skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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 VIα3 collagen, which significantly upregulated AXL and cKIT, as well as a plasticity-relatedmore » 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 Laboratory (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:
Journal Article: 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. https://doi.org/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. 2018. "Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance". Switzerland. https://doi.org/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},
url = {https://www.osti.gov/biblio/1433449}, journal = {Frontiers in Cell and Developmental Biology},
issn = {2296-634X},
number = ,
volume = 6,
place = {Switzerland},
year = {Tue Apr 17 00:00:00 EDT 2018},
month = {Tue Apr 17 00:00:00 EDT 2018}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at https://doi.org/10.3389/fcell.2018.00041

Citation Metrics:
Cited by: 13 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Genetic Variation in IL-8 Associated with Increased Risk and Poor Prognosis of Breast Carcinoma
journal, January 2006


Context, tissue plasticity, and cancer
journal, January 2005


The clonal and mutational evolution spectrum of primary triple-negative breast cancers
journal, April 2012


Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival
journal, December 2009


A role for collagen XXIII in cancer cell adhesion, anchorage-independence and metastasis
journal, October 2011


Processing of Human Reduction Mammoplasty and Mastectomy Tissues for Cell Culture
journal, January 2013


Collagen VI in cancer and its biological mechanisms
journal, July 2013


Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance
journal, June 2017


Endocrine resistance in breast cancer
journal, December 2013


Collagen VI and Hyaluronan: The Common Role in Breast Cancer
journal, January 2014


The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups
journal, April 2012


The Role of Cytokines in Breast Cancer Development and Progression
journal, January 2015

  • Esquivel-Velázquez, Marcela; Ostoa-Saloma, Pedro; Palacios-Arreola, Margarita Isabel
  • Journal of Interferon & Cytokine Research, Vol. 35, Issue 1
  • https://doi.org/10.1089/jir.2014.0026

Epithelial-Mesenchymal Transitions in Development and Disease
journal, November 2009


The Biology of Leptin and Its Implications in Breast Cancer: A General View
journal, December 2013


Growth arrest-specific gene 6 expression in human breast cancer
journal, February 2008


The Role of Chemokines in Breast Cancer Pathology and Its Possible Use as Therapeutic Targets
journal, January 2014


Induction of transformation and continuous cell lines from normal human mammary epithelial cells after exposure to benzo[a]pyrene.
journal, April 1985


Epithelial Mesenchymal Transition Traits in Human Breast Cancer Cell Lines Parallel the CD44hi/CD24lo/- Stem Cell Phenotype in Human Breast Cancer
journal, June 2010


A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations
journal, April 2010


Role of collagenous matrices in the adhesion and growth of cells
journal, March 1981


184AA3: a xenograft model of ER+ breast adenocarcinoma
journal, December 2015


Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells.
journal, October 1992


Plasticity of epithelial stem cells in tissue regeneration
journal, June 2014


Correction: MiR-34a-5p promotes the multi-drug resistance of osteosarcoma by targeting the CD117 gene
journal, September 2017


The role of steroid hormones in breast cancer stem cells
journal, September 2015


The Epithelial-Mesenchymal Transition and Cancer Stem Cells: Functional and Mechanistic Links
journal, February 2015


The clinical and functional significance of c-Met in breast cancer: a review
journal, April 2015


Collagen reorganization at the tumor-stromal interface facilitates local invasion
journal, December 2006


The extracellular matrix in breast cancer
journal, February 2016


Fabrication and Use of MicroEnvironment microArrays (MEArrays)
journal, January 2012


Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers
journal, August 2009


Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis
journal, August 2013


Homeostatic Signaling by Cell–Cell Junctions and Its Dysregulation during Cancer Progression
journal, February 2016


Insulin-Like Growth Factor and Epidermal Growth Factor Signaling in Breast Cancer Cell Growth: Focus on Endocrine Resistant Disease
journal, January 2015


viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia
journal, May 2013


Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers
journal, September 2007


The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells
journal, May 2008


Lumican affects tumor cell functions, tumor–ECM interactions, angiogenesis and inflammatory response
journal, April 2014


Adaptive mechanisms of resistance to anti-neoplastic agents
journal, January 2017


Osteoprotegerin in breast cancer: beyond bone remodeling
journal, June 2015


Osteopontin: a bridge between bone and blood
journal, September 2006


Slug and Sox9 Cooperatively Determine the Mammary Stem Cell State
journal, March 2012


Stem Cells in the Human Breast
journal, May 2010


Chromosome analyses of human mammary epithelial cells at stages of chemical-induced transformation progression to immortality
journal, February 1989


Works referencing / citing this record:

Gas6 is dispensable for pubertal mammary gland development
journal, December 2018


AXL Controls Directed Migration of Mesenchymal Triple-Negative Breast Cancer Cells
journal, January 2020