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Title: Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance

Abstract

The existence of rare cancer cells that sporadically acquire drug-tolerance through epigenetic mechanisms is proposed as one mechanism that drives cancer therapy failure. In this work we provide evidence that specific microenvironments impose non-sporadic expression of proteins related to epithelial plasticity and drug resistance. Microarrays of robotically printed combinatorial microenvironments of known composition were used to make cell-based functional associations between microenvironments, which were design-inspired by normal and tumor-burdened breast tissues, and cell phenotypes. We hypothesized that specific combinations of microenvironment constituents non-sporadically impose the induction of the AXL and cKIT receptor tyrosine kinase proteins, which are known to be involved in epithelial plasticity and drug-tolerance, in an isogenic human mammary epithelial cell (HMEC) malignant progression series. Dimension reduction analysis reveals type I collagen as a dominant feature, inducing expression of both markers in pre-stasis finite lifespan HMECs, and transformed non-malignant and malignant immortal cell lines. Basement membrane-associated matrix proteins, laminin-111 and type IV collagen, suppress AXL and cKIT expression in pre-stasis and non-malignant cells. Yet, AXL and cKIT are not suppressed by laminin-111 in malignant cells. General linear models identified key factors, osteopontin, IL-8, and type VIα 3 collagen, which significantly upregulated AXL and cKIT, as well as amore » plasticity-related gene expression program that is often observed in stem cells and in epithelial-to-mesenchymal-transition. These factors are co-located with AXL-expressing cells in situ in normal and breast cancer tissues, and associated with resistance to paclitaxel. A greater diversity of microenvironments induced AXL and cKIT expression consistent with plasticity and drug-tolerant phenotypes in tumorigenic cells compared to normal or immortal cells, implying a reduced perception of microenvironment specificity in malignant cells. Microenvironment-imposed reprogramming could explain why resistant cells are seemingly persistent and rapidly adaptable to multiple classes of drugs. These results support the notion that specific microenvironments drive drug-tolerant cellular phenotypes and suggest a novel interventional avenue for preventing acquired therapy resistance.« less

Authors:
; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Research Foundation of Norway; Norwegian Research Council
OSTI Identifier:
1433449
Alternate Identifier(s):
OSTI ID: 1532314
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Published Article
Journal Name:
Frontiers in Cell and Developmental Biology
Additional Journal Information:
Journal Name: Frontiers in Cell and Developmental Biology Journal Volume: 6; Journal ID: ISSN 2296-634X
Publisher:
Frontiers Media SA
Country of Publication:
Switzerland
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; breast cancer; MEMA; microenvironment; epithelial plasticity; AXL; cKIT; drug resistance

Citation Formats

Jokela, Tiina A., Engelsen, Agnete S. T., Rybicka, Agata, Pelissier Vatter, Fanny A., Garbe, James C., Miyano, Masaru, Tiron, Crina, Ferariu, Dan, Akslen, Lars A., Stampfer, Martha R., Lorens, James B., and LaBarge, Mark A. Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance. Switzerland: N. p., 2018. Web. doi:10.3389/fcell.2018.00041.
Jokela, Tiina A., Engelsen, Agnete S. T., Rybicka, Agata, Pelissier Vatter, Fanny A., Garbe, James C., Miyano, Masaru, Tiron, Crina, Ferariu, Dan, Akslen, Lars A., Stampfer, Martha R., Lorens, James B., & LaBarge, Mark A. Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance. Switzerland. doi:10.3389/fcell.2018.00041.
Jokela, Tiina A., Engelsen, Agnete S. T., Rybicka, Agata, Pelissier Vatter, Fanny A., Garbe, James C., Miyano, Masaru, Tiron, Crina, Ferariu, Dan, Akslen, Lars A., Stampfer, Martha R., Lorens, James B., and LaBarge, Mark A. Tue . "Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance". Switzerland. doi:10.3389/fcell.2018.00041.
@article{osti_1433449,
title = {Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance},
author = {Jokela, Tiina A. and Engelsen, Agnete S. T. and Rybicka, Agata and Pelissier Vatter, Fanny A. and Garbe, James C. and Miyano, Masaru and Tiron, Crina and Ferariu, Dan and Akslen, Lars A. and Stampfer, Martha R. and Lorens, James B. and LaBarge, Mark A.},
abstractNote = {The existence of rare cancer cells that sporadically acquire drug-tolerance through epigenetic mechanisms is proposed as one mechanism that drives cancer therapy failure. In this work we provide evidence that specific microenvironments impose non-sporadic expression of proteins related to epithelial plasticity and drug resistance. Microarrays of robotically printed combinatorial microenvironments of known composition were used to make cell-based functional associations between microenvironments, which were design-inspired by normal and tumor-burdened breast tissues, and cell phenotypes. We hypothesized that specific combinations of microenvironment constituents non-sporadically impose the induction of the AXL and cKIT receptor tyrosine kinase proteins, which are known to be involved in epithelial plasticity and drug-tolerance, in an isogenic human mammary epithelial cell (HMEC) malignant progression series. Dimension reduction analysis reveals type I collagen as a dominant feature, inducing expression of both markers in pre-stasis finite lifespan HMECs, and transformed non-malignant and malignant immortal cell lines. Basement membrane-associated matrix proteins, laminin-111 and type IV collagen, suppress AXL and cKIT expression in pre-stasis and non-malignant cells. Yet, AXL and cKIT are not suppressed by laminin-111 in malignant cells. General linear models identified key factors, osteopontin, IL-8, and type VIα3 collagen, which significantly upregulated AXL and cKIT, as well as a plasticity-related gene expression program that is often observed in stem cells and in epithelial-to-mesenchymal-transition. These factors are co-located with AXL-expressing cells in situ in normal and breast cancer tissues, and associated with resistance to paclitaxel. A greater diversity of microenvironments induced AXL and cKIT expression consistent with plasticity and drug-tolerant phenotypes in tumorigenic cells compared to normal or immortal cells, implying a reduced perception of microenvironment specificity in malignant cells. Microenvironment-imposed reprogramming could explain why resistant cells are seemingly persistent and rapidly adaptable to multiple classes of drugs. These results support the notion that specific microenvironments drive drug-tolerant cellular phenotypes and suggest a novel interventional avenue for preventing acquired therapy resistance.},
doi = {10.3389/fcell.2018.00041},
journal = {Frontiers in Cell and Developmental Biology},
number = ,
volume = 6,
place = {Switzerland},
year = {2018},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.3389/fcell.2018.00041

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Cited by: 4 works
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