scholarly journals Multi-omics analysis defines 5-fluorouracil drug resistance in 3D HeLa carcinoma cell model

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Lin Wang ◽  
Xueting Wang ◽  
Tong Wang ◽  
Yingping Zhuang ◽  
Guan Wang
Keyword(s):  
Drug Resistance ◽  
Drug Screening ◽  
Molecular Mechanisms ◽  
Monolayer Culture ◽  
Tricarboxylic Acid Cycle ◽  
Critical Role ◽  
Carcinoma Cells ◽  
Holistic View ◽  
Ecm Proteins

AbstractCervical cancer is a serious health problem in women around the globe. However, the use of clinical drug is seriously dampened by the development of drug resistance. Efficient in vitro tumor model is essential to improve the efficiency of drug screening and the accuracy of clinical application. Multicellular tumor spheroids (MTSs) can in a way recapitulates tumor traits in vivo, thereby representing a powerful transitional model between 2D monolayer culture and xenograft. In this study, based on the liquid overlay method, a protocol for rapid generation of the MTSs with uniform size and high reproducibility in a high-throughput manner was established. As expected, the cytotoxicity results showed that there was enhanced 5-fluorouracil (5-FU) resistance of HeLa carcinoma cells in 3D MTSs than 2D monolayer culture with a resistance index of 5.72. In order to obtain a holistic view of the molecular mechanisms that drive 5-FU resistance in 3D HeLa carcinoma cells, a multi-omics study was applied to discover hidden biological regularities. It was observed that in the 3D MTSs mitochondrial function-related proteins and the metabolites of the tricarboxylic acid cycle (TCA cycle) were significantly decreased, and the cellular metabolism was shifted towards glycolysis. The differences in the protein synthesis, processing, and transportation between 2D monolayer cultures and 3D MTSs were significant, mainly in the heat shock protein family, with the up-regulation of protein folding function in endoplasmic reticulum (ER), which promoted the maintenance of ER homeostasis in the 3D MTSs. In addition, at the transcript and protein level, the expression of extracellular matrix (ECM) proteins (e.g., laminin and collagen) were up-regulated in the 3D MTSs, which enhanced the physical barrier of drug penetration. Summarizing, this study formulates a rapid, scalable and reproducible in vitro model of 3D MTS for drug screening purposes, and the findings establish a critical role of glycolytic metabolism, ER hemostasis and ECM proteins expression profiling in tumor chemoresistance of HeLa carcinoma cells towards 5-FU. Graphical Abstract

scholarly journals Multi-Omics Analysis Defines 5-Fluorouracil Drug Resistance in 3D Hela Carcinoma Cell Model

2021 ◽  
Author(s):  
Lin Wang ◽  
Xueting Wang ◽  
Tong Wang ◽  
Yingping Zhuang ◽  
GUAN WANG
Keyword(s):  
Drug Resistance ◽  
Drug Screening ◽  
Monolayer Culture ◽  
Tricarboxylic Acid Cycle ◽  
Critical Role ◽  
Carcinoma Cells ◽  
Metabolic Reprogramming ◽  
Holistic View ◽  
Ecm Proteins

