Epithelial–mesenchymal plasticity and circulating tumor cells: Travel companions to metastases

Francart, Marie-Emilie; Lambert, Justine; Vanwynsberghe, Aline; Thompson, Erik W.; Bourcy, Morgane; Polette, Myriam; Gilles, Christine

doi:10.1002/dvdy.24506

Cited by 96 publications

(105 citation statements)

References 212 publications

(340 reference statements)

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“…Like those in the primary tissues, CTCs are also heterogeneous and only certain subpopulation is able to make their way to final metastatic growth [35]. Accumulating evidence indicates that hypoxia-induced EMT allows the intravasated CTCs to survive, most likely via resistance to detachment-induced anoikis and/or NK-mediated immunosurveillance, and to colonize distant organs [36,37] (Figure 3).…”

Section: Tumor Cell Survival In the Circulationmentioning

confidence: 99%

Fibronectin in Cancer: Friend or Foe

Lin

Yang

et al. 2019

Cells

147

117

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The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies. Figure 1. (A) The structure of fibronectin (FN) containing three types of repeats and three alternative splicing regions (EDA, EDB, and IIICS) with several well-known binding sites for extracellular matrix (ECM) components (fibrin, heparin, collagen, and gelatin), polymeric assembly (FN-FN), cell adhesion (integrin α5β1), DPP IV, and two C-terminal disulfide bonds for dimeric FN. (B) Publications in recent some forty years regarding the roles of cancerous FN and stromal FN in ECM in tumor progression as represented in a time-line pattern. Among 26 publications before 2000, 15 (57.7%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 3 (11.5%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 8 (30.8%) papers are related to the role of stromal FN in promoting early tumor progression but not late metastasis (in dark green boxes). On the contrary, Among 46 publications after 2000, 7 (15.2%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 25 (54.4%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 14 (30.4%) papers are related to the role of stromal FN in promoting early tumor progression but not late metastasis (in dark green boxes). Abbreviations in boxes are referred to the context of this article. (C) Percentages of articles for the three various roles of FN (the same colors as depicted in (B) before 2000 and after 2000. Numbers in the parenthesis represent article numbers. The Pathobiology of CancerFigure 1. (A) The structure of fibronectin (FN) containing three types of repeats and three alternative splicing regions (EDA, EDB, and IIICS) with several well-known binding sites for extracellular matrix (ECM) components (fibrin, heparin, collagen, and gelatin), polymeric assembly (FN-FN), cell adhesion (integrin α5β1), DPP IV, and two C-terminal disulfide bonds for dimeric FN. (B) Publications in recent some forty years regarding the roles of cancerous FN and stromal FN in ECM in tumor progression as represented in a time-line pattern. Among 26 publications before 2000, 15 (57.7%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 3 (11.5%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 8 (30.8%) papers are related to the r...

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Section: Tumor Cell Survival In the Circulationmentioning

confidence: 99%

Fibronectin in Cancer: Friend or Foe

Lin

Yang

et al. 2019

Cells

147

117

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“…While EpCAM expressing CTC have shown to be highly clinically relevant, recently, the relevance of the presence of CTC expressing no or low EpCAM in cancer patients, is the subject of debate. While many subpopulations can be described, the clinical utility of these cells is barely addressed …”

Section: Introductionmentioning

confidence: 99%

“…While many subpopulations can be described, the clinical utility of these cells is barely addressed. [19][20][21][22][23] The use of ctDNA as a clinical response marker for NSCLC patients has already moved into the clinical routine and EGFR T790 M testing from plasma has been proven to complement tissue-based testing. 5 However, this can be applied to only a subset of patients harboring an activating EFGR mutation, while an untargeted approach, which does not require prior knowledge of the mutation status the tumor, would facilitate a more widespread application.…”

