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

Journal Article · 17 April 2018 · Frontiers in Cell and Developmental Biology

DOI: https://doi.org/10.3389/fcell.2018.00041 · OSTI ID:1433449

Jokela, Tiina A.  ^[1]; Engelsen, Agnete S. T.  ^[2]; Rybicka, Agata ^[2]; Pelissier Vatter, Fanny A. ^[2]; Garbe, James C. ^[3]; Miyano, Masaru ^[4]; Tiron, Crina ^[5]; Ferariu, Dan ^[5]; Akslen, Lars A. ^[2]; Stampfer, Martha R.  ^[3]; Lorens, James B. ^[2]; LaBarge, Mark A. ^[6]

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1. Bergen Univ. (Norway); Center for Cancer and Aging, Duarte, CA (United States)
2. Bergen Univ. (Norway)
3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
4. Center for Cancer and Aging, Duarte, CA (United States)
5. Regional Inst. of Oncology, Iasi (Romania)
6. Center for Cancer and Aging, Duarte, CA (United States); Bergen Univ. (Norway); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

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.

• Research Organization: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
• Sponsoring Organization: USDOE Office of Science (SC); National Research Foundation of Norway; Norwegian Research Council
• Grant/Contract Number: AC02-05CH11231
• OSTI ID: 1433449
• Alternate ID(s): OSTI ID: 1532314
• Journal Information: Frontiers in Cell and Developmental Biology, Vol. 6, Issue APR; ISSN 2296-634X
• Publisher: Frontiers Media S.A.Copyright Statement
• Country of Publication: United States
• Language: English