ORCID Profile
0000-0003-2257-2862
Current Organisations
The University of Auckland
,
University of Glasgow
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Publisher: Frontiers Media SA
Date: 11-08-2017
Publisher: Cold Spring Harbor Laboratory
Date: 20-02-2020
DOI: 10.1101/2020.02.19.956508
Abstract: Triple negative breast cancer is the most aggressive subtype of breast cancer with poor prognosis and high rates of relapse. The lack of actionable targets for TNBC has contributed to the high mortality rates of this disease, and new candidate molecules for potential manipulation are urgently required. Here, we show that macrophage-stimulating protein (MSP) and its tyrosine kinase receptor, RON, are potent drivers of cancer cell growth and tumor progression in a mouse model of TNBC driven by the loss of Trp53 and Brca1 . After comparison of two genetically engineered mouse models of TNBC, we found that mammary tumors from K14-Cre Brca1 F/F Trp53 F/F (KB1P) mice exhibit high endogenous levels of MSP and RON expression. We show that MSP stimulates AKT and ERK1/2 activation as well as cancer cell growth in KB1P cell lines, while genetic and pharmacological inhibition of RON prevents these effects. Similarly, KB1P tumor progression in mice was robustly attenuated by treatment with a RON inhibitor with accompanied reduction in the proliferation marker, Ki-67. Our findings in a mouse model where MSP and RON expression are naturally increased provide evidence that this receptor and its ligand are viable candidate molecules for targeted treatment of TNBC.
Publisher: Elsevier BV
Date: 11-2019
Publisher: Wiley
Date: 17-06-2020
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1002/JPS.24099
Publisher: Springer Science and Business Media LLC
Date: 18-07-2011
DOI: 10.1038/ONC.2011.295
Abstract: Autophagy, hallmarked by the formation of double-membrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in early-stage carcinogenesis, autophagy inhibits inflammation and promotes genomic stability. Moreover, disruption of autophagy-related genes accelerates tumorigenesis in animals. However, autophagy may also act as a pro-survival mechanism to protect cancer cells from various forms of cellular stress. In cancer therapy, adaptive autophagy in cancer cells sustains tumor growth and survival in face of the toxicity of cancer therapy. To this end, inhibition of autophagy may sensitize cancer cells to chemotherapeutic agents and ionizing radiation. Nevertheless, in certain circumstances, autophagy mediates the therapeutic effects of some anticancer agents. Data from recent studies are beginning to unveil the apparently paradoxical nature of autophagy as a cell-fate decision machinery. Taken together, modulation of autophagy is a novel approach for enhancing the efficacy of existing cancer therapy, but its Janus-faced nature may complicate the clinical development of autophagy modulators as anticancer therapeutics.
Publisher: Wiley
Date: 20-08-2010
DOI: 10.1002/IJC.25489
Publisher: Elsevier BV
Date: 04-2014
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: Netherlands
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Seth Coffelt.