Regulation of metastatic ability and drug resistance in pulmonary adenocarcinoma by matrix rigidity via activating c-Met and EGFR

Chang, Chih Cheng; Hsieh, Ting Lieh; Tiong, Tung Yu; Hsiao, Chi Hao; Ji, Andrea Tung Qian; Hsu, Wei-Feng; Lee, Oscar K.; Ho, Jennifer H.

doi:10.1016/j.biomaterials.2015.04.058

Cited by 24 publications

(22 citation statements)

References 53 publications

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“…In agreement with our findings, myeloid leukemia cells have a stiffness-dependent response to drugs, including sorafenib and a MEK inhibitor, which target the RAF/MAPK pathway 48, 49 . We have previously shown that sorafenib resistance increased with increasing hydrogel stiffness 10 , and many others have also demonstrated that stiffness is a significant driving force for drug resistance 9, 10, 30, 31, 50–53 . Thus, we were surprised to find that drug resistance was only minimally affected by stiffness within the modest range examined here (Figure 1e–f).…”

Section: Discussionmentioning

confidence: 90%

A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance

Schwartz

Barney

Jansen

et al. 2017

Integrative Biology

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Traditional drug screening methods lack features of the tumor microenvironment that contribute to resistance. Most studies examine cell response in a single biomaterial platform in depth, leaving a gap in understanding how extracellular signals such as stiffness, dimensionality, and cell-cell contacts act independently or are integrated within a cell to affect either drug sensitivity or resistance. This is critically important, as adaptive resistance is mediated, at least in part, by the extracellular matrix (ECM) of the tumor microenvironment. We developed an approach to screen drug responses in cells cultured on 2D and in 3D biomaterial environments to explore how key features of ECM mediate drug response. This approach uncovered that cells on 2D hydrogels and spheroids encapsulated in 3D hydrogels were less responsive to receptor tyrosine kinase (RTK)-targeting drugs sorafenib and lapatinib, but not cytotoxic drugs, compared to single cells in hydrogels and cells on plastic. We found that transcriptomic differences between these in vitro models and tumor xenografts did not reveal mechanisms of ECM-mediated resistance to sorafenib. However, a systems biology analysis of phospho-kinome data uncovered that variation in MEK phosphorylation was associated with RTK-targeted drug resistance. Using sorafenib as a model drug, we found that co-administration with a MEK inhibitor decreased ECM-mediated resistance in vitro and reduced in vivo tumor burden compared to sorafenib alone. In sum, we provide a novel strategy for identifying and overcoming ECM-mediated resistance mechanisms by performing drug screening, phospho-kinome analysis, and systems biology across multiple biomaterial environments.

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Section: Discussionmentioning

confidence: 90%

A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance

Schwartz

Barney

Jansen

et al. 2017

Integrative Biology

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show abstract

“…In agreement with our findings, myeloid leukemia cells have a stiffness-dependent response to drugs, including sorafenib and a MEK inhibitor, which target the RAF/MAPK pathway 46,47 . We have previously shown that sorafenib resistance increased with increasing hydrogel stiffness 10 , and many others have also demonstrated that stiffness is a significant driving force for drug resistance 9,10,28,29,[48][49][50][51] . Thus, we were surprised to find that drug resistance was only minimally affected by stiffness within the modest range examined here (Figure 1e-f).…”

Section: Discussionmentioning

confidence: 92%

A Biomaterial Screening Approach Reveals Microenvironmental Mechanisms of Drug Resistance

Schwartz

Barney

Jansen

et al. 2017

Preprint

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TOC FigureDrug response screening, gene expression, and kinome signaling were combined across biomaterial platforms to combat adaptive resistance to sorafenib.Insight BoxWe combined biomaterial platforms, drug screening, and systems biology to identify mechanisms of extracellular matrix-mediated adaptive resistance to RTK-targeted cancer therapies. Drug response was significantly varied across biomaterials with altered stiffness, dimensionality, and cell-cell contacts, and kinome reprogramming was responsible for these differences in drug sensitivity. Screening across many platforms and applying a systems biology analysis were necessary to identify MEK phosphorylation as the key factor associated with variation in drug response. This method uncovered the combination therapy of sorafenib with a MEK inhibitor, which decreased viability on and within biomaterials in vitro, but was not captured by screening on tissue culture plastic alone. This combination therapy also reduced tumor burden in vivo, and revealed a promising approach for combating adaptive drug resistance.AbstractTraditional drug screening methods lack features of the tumor microenvironment that contribute to resistance. Most studies examine cell response in a single biomaterial platform in depth, leaving a gap in understanding how extracellular signals such as stiffness, dimensionality, and cell-cell contacts act independently or are integrated within a cell to affect either drug sensitivity or resistance. This is critically important, as adaptive resistance is mediated, at least in part, by the extracellular matrix (ECM) of the tumor microenvironment. We developed an approach to screen drug responses in cells cultured on 2D and in 3D biomaterial environments to explore how key features of ECM mediate drug response. This approach uncovered that cells on 2D hydrogels and spheroids encapsulated in 3D hydrogels were less responsive to receptor tyrosine kinase (RTK)-targeting drugs sorafenib and lapatinib, but not cytotoxic drugs, compared to single cells in hydrogels and cells on plastic. We found that transcriptomic differences between these in vitro models and tumor xenografts did not reveal mechanisms of ECM-mediated resistance to sorafenib. However, a systems biology analysis of phospho-kinome data uncovered that variation in MEK phosphorylation was associated with RTK-targeted drug resistance. Using sorafenib as a model drug, we found that co-administration with a MEK inhibitor decreased ECM-mediated resistance in vitro and reduced in vivo tumor burden compared to sorafenib alone. In sum, we provide a novel strategy for identifying and overcoming ECM-mediated resistance mechanisms by performing drug screening, phospho-kinome analysis, and systems biology across multiple biomaterial environments.

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“…For example, we and others have shown that cellular response to chemotherapy and/or other targeted drugs is sensitive to the stiffness of the surrounding ECM ( Fig. 2d) 7,40,48,[54][55][56][57][58][59][60][61][62] . Second, ECM stiffness plays a critical role in regulating cancer cell growth [63][64][65] and motility 66,67 .…”

Section: Implications For Persistent Mechanical Activation Of Cancer mentioning

confidence: 99%

Emerging Concepts and Tools in Cell Mechanomemory

2019

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Studying a cell's ability to sense and respond to mechanical cues has emerged as a field unto itself over the last several decades, and this research area is now populated by engineers and biologists alike. As just one example of this cell mechanosensing, fibroblasts on soft substrates have slower growth rates, smaller spread areas, lower traction forces, and slower migration speeds compared to cells on stiff substrates. This phenomenon is not unique to fibroblasts, as these behaviors, and others, on soft substrates has been shown across a variety of cell types, and reproduced in many different labs. Thus far, the field has focused on discerning the mechanisms of cell mechanosensing through ion channels, focal adhesions and integrin-binding sites to the ECM, and the cell cytoskeleton. A relatively new concept in the field is that of mechanical memory, which refers to persistent effects of mechanical stimuli long after they have been removed from said stimulus. Here, we review this literature, provide an overview of emerging substrate fabrication approaches likely to be helpful for the field, and suggest the adaption of genetic tools for studying mechanical memory.

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Regulation of metastatic ability and drug resistance in pulmonary adenocarcinoma by matrix rigidity via activating c-Met and EGFR

Cited by 24 publications

References 53 publications

A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance

A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance

A Biomaterial Screening Approach Reveals Microenvironmental Mechanisms of Drug Resistance

Emerging Concepts and Tools in Cell Mechanomemory

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