Abstract Cervical cancer is a serious health problem in women around the globe, with 600 thousand new cases each year. However, the use of clinical drug is seriously dampened by the development of drug resistance, which has been evidenced to be associated with metabolic reprogramming and heterogeneity in tumor cells. Efficient in vitro tumor model is essential to improve the efficiency of drug screening and the accuracy of clinical application. Multicellular tumor spheroids (MTSs) can in a way recapitulates tumor traits in vivo, thereby representing a powerful transitional model between 2D monolayer culture and xenograft. In this study, based on the liquid overlay method, a protocol for rapid generation of the MTSs with uniform size and high reproducibility in a high-throughput manner was established. As expected, the cytotoxicity results showed that there was enhanced 5-FU resistance of HeLa carcinoma cells in 3D MTSs than 2D monolayer culture with a resistance index of 5.72. In the presence of both glucose and glutamine, HeLa carcinoma cells preferentially used glutamine as the bioenergetic substrate to support cell proliferation and maintenance under all conditions, while the ubiquitous by-product ammonium might be only recycled in the 3D MTSs. Furthermore, in order to obtain a holistic view of the molecular mechanisms that drive 5-FU resistance in 3D HeLa carcinoma cells, a multi-omics study was applied to discover hidden biological regularities. It was observed that in the 3D MTSs mitochondrial function-related proteins and the metabolites of the tricarboxylic acid cycle (TCA cycle) were significantly decreased, and the cellular metabolism was shifted towards glycolysis. The differences in the protein synthesis, processing, and transportation between 2D monolayer cultures and 3D MTSs was significant, mainly in the heat shock protein family, with the upregulation of protein folding function in endoplasmic reticulum (ER), which promoted the maintenance of ER homeostasis in the 3D MTSs. In addition, at the transcript and protein level, the expression of extracellular matrix (ECM) proteins (e.g., laminin and collagen) were up-regulated in the 3D MTSs, which enhanced the physical barrier of drug penetration. Summarizing, this study formulates a rapid, scalable and reproducible in vitro model of 3D MTS for drug screening purposes, and the findings establish a critical role of glycolytic metabolism, ER hemostasis and ECM proteins expression profiling in tumor chemoresistance of HeLa carcinoma cells towards 5-FU.

scholarly journals Capn4 Enhances Osteopontin Expression through Activation of the Wnt/β-Catenin Pathway to Promote Epithelial Ovarian Carcinoma Metastasis

2017 ◽  
Vol 42 (1) ◽  
pp. 185-197 ◽  
Author(s):  
Xiaoming Yang ◽  
Jing Sun ◽  
Dandan Xia ◽  
Xupei Can ◽  
Lei Liu ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Western Blotting ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Epithelial Ovarian Carcinoma ◽  
Regulatory Subunit ◽  
Epithelial Tissue

Background and Aim: Increasing evidence shows that the calpain regulatory subunit Capn4 can modulate the proliferation and metastasis of cancer cells, and plays an important role in the development of malignant tumors. However, there is no information on the clinical significance of Capn4 in epithelial ovarian carcinoma (EOC) or the molecular mechanisms by which Capn4 promotes the growth and metastasis of EOC. Therefore, the aim of this study was to clarify the role of Capn4 in EOC. Methods: We evaluated Capn4 and osteopontin (OPN) expression in EOC cell lines and tissues from patients with ovarian cancer by western blotting and immunohistochemical analysis. We then created cell lines with downregulated and upregulated Capn4 expression, using Capn4-targeting small interfering RNA and a pcDNA3.1-Capn4 overexpression vector, respectively, to investigate its function in EOC in vitro. In addition, we investigated the potential mechanism underlying the function of Capn4 by examining the effect of modifying Capn4 expression on Wnt/β-catenin signaling pathway-related genes by western blotting. Results: Capn4 was overexpressed in clinical EOC tissues compared with that in normal ovarian epithelial tissue, and was associated with poor clinical outcomes. Upon silencing or overexpressing Capn4 in EOC cells, we concluded that Capn4 promotes cell proliferation and migration in vitro. Furthermore, Capn4 promoted EOC metastasis by interacting with the Wnt/β-catenin signaling pathway to upregulate OPN expression. Conclusion: Our study indicates that Capn4 plays a critical role in the progression and metastasis of EOC, and could be a potential therapeutic target for EOC management.

scholarly journals Hydroxychloroquine Synergizes With The PI3K Inhibitor BKM120 to Exhibit Antitumor Efficacy Independent of Autophagy

2021 ◽  
Author(s):  
Xin Peng ◽  
Shaolu Zhang ◽  
Wenhui Jiao ◽  
Zhenxing Zhong ◽  
Yuqi Yang ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Single Agent ◽  
Antitumor Efficacy ◽  
Antitumor Effects ◽  
Autophagy Inhibitor

Abstract Background: The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer.Methods: The antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining. Results: HCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51. Conclusions: Our study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the “off target” effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer.

