Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding

Gkountela, Sofia; Castro-Giner, Francesc; Szczerba, Barbara M.; Vetter, Marcus; Landin, Julia; Scherrer, Ramona; Krol, Ilona; Scheidmann, Manuel C.; Beisel, Christian; Stirnimann, Christian U.; Kurzeder, Christian; Heinzelmann‐Schwarz, Viola; Rochlitz, Christoph; Weber, Walter; Aceto, Nicola

doi:10.1016/j.cell.2018.11.046

Cited by 664 publications

(659 citation statements)

References 69 publications

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“…The question of whether different cancers use a unique set of stemness molecules to induce cluster formation (such as CD24 in the current study) is worth further investigation. A recent study reported that CTC clusters showed a profile of overmethylation that promoted cancer stemness of the patient breast cancer cells, supporting our hypothesis. Therefore, our study provides a good in vitro model to study the relationship between cancer stemness and cluster formation and metastasis in colon cancer.…”

Section: Discussionsupporting

confidence: 88%

“…24 Indeed, some recent studies have demonstrated that breast cancer CTC clusters possess much high metastatic potential and were more tumorigenic and resistant to apoptosis. 4,25 Therefore, the clustering process can be regarded as an initial mechanism for cancer cells to maintain their tumorigenicity during development, which is particularly relevant to CTCs during circulation and initiating new tumours at secondary sites. Understanding this mechanism is therefore essential for developing effective intervention therapies of metastasis in cancer.…”

Section: Discussionmentioning

confidence: 99%

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Cancer stemness contributes to cluster formation of colon cancer cells and high metastatic potentials

Kapeleris

Zou

Yan

et al. 2020

Clin Exp Pharma Physio

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The ability of cancer cells to form clusters is a characteristic feature in the development of metastatic tumours with drug resistance. Several studies demonstrated that clusters of circulating tumour cells (CTCs) have a greater metastatic potential to establish new tumours at secondary sites than single CTCs. However, the mechanism of cluster formation is not well understood. In this study, we investigated whether cancer stemness would contribute to cluster formation. We used a tumour sphere culture method to enrich cancer stem cells (CSCs) from colon cancer cells and found that during the second generation of sphere culture, clusters (between 3 and 5 cells) formed within the first 24 hours, whereas the rest remained as single cells. The clusters were analysed for stemness and metastatic potential, including gene expressions for cancer stemness (CD133 and Lgr5), epithelial‐mesenchymal transition (E‐cadherin and TGF‐β 1‐3) and hypoxia‐induced factors (HIF‐1α and HIF‐2α). The results showed that the clusters expressed higher levels of these genes and colon CSC surface markers (including CD24, CD44 and CD133) than the single cells. Among these markers, CD24 seemed the major contributor linking the cells into the clusters. These clusters also showed a stronger ability to both form colonies and migrate. Our data collectively suggest that colon cancer stemness contributes to cluster formation and that clustered cells exhibit a great metastatic potential. Our study thus provides a method to study the CTC clusters and derive insight into oncogenesis and metastasis.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Cancer stemness contributes to cluster formation of colon cancer cells and high metastatic potentials

Kapeleris

Zou

Yan

et al. 2020

Clin Exp Pharma Physio

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“…The prognostic value of CTCs has been proven in abundant studies, especially in patients with advanced BC. 2,28,29 However, there is still a lack of consistent conclusions regarding whether CTCs could be applied as an independent predictor of NCT effectiveness in early BC. In this study, we used the CanPatrol technique to determine the relationship circulation.…”

Section: Discussionmentioning

confidence: 99%

Prospective study of the relevance of circulating tumor cell status and neoadjuvant chemotherapy effectiveness in early breast cancer

Fang

Zhang

et al. 2020

Cancer Medicine

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Although unequivocal evidence has shown the prognostic relevance of circulating tumor cells (CTCs) in patients with metastatic breast cancer (MBC), less evidence is available for its significance in neoadjuvant chemotherapy (NCT) in early breast cancer (BC). Here we conducted an analysis of individual data from 86 patients confirmed as invasive BC by core‐needle biopsy in Zhejiang Provincial People's Hospital between June 2013 and January 2017. The CTCs were assessed at the time after diagnosis and before surgery with the CanPatrol technique. The median follow‐up duration was 46.3 months. CTCs were detected in 37.2% of all patients (29/78) at baseline, and the presence of CTCs was associated with tumor size, tumor stage, and molecular classification. After NCT, the CTC‐positive patients were dropped from 29 to 8, and the EC‐T (epirubicin/cyclophosphamide followed by docetaxel) and TEC (docetaxel/epirubicin/cyclophosphamide) strategies reduce CTC‐positive patients from 16 to 3 and 13 to 5, respectively. The CTC‐negative conversion rates were similar in ER/PR+ HER2+ (5/7, 71.4%), ER/PR− HER2+ (8/11, 72.7%), and TNBC (7/10, 70%) during NCT. In addition, we explored the association between CTC‐negative conversion and objective response rate (partial response and complete response, ORR) and pathological complete response rate (pCR), and our results indicate that ORR was higher in patients with positive CTCs and converted to negative after NCT (ORR, P = .013; pCR, P = .0608). Our study preliminarily highlights the relevance of CTC status and NCT effectiveness in early BC using the CanPatrol system.

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“…Other data suggested that intravascular aggregation and proliferation could be excluded as potential sources of tumour clusters due to the unfavourable conditions present in the bloodstream [9]. Very recently, Gkountela et al [10] demonstrated that -in strong contrast to circulating tumour cells -the pattern of transcription factors in tumour clusters reveals similarities to embryonic stem cells along with increased proliferation. However, some cluster processes are still unknown regarding their genesis,transit and settlement and about the precise cellular and molecular mechanism.…”

Section: Introductionmentioning

confidence: 99%

In vivo detection of circulating tumour cell clusters by photodiagnostic spectroscopy

Schikora

2020

Photodiagnosis and Photodynamic Therapy

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A B S T R A C TBackground: We demonstrate a new diagnostic method, Photodiagnostic Infrared Spectroscoppy (PDIS), which is able to detect circulating tumor clusters and circulating tumor cells in the circulatory system. Methods: The PDIS method is based on photodiagnostic physics and high resolution spectroscopy and is using calibrated spectroscopic data for the diagnostic analysis of the blood screening spectra. Using Confocal Laser Scanning Mikcroscopy the Indocyangreen-uptake of different cell lines of breast cancer cells is studied. Results: The PDIS supplies calibrated diagnostic data about the presence or absence of CTCs and CTC clusters in the bloodstream with a sensitivity of 98 %. Therefore, the PDIS is suited to control the blood of cancer patients with respect of CTC and CTC clusters with an resolution of one CTC and one CTC cluster per blood volume. PDIS distinguishes the different phenotypes of CTC clusters. Conclusion: Circulating tumor cell slusters play a key role in the metastatic process and are formed only in solid tumors, they are appropriate objects to validate cancer treatments and to recognice cancer formation. The PDIS is a calibrated diagnostic method which allows to evaluate the results of solid tumor treatments and of chemotherapy treatments and to optimize the individual cancer treatment strategies.

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Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding

Cited by 664 publications

References 69 publications

Cancer stemness contributes to cluster formation of colon cancer cells and high metastatic potentials

Cancer stemness contributes to cluster formation of colon cancer cells and high metastatic potentials

Prospective study of the relevance of circulating tumor cell status and neoadjuvant chemotherapy effectiveness in early breast cancer

In vivo detection of circulating tumour cell clusters by photodiagnostic spectroscopy

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