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The Role of Desmoplasia and Stromal Fibroblasts on Anti-cancer Drug Resistance in a Microengineered Tumor Model

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Abstract

Introduction

Cancer associated fibroblasts (CAFs) are known to participate in anti-cancer drug resistance by upregulating desmoplasia and pro-survival mechanisms within the tumor microenvironment. In this regard, anti-fibrotic drugs (i.e., tranilast) have been repurposed to diminish the elastic modulus of the stromal matrix and reduce tumor growth in presence of chemotherapeutics (i.e., doxorubicin). However, the quantitative assessment on impact of these stromal targeting drugs on matrix stiffness and tumor progression is still missing in the sole presence of CAFs.

Methods

We developed a high-density 3D microengineered tumor model comprised of MDA-MB-231 (highly invasive breast cancer cells) embedded microwells, surrounded by CAFs encapsulated within collagen I hydrogel. To study the influence of tranilast and doxorubicin on fibrosis, we probed the matrix using atomic force microscopy (AFM) and assessed matrix protein deposition. We further studied the combinatorial influence of the drugs on cancer cell proliferation and invasion.

Results

Our results demonstrated that the combinatorial action of tranilast and doxorubicin significantly diminished the stiffness of the stromal matrix compared to the control. The two drugs in synergy disrupted fibronectin assembly and reduced collagen fiber density. Furthermore, the combination of these drugs, condensed tumor growth and invasion.

Conclusion

In this work, we utilized a 3D microengineered model to tease apart the role of tranilast and doxorubicin in the sole presence of CAFs on desmoplasia, tumor growth and invasion. Our study lay down a ground work on better understanding of the role of biomechanical properties of the matrix on anti-cancer drug efficacy in the presence of single class of stromal cells.

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Abbreviations

2D:

Two dimensional

3D:

Three dimensional

AFM:

Atomic force microscopy

APTES:

2-Aminopropyl-3 triethoxy silane

CAFs:

Cancer associated fibroblasts

DAPI:

4′,6-Diamidino-2-phenylindole, dihydrochloride

DMSO:

Dimethyl sulfoxide

ECM:

Extracellular matrix

EDU:

5-Ethynyl-2′-deoxyuridine

FAK:

Focal adhesion kinase signaling

GA:

Glutaraldehyde

PDL:

Poly d-lysine

PDMS:

Poly dimethoxy siloxane

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Acknowledgments

The authors would like to acknowledge National Science Foundation (NSF) Award # 1510700 and ASU Fulton undergraduate research initiative (FURI).

Conflict of interest

HS, KRE, CS, MA, GM, RR, MN declare no conflict of interest.

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No human and animal studies were carried out by the authors for this article.

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Correspondence to Mehdi Nikkhah.

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Associate Editor Michael R. King oversaw the review of this article.

Mehdi Nikkhah is currently an Assistant Professor of Biomedical Engineering at the School of Biological and Health Systems Engineering (SBHSE), Arizona State University. His laboratory research is focused on the integration of innovative biomaterial and micro-/nanoscale technologies to create biomimetic tissue constructs for disease modeling and regenerative medicine applications. Dr. Nikkhah completed his postdoctoral fellowship at Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology (HST), working in the areas of Biomaterials and regenerative medicine. He received his Ph.D. degree in Mechanical Engineering from Virginia Tech, where his research was focused on cell-biomaterial interface and identification of cancer cell biomechanical signatures using isotropic microstructures. Dr. Nikkhah has published more than 50 journal articles, 7 book chapters and 70 peer-reviewed conference papers (~ 3500 citations, H-index of 30), and holds numerous invention disclosures and patents. He has also received many prestigious awards and recognitions during his career some of which include: National Science Foundation (NSF) CAREER Award, Arizona New Investigator Award, Young Investigator Award from Polymeric Materials Science and Engineering division of American Chemical Society (ACS), National Institute of Health (NIH) Ruth L. Kirschstein National Research Service Awards (NRSA) for Individual Postdoctoral Fellows, and Outstanding Ph.D. Dissertation Award at Virginia Tech.

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This article is part of the 2018 CMBE Young Innovators special issue.

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12195_2018_544_MOESM1_ESM.tif

Supplementary material 1 (TIFF 21449 kb). Supplementary Figure 1: IC 50 values in 3D assay for MDA-MB-231 and CAFs in response to different concentrations of (A) Tranilast and (B) Doxorubicin in 3D assay. (C) IC 50 values of MDA-MB-231 and CAFs at higher concentration of doxorubicin.

12195_2018_544_MOESM2_ESM.tif

Supplementary material 2 (TIFF 14568 kb). Supplementary Figure 2: Representative immunofluorescent images demonstrating fibronectin deposition and assembly within 3D matrix across experimental groups. Arrows representing the fibronectin fibers. * represent the microwells molded in collagen. Scale bars represent 20 µm.

12195_2018_544_MOESM3_ESM.tif

Supplementary material 3 (TIFF 11664 kb). Supplementary Figure 3: Scatter dot plot of data replicates for elastic modulus measurement showing variation of stiffness across all groups on day 1 and day 3 of the culture.

12195_2018_544_MOESM4_ESM.tif

Supplementary material 4 (TIFF 34388 kb). Supplementary Figure 4: (A) Representative immunofluorescent images of EdU assay depicting proliferation of MCF7 and MCF10A in control and Tranilast+Doxorubcin treated group. (B) Quantification of proliferation of MCF7 and MCF10A cells across culture conditions. Scale bars represents 50 µm. (* represents p value < 0.05).

12195_2018_544_MOESM5_ESM.tif

Supplementary material 5 (TIFF 50639 kb). Supplementary Figure 5: (A) Representative phase contrast and fluorescent images of tumor cell dispersion in DMSO, tranilast and doxorubicin conditions on day 1 and day 3. (B) Representative triangulation graphs depicting tumor cell invasion into the stroma within DMSO, tranilast and doxorubicin group. (C) Quantification of area disorder of MDA-MB-231 cells across all the groups. Scale bars represent 100 µm. (* represents p value < 0.05).

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Saini, H., Rahmani Eliato, K., Silva, C. et al. The Role of Desmoplasia and Stromal Fibroblasts on Anti-cancer Drug Resistance in a Microengineered Tumor Model. Cel. Mol. Bioeng. 11, 419–433 (2018). https://doi.org/10.1007/s12195-018-0544-9

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