Abstract MP175: Disruption of the Genome Architecture at the PRRX1 Locus is Associated With the Pathogenesis of LMNA -related Dilated Cardiomyopathy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yuan Zhang ◽  
Mohamed Ameen ◽  
Isaac Perea Gil ◽  
Jennifer Arthur ◽  
Alexandra A Gavidia ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Single Cell ◽  
Genome Organization ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Lamin A ◽  
Candidate Locus ◽  
Gene Encoding ◽  
Gene Dysregulation

Background: LMNA , a gene encoding A-type lamin proteins (abbreviated as lamin A), is one of the most frequently mutated genes in dilated cardiomyopathy (DCM). The molecular mechanisms underlying cardiomyocyte dysfunction in LMNA -related DCM remain elusive, translating to the lack of disease-specific therapies. Lamin A has been shown to play a critical role in genome organization via interactions with the chromatin at specific regions called lamina-associated domains (LADs). However, little is known about whether DCM-causing LMNA mutations rearrange the genome conformation and chromosome accessibility. The overarching goal of this study is to define the role of genome organization in LMNA -related DCM. Methods: LMNA -related DCM was modeled in vitro using cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) from DCM patients carrying a frameshift mutation in the LMNA gene (c. 348_349insG; p. K117fs) and isogenic controls. We combined genome-wide single cell functional genomic and epigenomic mapping analyses to define the gene regulation and cis-regulatory interactions in isogenic iPSC-CMs. Results: Single-cell RNA-seq revealed global gene dysregulation in LMNA mutant compared to isogenic control iPSC-CMs. The homeodomain transcription factor PRRX1 was significantly upregulated in mutant cells. We showed that LAD integrity is disrupted at the PRRX1 locus in mutant iPSC-CMs. In agreement, DNA fluorescence in situ hybridization (FISH) revealed that the PRRX1 locus loses peripheral association and relocates towards the transcriptionally active nuclear interior in mutant iPSC-CMs. Correspondingly, single-cell assay for transposase accessible chromatin (ATAC)-seq showed increased chromatin co-accessibility at the PRRX1 locus, providing a plausible explanation for ectopic activation of PRRX1 in LMNA mutant iPSC-CMs. Conclusion: Our data suggest that LMNA haploinsufficiency disrupts the structure of LADs, leading to ectopic promoter interactions and altered gene expression in LMNA -related DCM iPSC-CMs. We identified PRRX1 as a promising candidate locus linking changes in LAD organization with gene dysregulation in LMNA -related DCM.

Bioactive Compounds from Seaweed with Anti-Leukemic Activity: A Mini-Review on Carotenoids and Phlorotannins

2020 ◽  
Vol 20 (1) ◽  
pp. 39-53 ◽  
Author(s):  
Tânia P. Almeida ◽  
Alice A. Ramos ◽  
Joana Ferreira ◽  
Amaya Azqueta ◽  
Eduardo Rocha
Keyword(s):  
Drug Resistance ◽  
Bioactive Compounds ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
First Line ◽  
In Vivo Models ◽  
Few Data

: Chronic Myeloid Leukemia (CML) represents 15-20% of all new cases of leukemia and is characterized by an uncontrolled proliferation of abnormal myeloid cells. Currently, the first-line of treatment involves Tyrosine Kinase Inhibitors (TKIs), which specifically inhibits the activity of the fusion protein BCR-ABL. However, resistance, mainly due to mutations, can occur. In the attempt to find more effective and less toxic therapies, several approaches are taken into consideration such as research of new anti-leukemic drugs and “combination chemotherapy” where different drugs that act by different mechanisms are used. Here, we reviewed the molecular mechanisms of CML, the main mechanisms of drug resistance and current strategies to enhance the therapeutic effect of TKIs in CML. Despite major advances in CML treatment, new, more potent anticancer drugs and with fewer side effects are needed. Marine organisms, and particularly seaweed, have a high diversity of bioactive compounds with some of them having anticancer activity in several in vitro and in vivo models. The state-of-art suggests that their use during cancer treatment may improve the outcome. We reviewed here the yet few data supporting anti-leukemic activity of some carotenoids and phlorotannins in some leukemia models. Also, strategies to overcome drug resistance are discussed, particularly the combination of conventional drugs with natural compounds.

