Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization

Labuschagne, Christiaan F.; Cheung, Eric C.; Blagih, Julianna; Domart, Marie-Charlotte; Vousden, Karen H.

doi:10.1016/j.cmet.2019.07.014

Cited by 172 publications

(120 citation statements)

References 46 publications

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“…We noted that the constraints on proliferation for those CTCs able to grow eventually are significantly reduced once single CTCs achieve a critical mass. This suggests that cell-cell contact mitigates stress, in line with recent findings on the survival advantage of CTC clusters 23,27 .This also indicates that compounds promoting CTC proliferation can be applied in the short term, and need not confound the downstream characterization of CTC biology. Our…”

Section: Discussionsupporting

confidence: 83%

A small molecule screen identified N-Acetyl-L-cysteine for promotingex vivogrowth of single circulating tumor cells

Teng

Kamal

Iriondo

et al. 2020

Preprint

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Circulating tumor cells (CTCs) can be isolated via a minimally invasive blood draw and are considered a liquid biopsy of their originating solid tumors. CTCs contain a small subset of metastatic precursors that can form metastases in secondary organs, and provide a resource to identify mechanisms underlying metastasis-initiating properties. Despite technological advancements that allow for highly sensitive approaches of detection and isolation, CTCs are very rare and often present as single cells, posing an extreme challenge for ex vivo expansion after isolation. Here, using previously established patient-derived CTC lines, we performed a small molecule drug screening to identify compounds that can improve ex vivo culture efficiency for single CTCs. We found that N-acetylcysteine (NAC) and other antioxidants can promote ex vivo expansion of single CTCs, by reducing oxidative and other stress particularly at the initial stage of single cell expansion. RNA-seq analysis of growing clones and non-growing clones confirmed the effect by NAC, but also indicate that NAC-induced decrease in oxidative stress is insufficient for promoting proliferation of a subset of cells with heterogeneous quiescent and senescent features. Despite the challenge in expanding all CTCs, NAC treatment lead to establishment of single CTC clones that have similar tumorigenic features, which will facilitate future functional analyses.

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Section: Discussionsupporting

confidence: 83%

A small molecule screen identified N-Acetyl-L-cysteine for promotingex vivogrowth of single circulating tumor cells

Teng

Kamal

Iriondo

et al. 2020

Preprint

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show abstract

“…Although the existence of CTC clusters has been known for decades [51][52][53][54][55], the biological mechanisms behind their formation, survival, dissemination, and superior metastatic ability are only partially understood [48]. Recently, an in vitro study has suggested that cell aggregation might protect the clustered cells from reactive oxygen species (ROS) that are produced in response to detachment from the extracellular matrix, by inducing hypoxiainducible factor 1-alpha (Hif1α)-mediated mitophagy of ROS-producing mitochondria [56]. The consequences of this response are a metabolic switch to glycolysis and an increment of survival and metastatic capacity.…”

Section: Single Ctcs Versus Ctc Clustersmentioning

confidence: 99%

Tracking cancer progression: from circulating tumor cells to metastasis

2020

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The analysis of circulating tumor cells (CTCs) is an outstanding tool to provide insights into the biology of metastatic cancers, to monitor disease progression and with potential for use in liquid biopsy-based personalized cancer treatment. These goals are ambitious, yet recent studies are already allowing a sharper understanding of the strengths, challenges, and opportunities provided by liquid biopsy approaches. For instance, through single-cellresolution genomics and transcriptomics, it is becoming increasingly clear that CTCs are heterogeneous at multiple levels and that only a fraction of them is capable of initiating metastasis. It also appears that CTCs adopt multiple ways to enhance their metastatic potential, including homotypic clustering and heterotypic interactions with immune and stromal cells. On the clinical side, both CTC enumeration and molecular analysis may provide new means to monitor cancer progression and to take individualized treatment decisions, but their use for early cancer detection appears to be challenging compared to that of other tumor derivatives such as circulating tumor DNA. In this review, we summarize current data on CTC biology and CTC-based clinical applications that are likely to impact our understanding of the metastatic process and to influence the clinical management of patients with metastatic cancer, including new prospects that may favor the implementation of precision medicine. Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…It has been suggested that common hexoses other than glucose, such as galactose and fructose, are also involved in the growth and metastasis of cancer cells. Galactose has been shown to induce OXPHOS-dependent metabolism and suppress the growth and metastasis of cancer cells [ 84 , 85 , 86 ]. On the other hand, fructose has been shown to promote liver metastasis in colon cancer and breast cancer [ 87 ].…”

Section: Tumor Metabolismmentioning

confidence: 99%

“…The antioxidant system is enhanced in circulating cancer cells in order to remove the increased amounts of ROS resulting from the activation of OXPHOS [ 99 ]. In addition, to prevent cell death due to the ROS, some cancer cells create a hypoxic environment by clustering, and induce mitophagy and glycolytic metabolism [ 84 ]. Thus, the metabolic reprogramming of cancer cells found in the blood circulation plays an important role in determining the metastatic target and the formation of metastatic foci [ 100 , 101 , 102 ].…”

Section: Tumor Metabolismmentioning

confidence: 99%

The Metabolic Heterogeneity and Flexibility of Cancer Stem Cells

Tanabe

Sahara

2020

Cancers

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Numerous findings have indicated that CSCs, which are present at a low frequency inside primary tumors, are the main cause of therapy resistance and cancer recurrence. Although various therapeutic methods targeting CSCs have been attempted for eliminating cancer cells completely, the complicated characteristics of CSCs have hampered such attempts. In analyzing the biological properties of CSCs, it was revealed that CSCs have a peculiar metabolism that is distinct from non-CSCs to maintain their stemness properties. The CSC metabolism involves not only the catabolic and anabolic pathways, but also intracellular signaling, gene expression, and redox balance. In addition, CSCs can reprogram their metabolism to flexibly respond to environmental changes. In this review, we focus on the flexible metabolic mechanisms of CSCs, and highlight the new therapeutics that target CSC metabolism.

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Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization

Cited by 172 publications

References 46 publications

A small molecule screen identified N-Acetyl-L-cysteine for promotingex vivogrowth of single circulating tumor cells

A small molecule screen identified N-Acetyl-L-cysteine for promotingex vivogrowth of single circulating tumor cells

Tracking cancer progression: from circulating tumor cells to metastasis

The Metabolic Heterogeneity and Flexibility of Cancer Stem Cells

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