Bi-directional signaling between melanoma and the microenvironment generates a protective niche that mediates therapeutic escape

Very few cancer patients are cured through drug therapy alone, with the majority exhibiting acquired resistance. To date, most studies of therapeutic escape have focused upon tumor-intrinsic mechanisms of drug resistance with little attention paid to the role of normal host cells in preventing compl...

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Main Author: Fedorenko, Inna
Format: Others
Published: Scholar Commons 2014
Subjects:
Online Access:https://scholarcommons.usf.edu/etd/5215
https://scholarcommons.usf.edu/cgi/viewcontent.cgi?article=6411&context=etd
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spelling ndltd-USF-oai-scholarcommons.usf.edu-etd-64112019-10-04T05:12:12Z Bi-directional signaling between melanoma and the microenvironment generates a protective niche that mediates therapeutic escape Fedorenko, Inna Very few cancer patients are cured through drug therapy alone, with the majority exhibiting acquired resistance. To date, most studies of therapeutic escape have focused upon tumor-intrinsic mechanisms of drug resistance with little attention paid to the role of normal host cells in preventing complete tumor eradication. In the present study we implicate co-operative bi-directional signaling between melanoma cells and fibroblasts in the generation of a pro-survival niche that mediates drug resistance. Mass-spectrometry based phosphoproteomics was used to show that BRAF inhibition and chemotherapy drugs enhanced the survival of both melanoma cells and fibroblasts through the induction of fibronectin (FN)/integrin α5β1 signaling. Immunohistochemical staining confirmed the induction of FN in mouse xenografts and human melanoma specimens following BRAF inhibitor treatment. Adhesion to FN amplified the adaptive EGFR, HER3 and c-MET receptor tyrosine kinase (RTK) signals required for PI3K/AKT/Mcl-1-mediated melanoma cell survival when BRAF was inhibited. At the same time, BRAF inhibition led, directly and indirectly, to the paracrine release of HGF and neuregulin from fibroblasts, with TGF-β release from the melanoma cells increasing both fibroblast differentiation and survival. Although dual inhibition of RTKs and BRAF did not reverse host-mediated resistance, therapeutic escape was overcome through combined BRAF/PI3K inhibition, suggesting the PI3K/AKT pathway to be a common signaling vulnerability in microenvironment-mediated drug resistance. Our work suggests that durable responses to targeted therapies will only be achieved through dual targeting of the tumor and the adaptive host responses to therapy. These findings are especially important for a cancer such as melanoma, where as few as one cell can repopulate the entire tumor in vivo. 2014-07-08T07:00:00Z text application/pdf https://scholarcommons.usf.edu/etd/5215 https://scholarcommons.usf.edu/cgi/viewcontent.cgi?article=6411&context=etd default Graduate Theses and Dissertations Scholar Commons Fibronectin Integrins Melanoma PTEN Resistance Vemurafenib Cell Biology
collection NDLTD
format Others
sources NDLTD
topic Fibronectin
Integrins
Melanoma
PTEN
Resistance
Vemurafenib
Cell Biology
spellingShingle Fibronectin
Integrins
Melanoma
PTEN
Resistance
Vemurafenib
Cell Biology
Fedorenko, Inna
Bi-directional signaling between melanoma and the microenvironment generates a protective niche that mediates therapeutic escape
description Very few cancer patients are cured through drug therapy alone, with the majority exhibiting acquired resistance. To date, most studies of therapeutic escape have focused upon tumor-intrinsic mechanisms of drug resistance with little attention paid to the role of normal host cells in preventing complete tumor eradication. In the present study we implicate co-operative bi-directional signaling between melanoma cells and fibroblasts in the generation of a pro-survival niche that mediates drug resistance. Mass-spectrometry based phosphoproteomics was used to show that BRAF inhibition and chemotherapy drugs enhanced the survival of both melanoma cells and fibroblasts through the induction of fibronectin (FN)/integrin α5β1 signaling. Immunohistochemical staining confirmed the induction of FN in mouse xenografts and human melanoma specimens following BRAF inhibitor treatment. Adhesion to FN amplified the adaptive EGFR, HER3 and c-MET receptor tyrosine kinase (RTK) signals required for PI3K/AKT/Mcl-1-mediated melanoma cell survival when BRAF was inhibited. At the same time, BRAF inhibition led, directly and indirectly, to the paracrine release of HGF and neuregulin from fibroblasts, with TGF-β release from the melanoma cells increasing both fibroblast differentiation and survival. Although dual inhibition of RTKs and BRAF did not reverse host-mediated resistance, therapeutic escape was overcome through combined BRAF/PI3K inhibition, suggesting the PI3K/AKT pathway to be a common signaling vulnerability in microenvironment-mediated drug resistance. Our work suggests that durable responses to targeted therapies will only be achieved through dual targeting of the tumor and the adaptive host responses to therapy. These findings are especially important for a cancer such as melanoma, where as few as one cell can repopulate the entire tumor in vivo.
author Fedorenko, Inna
author_facet Fedorenko, Inna
author_sort Fedorenko, Inna
title Bi-directional signaling between melanoma and the microenvironment generates a protective niche that mediates therapeutic escape
title_short Bi-directional signaling between melanoma and the microenvironment generates a protective niche that mediates therapeutic escape
title_full Bi-directional signaling between melanoma and the microenvironment generates a protective niche that mediates therapeutic escape
title_fullStr Bi-directional signaling between melanoma and the microenvironment generates a protective niche that mediates therapeutic escape
title_full_unstemmed Bi-directional signaling between melanoma and the microenvironment generates a protective niche that mediates therapeutic escape
title_sort bi-directional signaling between melanoma and the microenvironment generates a protective niche that mediates therapeutic escape
publisher Scholar Commons
publishDate 2014
url https://scholarcommons.usf.edu/etd/5215
https://scholarcommons.usf.edu/cgi/viewcontent.cgi?article=6411&context=etd
work_keys_str_mv AT fedorenkoinna bidirectionalsignalingbetweenmelanomaandthemicroenvironmentgeneratesaprotectivenichethatmediatestherapeuticescape
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