Section: Introductionmentioning

confidence: 99%

Single tube liquid biopsy for advanced non‐small cell lung cancer

Wit

Rossi

Weber

et al. 2019

Intl Journal of Cancer

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The need for a liquid biopsy in non‐small cell lung cancer (NSCLC) patients is rapidly increasing. We studied the relation between overall survival (OS) and the presence of four cancer biomarkers from a single blood draw in advanced NSCLC patients: EpCAMhigh circulating tumor cells (CTC), EpCAMlow CTC, tumor‐derived extracellular vesicles (tdEV) and cell‐free circulating tumor DNA (ctDNA). EpCAMhigh CTC were detected with CellSearch, tdEV in the CellSearch images and EpCAMlow CTC with filtration after CellSearch. ctDNA was isolated from plasma and mutations present in the primary tumor were tracked with deep sequencing methods. In 97 patients, 21% had ≥2 EpCAMhigh CTC, 15% had ≥2 EpCAMlow CTC, 27% had ≥18 tdEV and 19% had ctDNA with ≥10% mutant allele frequency. Either one of these four biomarkers could be detected in 45% of the patients and all biomarkers were present in 2%. In 11 out of 16 patients (69%) mutations were detected in the ctDNA. Two or more unfavorable biomarkers were associated with poor OS. The presence of EpCAMhigh CTC and elevated levels of tdEV and ctDNA was associated with a poor OS; however, the presence of EpCAMlow CTC was not. This single tube approach enables simultaneous analysis of multiple biomarkers to explore their potential as a liquid biopsy.

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“…The above-explained difference between more mesenchymal-like and more epithelial-like cancer cells together with this differentiation between active and passive intravasation gives rise to three entry modes of cancer cells into the vasculature, which are further explained in (Francart et al, 2018):…”

Section: Intravasationmentioning

confidence: 99%

A mathematical framework for modelling the metastatic spread of cancer

Franssen

Lorenzi

Burgess

et al. 2018

Preprint

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Cancer is a complex disease that starts with mutations of key genes in one cell or a small group of cells at a primary site in the body. If these cancer cells continue to grow successfully and, at some later stage, invade the surrounding tissue and acquire a vascular network (tumour-induced angiogenesis), they can spread to distant secondary sites in the body. This process, known as metastatic spread, is responsible for around 90% of deaths from cancer and is one of the so-called hallmarks of cancer.To shed light on the metastatic process, we present a mathematical modelling framework that captures for the first time the interconnected processes of invasion and metastatic spread of individual cancer cells in a spatially explicit manner -a multi-grid, hybrid, individual-based approach. This framework accounts for the spatio-temporal evolution of mesenchymal-and epithelial-like cancer cells, as well as MT1-MMP and MMP-2 dynamics, and interactions with the extracellular matrix.Using computational simulations, we demonstrate that our model captures all the key steps of the invasion-metastasis cascade, i.e. invasion by both heterogeneous cancer cell clusters and by single mesenchymal-like cancer cells; intravasation of these clusters and single cells both via active mechanisms mediated by matrix degrading enzymes (MDEs) and via passive shedding; circulation of cancer cell clusters and single cancer cells in the vasculature with the associated risk of cell death and disaggregation of clusters; extravasation of clusters and single cells; and metastatic growth at distant secondary sites in the body. By faithfully reproducing experimental results, our simulations support the evidence-based hypothesis that the membrane-bound MT1-MMP is the main driver of invasive spread rather than diffusible MDEs like MMP-2.Keywords Metastatic spread · Mathematical oncology · Tumour microenvironment · Individual-based model · Multi-grid framework LCF is funded by the Engineering and Physical Sciences Research Council (EPSRC). MAJC gratefully acknowledges the support of EPSRC Grant

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Epithelial–mesenchymal plasticity and circulating tumor cells: Travel companions to metastases

Cited by 96 publications

References 212 publications

Fibronectin in Cancer: Friend or Foe

Fibronectin in Cancer: Friend or Foe

Single tube liquid biopsy for advanced non‐small cell lung cancer

A mathematical framework for modelling the metastatic spread of cancer

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