for Host-Microbial Interactions for running the ATAC-Sequencing libraries. We thank Penn Vet Comparative Pathology Core for embedding and sectioning of tumor and lung tissues. We thank Penn Vet imaging core for providing confocal microscopy service. We thank Flow Cytometry core at Children’s Hospital of Philadelphia and the University of Pennsylvania for FACS analysis and cell sorting. This work was supported by grants from Abramson Cancer Center Emerson Collective Fund, American Cancer Society, McCabe Fund Fellow Award from Perelman School of Medicine, UPENN and NCI-K22 grant to R.C. (K22CA193661) and American Cancer Society grant to R.C. (RSG DDC - 133604). American Cancer Society, ACS; National Cancer Institute, NCI; University of Pennsylvania: K22CA193661, NCI-K22, RSG DDC - 133604; Perelman School of Medicine, University of Pennsylvania |
| Corresponding Author: | Chakrabarti, R.; Department of Biomedical Sciences, United States; email: rumela@vet.upenn.edu |
| Appears in Collections: | Journal Publications [BT] |
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