Limiting Self-Renewal of the Basal Compartment by PKA Activation Induces Differentiation and Alters the Evolution of Mammary Tumors.

Autor:	Ognjenovic NB; Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA., Bagheri M; Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA., Mohamed GA; Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA., Xu K; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Chen Y; Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA., Mohamed Saleem MA; Lifebytes India Pvt Ltd, Bengaluru, India., Brown MS; Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA., Nagaraj SH; Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4001, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia; Translational Research Institute, Brisbane, QLD 4102, Australia., Muller KE; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA; Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA., Gerber SA; Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA., Christensen BC; Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA; Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA., Pattabiraman DR; Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA. Electronic address: raman@dartmouth.edu.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2020 Dec 07; Vol. 55 (5), pp. 544-557.e6. Date of Electronic Publication: 2020 Oct 28.
DOI:	10.1016/j.devcel.2020.10.004
Abstrakt:	Differentiation therapy utilizes our understanding of the hierarchy of cellular systems to pharmacologically induce a shift toward terminal commitment. While this approach has been a paradigm in treating certain hematological malignancies, efforts to translate this success to solid tumors have met with limited success. Mammary-specific activation of PKA in mouse models leads to aberrant differentiation and diminished self-renewing potential of the basal compartment, which harbors mammary repopulating cells. PKA activation results in tumors that are more benign, exhibiting reduced metastatic propensity, loss of tumor-initiating potential, and increased sensitivity to chemotherapy. Analysis of tumor histopathology revealed features of overt differentiation with papillary characteristics. Longitudinal single-cell profiling at the hyperplasia and tumor stages uncovered an altered path of tumor evolution whereby PKA curtails the emergence of aggressive subpopulations. Acting through the repression of SOX4, PKA activation promotes tumor differentiation and represents a possible adjuvant to chemotherapy for certain breast cancers. Competing Interests: Declaration of Interests The lead author has a patent titled “Methods and Compositions for Targeting Cancer Stem Cells.” U.S. Patent no. 10,398,672 (issued September 3, 2019) for the activation of PKA as a means of targeting breast cancer stem cells. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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