The need for complex 3D culture models to unravel novel pathways and identify accurate biomarkers in breast cancer

Weigelt, Britta; Ghajar, Cyrus M.; Bissell, Mina J.

doi:10.1016/j.addr.2014.01.001

Cited by 290 publications

(257 citation statements)

References 141 publications

(158 reference statements)

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“…3D human-cell models may also provide more effective and economical screening of new drugs than the use of animal models. 8,9 Furthermore, in vitro 3D modeling of native tissue provides tools for regenerative medicine. However, understanding the fundamental cell biology is critical in translating in vitro discoveries into clinical applications, e.g., functional replacement of damaged tissue.…”

Section: Introductionmentioning

confidence: 99%

Chromosome conformation and gene expression patterns differ profoundly in human fibroblasts grown in spheroids versus monolayers

Chen

Seaman

Liu

et al. 2017

Nucleus

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Human cells derived for in vitro cultures are conventionally grown as adherent monolayers (2D) which do not resemble natural 3 dimensional (3D) tissue architecture. We examined genome structure with chromosome conformation capture (Hi-C) and gene expression with RNA-seq in fibroblasts derived from human foreskin grown in 2D and 3D conditions. Our combined analysis of Hi-C and RNA-seq data shows a large number of differentially expressed genes between 2D and 3D cells, and these changes are localized in genomic regions that displayed structural changes. We also find a trend of expression in a subset of skin-specific genes in fibroblast cells grown in 3D that resembles those in native tissue.

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Section: Introductionmentioning

confidence: 99%

Chromosome conformation and gene expression patterns differ profoundly in human fibroblasts grown in spheroids versus monolayers

Chen

Seaman

Liu

et al. 2017

Nucleus

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“…Indeed, preclinical and patient data have suggested that PIK3CA mutations mediate resistance to therapies that target receptors in the ErbB family, specifically HER2 and EGFR (23,24,26,28). Increasing evidence has also implicated autocrine/paracrine signaling in drug resistance (37,38).…”

Section: Discussionmentioning

confidence: 99%

“…To determine how constitutively activating mutations in PIK3CA affect responsiveness to HRG, we used a three-dimensional (3D), in vitro culture system in which cells form multicellular spheroids on micro-patterned culture plates, previously suggested to bridge the gap between monolayer and in vivo systems (28). We have found that cellular responses to growth factors are generally more pronounced when cells are grown in 3D culture than when grown in two-dimensional monolayers (unpublished observations).…”

Section: Pi3k Wt and Mutant Cells Exhibit Variable Responsiveness To Hrgmentioning

confidence: 99%

Heregulin–ErbB3-Driven Tumor Growth Persists in PI3 Kinase Mutant Cancer Cells

Yarar

Lahdenranta

Kubasek

et al. 2015

Molecular Cancer Therapeutics

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PI3K is frequently mutated in cancer and plays an important role in cell growth and survival. Heregulin (HRG)-mediated autocrine or paracrine signaling through the receptor tyrosine kinase ErbB3 potently activates the PI3K/AKT pathway and has been shown to mediate resistance to a wide variety of anticancer agents. Although PI3K functions downstream of HRG-ErbB3, it is unknown whether activating mutations in PI3K render HRG ineffective. If so, patients with PI3K mutations would not be expected to benefit from ErbB3-directed therapies. Here, we find that a subset of cell lines harboring activating PI3K mutations can be further growth-stimulated by HRG, and this effect is blocked by incubation with seribantumab (MM-121), a monoclonal antiErbB3 antibody. Although expression of mutant PI3K in wild-type PI3K cells frequently results in loss of HRG-stimulated growth, some cell lines continue to respond to HRG. In cell lines where HRG-stimulated growth is lost, this loss is invariably accompanied by a reduction in ErbB3 levels, a corresponding increase in basal phosphorylation levels of FOXO-family transcription factors, and a reduction in HRG-induced downstream signaling. Importantly, HRG-stimulated growth is partially rescued by reexpressing ErbB3. This response is blocked by seribantumab, indicating that ErbB3 levels rather than downstream signaling proteins limit HRG-stimulated growth in PI3K mutant cells.

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“…A series of excellent reviews have recently described in depth the use of 3D tissue culture model systems in pathophysiology [49] and high-throughput drug candidate toxicity analysis, [50] to identify tumor-specific signaling pathways and biomarkers, [51] and to determine growth determinants for drug target discovery. [52] These reviews delineate what parameters contribute to a disease representing, efficient [53] and dye [102]…”

Section: Current In Vitro Model Systems To Address Functions Of Metasmentioning

confidence: 99%

Dissecting brain tumor growth and metastasis in vitro and ex vivo

Grotzer¹,

Neve²,

Baumgärtner³

2016

JCMT

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Local infiltration and distal dissemination of tumor cells hamper efficacy of current treatments against central nervous system (CNS) tumors and greatly influence mortality and therapy-induced longterm morbidity in survivors. A number of in vitro and ex vivo assay systems have been established to better understand the infiltration and metastatic processes, to search for molecules that specifically block tumor cell infiltration and metastatic dissemination and to pre-clinically evaluate their efficaciousness. These systems allow analytical testing of tumor cell viability and motile and invasive capabilities in simplified and well-controlled environments. However, the urgent need for novel anti-metastatic therapies has provided an incentive for the further development of not only classical in vitro methods but also of novel, physiologically more relevant assay systems including organotypic brain slice culture. In this review, using publicly available peer-reviewed primary research and review articles, we provide an overview of a selection of in vitro and ex vivo techniques widely used to study growth and dissemination of primary metastatic brain tumors. Furthermore, we discuss how our steadily increasing knowledge of tumor biology and the tumor microenvironment could be integrated to improve current research methods for metastatic brain tumors. We believe that such rationally improved methods will ultimately increase our understanding of the biology of brain tumors and facilitate the development of more efficacious anti-metastatic treatments. Local infiltration and distal dissemination of tumor cells hamper efficacy of current treatments against central nervous system (CNS) tumors and greatly influence mortality and therapy-induced long-term morbidity in survivors. A number of in vitro and ex vivo assay systems have been established to better understand the infiltration and metastatic processes, to search for molecules that specifically block tumor cell infiltration and metastatic dissemination and to pre-clinically evaluate their efficaciousness. These systems allow analytical testing of tumor cell viability and motile and invasive capabilities in simplified and well-controlled environments. However, the urgent need for novel anti-metastatic therapies has provided an incentive for the further development of not only classical in vitro methods but also of novel, physiologically more relevant assay systems including organotypic brain slice culture. In this review, using publicly available peer-reviewed primary research and review articles, we provide an overview of a selection of in vitro and ex vivo techniques widely used to study growth and dissemination of primary metastatic brain tumors. Furthermore, we discuss how our steadily increasing knowledge of tumor biology and the tumor microenvironment could be integrated to improve current research methods for metastatic brain tumors. We believe that such rationally improved methods will ultimately increase our understanding of the biology of brain tumors ...

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The need for complex 3D culture models to unravel novel pathways and identify accurate biomarkers in breast cancer

Cited by 290 publications

References 141 publications

Chromosome conformation and gene expression patterns differ profoundly in human fibroblasts grown in spheroids versus monolayers

Chromosome conformation and gene expression patterns differ profoundly in human fibroblasts grown in spheroids versus monolayers

Heregulin–ErbB3-Driven Tumor Growth Persists in PI3 Kinase Mutant Cancer Cells

Dissecting brain tumor growth and metastasis in vitro and ex vivo

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