scholarly journals P-selectin glycoprotein ligand regulates the interaction of multiple myeloma cells with the bone marrow microenvironment

Blood ◽  
2012 ◽  
Vol 119 (6) ◽  
pp. 1468-1478 ◽  
Author(s):  
Abdel Kareem Azab ◽  
Phong Quang ◽  
Feda Azab ◽  
Costas Pitsillides ◽  
Brian Thompson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Stromal Cells ◽  
Critical Role ◽  
Loss Of Function ◽  
Downstream Signaling ◽  
Target Organs ◽  
Regulation Of Growth

Abstract Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in the pathogenesis of MM and in the development of drug resistance by MM cells. Selectins are involved in extravasation and homing of leukocytes to target organs. In the present study, we focused on adhesion dynamics that involve P-selectin glycoprotein ligand-1 (PSGL-1) on MM cells and its interaction with selectins in the BM microenvironment. We show that PSGL-1 is highly expressed on MM cells and regulates the adhesion and homing of MM cells to cells in the BM microenvironment in vitro and in vivo. This interaction involves both endothelial cells and BM stromal cells. Using loss-of-function studies and the small-molecule pan-selectin inhibitor GMI-1070, we show that PSGL-1 regulates the activation of integrins and downstream signaling. We also document that this interaction regulates MM-cell proliferation in coculture with BM microenvironmental cells and the development of drug resistance. Furthermore, inhibiting this interaction with GMI-1070 enhances the sensitization of MM cells to bortezomib in vitro and in vivo. These data highlight the critical contribution of PSGL-1 to the regulation of growth, dissemination, and drug resistance in MM in the context of the BM microenvironment.

scholarly journals In Vitro and In Vivo Interactions of DNA Ligase IV with a Subunit of the Condensin Complex

2003 ◽  
Vol 14 (2) ◽  
pp. 685-697 ◽  
Author(s):  
Marcin R. Przewloka ◽  
Paige E. Pardington ◽  
Steven M. Yannone ◽  
David J. Chen ◽  
Robert B. Cary
Keyword(s):  
Molecular Mechanisms ◽  
Critical Role ◽  
Dna Ligase ◽  
Mitotic Chromosomes ◽  
Dna Ligase Iv ◽  
Cell Extracts ◽  
Condensin Complex ◽  
Human Dna ◽  
Ligase Iv

Several findings have revealed a likely role for DNA ligase IV, and interacting protein XRCC4, in the final steps of mammalian DNA double-strand break repair. Recent evidence suggests that the human DNA ligase IV protein plays a critical role in the maintenance of genomic stability. To identify protein–protein interactions that may shed further light on the molecular mechanisms of DSB repair and the biological roles of human DNA ligase IV, we have used the yeast two-hybrid system in conjunction with traditional biochemical methods. These efforts have resulted in the identification of a physical association between the DNA ligase IV polypeptide and the human condensin subunit known as hCAP-E. The hCAP-E polypeptide, a member of the Structural Maintenance of Chromosomes (SMC) super-family of proteins, coimmunoprecipitates from cell extracts with DNA ligase IV. Immunofluorescence studies reveal colocalization of DNA ligase IV and hCAP-E in the interphase nucleus, whereas mitotic cells display colocalization of both polypeptides on mitotic chromosomes. Strikingly, the XRCC4 protein is excluded from the area of mitotic chromosomes, suggesting the formation of specialized DNA ligase IV complexes subject to cell cycle regulation. We discuss our findings in light of known and hypothesized roles for ligase IV and the condensin complex.

IFNγ induces monopoiesis and inhibits neutrophil development during inflammation

Blood ◽  
2012 ◽  
Vol 119 (6) ◽  
pp. 1543-1554 ◽  
Author(s):  
Alexander M. de Bruin ◽  
Sten F. Libregts ◽  
Marijke Valkhof ◽  
Louis Boon ◽  
Ivo P. Touw ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Critical Role ◽  
Lymphocytic Choriomeningitis ◽  
In Vitro Assays ◽  
Myeloid Progenitor ◽  
Stat3 Phosphorylation ◽  
Dependent Inhibition ◽  
Myeloid Progenitor Cells ◽  
Neutrophil Differentiation

AbstractSteady-state hematopoiesis is altered on infection, but the cellular and molecular mechanisms driving these changes are largely unknown. Modulation of hematopoiesis is essential to increase the output of the appropriate type of effector cell required to combat the invading pathogen. In the present study, we demonstrate that the pro-inflammatory cytokine IFNγ is involved in orchestrating inflammation-induced myelopoiesis. Using both mouse models and in vitro assays, we show that IFNγ induces the differentiation of monocytes over neutrophils at the level of myeloid progenitors. Infection with lymphocytic choriomeningitis virus induces monopoiesis in wild-type mice, but causes increased neutrophil production in IFNγ−/− mice. We demonstrate that IFNγ enhances the expression of the monopoiesis-inducing transcription factors IRF8 and PU.1 in myeloid progenitor cells, whereas it reduces G-CSF–driven neutrophil differentiation via a SOCS3-dependent inhibition of STAT3 phosphorylation. These results establish a critical role for IFNγ in directing monocyte versus neutrophil development during immune activation.

scholarly journals Mathematical modeling quantifies ERK-activity in response to inhibition of the BRAFV600E-MEK-ERK cascade

2021 ◽  
Author(s):  
Sara Hamis ◽  
Yury Kapelyukh ◽  
Aileen McLaren ◽  
Colin J. Henderson ◽  
C. Roland Wolf ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Drug Resistance ◽  
Chemical Reactions ◽  
Molecular Mechanisms ◽  
Braf Inhibitor ◽  
Mass Action ◽  
Model Parameters ◽  
Mass Action Kinetics ◽  
Erk Activity

AbstractSimultaneous inhibition of multiple components of the BRAF-MEK-ERK cascade (vertical inhibition) has become a standard of care for treating BRAF-mutant melanoma. However, the molecular mechanisms of how vertical inhibition synergistically suppress intracellular ERK activity, and as a consequence cell proliferation, are yet to be fully elucidated.In this study, we develop a mechanistic mathematical model that describes how the mutant BRAF-inhibitor, dabrafenib, and the MEK-inhibitor, trametinib, affect signaling through the BRAFV600E-MEK-ERK cascade. We formulate a system of chemical reactions that describes cascade signaling dynamics and, using mass action kinetics, the chemical reactions are re-expressed as ordinary differential equations. Using model parameters obtained from in vitro data available in the literature, these equations are solved numerically to obtain the temporal evolution of the concentrations of the components in the signaling cascade.Our mathematical model provides a quantitative method to compute how dabrafenib and trametinib can be used in combination to synergistically inhibit ERK activity in BRAFV600E mutant melanoma cells. This work elucidates molecular mechanisms of vertical inhibition of the BRAFV600E-MEK-ERK cascade and delineates how elevated cellular BRAF concentrations generate drug resistance to dabrafenib and trametinib. In addition, the computational simulations suggest that elevated ATP levels could be a factor in drug resistance to dabrafenib. The mathematical model that is developed in this study will have generic application in the improved design of anticancer combination therapies that target BRAF-MEK-ERK pathways.

scholarly journals A Biomaterial Screening Approach Reveals Microenvironmental Mechanisms of Drug Resistance

2017 ◽  
Author(s):  
Alyssa D. Schwartz ◽  
Lauren E. Barney ◽  
Lauren E. Jansen ◽  
Thuy V. Nguyen ◽  
Christopher L. Hall ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Systems Biology ◽  
Drug Screening ◽  
Drug Response ◽  
Drug Sensitivity ◽  
Mek Inhibitor ◽  
Tumor Burden ◽  
Adaptive Resistance

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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