Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers

Klotz, Rémi; Thomas, Amal; Teng, Teng; Han, Sung Min; Iriondo, Oihana; Li, Lin; Restrepo-Vassalli, Sara; Wang, Alan; Izadian, Negeen; MacKay, Matthew; Moon, Byoung-San; Liu, Kevin J.; Ganesan, Sathish Kumar; Lee, Grace; Kang, Diane S.; Walmsley, Charlotte S.; Pinto, Christopher J.; Press, Michael F.; Lu, Wange; Lu, Janice; Juric, Dejan; Bardia, Aditya; Hicks, James; Salhia, Bodour; Attenello, Frank J.; Smith, Andrew D.; Yu, Min

doi:10.1158/2159-8290.cd-19-0384

Cited by 110 publications

(99 citation statements)

References 55 publications

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“…Gene expression profiling of CTCs in metastatic breast cancer suggests that CTCs that are associated with brain metastasis have increased activity of the Notch signaling pathways, along with an increase of pro-inflammatory chemokines (TNF, IL1β, and NF-κB), immunomodulatory networks (CXCL8, CXCR4, CD86), and mitogenic growth factors (PDGF-BB) [72]. In a separate study, a genome-wide assessment of CTC lines established from breast cancer patients suggests that copy-number gain of SEMA4D (a mediator of blood-brain barrier transmigration) and overexpression of MYC are novel markers for brain metastasis [41]. More generally, however, additional work will be needed to dissect the genetic requirements for organo-tropism of CTCs in several cancer types, and the identification of the fundamental networks that are involved might aid metastasis prevention strategies.…”

Section: Clinical Value Of Ctcsmentioning

confidence: 97%

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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Section: Clinical Value Of Ctcsmentioning

confidence: 97%

Tracking cancer progression: from circulating tumor cells to metastasis

2020

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“…Besides the elimination of CTCs, blocking metastatic progression could be more effective in the case of killing primary cancer cells that are a source of metastasis-initiating CTCs. As suggested by Klotz and colleagues [94], targeting of SEMA4D and GPX1 in primary tumors can be a potential therapeutic approach for the abrogating ability of CTCs to colonize the brain and for preventing brain metastasis in BC patients. This therapy would be an innovative strategy to prevent metastasis at an early stage and even before the tumor is clinically diagnosed.…”

Section: Discussionmentioning

confidence: 97%

“…Moreover, amplification of 8q24.21, as well as chromosome 9q in CTCs, was found to be a clonally selected event for the initiation of brain metastasis in BC. It turned out that overexpression of semaphorin-4D (9q) promoted CTCs transmigration through the blood-brain barrier whereas MYC (8q24.21) facilitated the adaptation of tumor cells to the activated brain microenvironment via upregulation of GPX1 enzyme [94].…”

Section: Genetic Heterogeneitymentioning

confidence: 99%

Heterogeneity of Circulating Tumor Cells in Breast Cancer: Identifying Metastatic Seeds

Menyailo

Tretyakova

Denisov

2020

IJMS

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Metastasis being the main cause of breast cancer (BC) mortality represents the complex and multistage process. The entrance of tumor cells into the blood vessels and the appearance of circulating tumor cells (CTCs) seeding and colonizing distant tissues and organs are one of the key stages in the metastatic cascade. Like the primary tumor, CTCs are extremely heterogeneous and presented by clusters and individual cells which consist of phenotypically and genetically distinct subpopulations. However, among this diversity, only a small number of CTCs is able to survive in the bloodstream and to form metastases. The identification of the metastasis-initiating CTCs is believed to be a critical issue in developing therapeutic strategies against metastatic disease. In this review, we summarize the available literature addressing morphological, phenotypic and genetic heterogeneity of CTCs and the molecular makeup of specific subpopulations associated with BC metastasis. Special attention is paid to the need for in vitro and in vivo studies to confirm the tumorigenic and metastatic potential of metastasis-associating CTCs. Finally, we consider treatment approaches that could be effective to eradicate metastatic CTCs and to prevent metastasis. with partial EMT) and high metastatic potential [18,19]. In addition to the EMT features, CTCs can also exhibit stem-like characteristics, particularly self-renewal and multilineage differentiation ability [20].There is still no highly effective therapy for metastatic BC. Therapy targeted directly against CTCs seems to be promising. To date, various molecular markers of CTCs and their therapeutic targets that can be used to prevent cancer progression are known [21]. In addition, different therapeutic approaches for the elimination of CTCs have been proposed; however, none of them has been clinically approved. The reason is that the molecular and biological characteristics of the primary tumor and CTCs are not well understood. In our opinion, the main focus should be on the search for specific populations of CTCs responsible for the development of metastasis and the study of their molecular makeup. These cells could be the primary therapeutic target for preventing metastatic progression [22]. Recent advances in single-cell sequencing allow one to determine the population structure of CTCs and identify metastasis-initiating cells [23][24][25][26], while in vitro and in vivo studies provide data on their proliferative, apoptotic, invasive, and other phenotypes [27].Nowadays, despite a large number of studies on CTC heterogeneity and their metastatic potential, there are still no generally accepted and universal markers of CTCs prone to metastasis. In this review, we systematized the data on metastatic CTCs in terms of their morphological, phenotypic, and genetic heterogeneity in BC, as well as emphasized the importance of studying these cells in vitro and in vivo and developing therapeutic approaches for their elimination to prevent metastasis. CTC Heterogeneity and the Molecular Makeup...

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“…Several studies have shown successful ex vivo expansion of CTCs isolated from patients with breast 7 , colorectal 8 , and prostate 9 cancer. These CTC lines have provided sufficient amounts of material for many analyses, including xenograft analysis and drug susceptibility assessment 7,10 .…”

Section: Introductionmentioning

confidence: 99%

“…We previously reported a method for the ex vivo culture of CTCs derived from metastatic breast cancer patients and established several CTC lines 7 . These CTC lines exhibit metastatic potential that represents the major metastatic lesions in corresponding patients 10 . In addition, they are cultured in suspension and physiological oxygen level, mimicking the environment of CTCs in venous blood circulation.…”

Section: Introductionmentioning

confidence: 99%

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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Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers

Cited by 110 publications

References 55 publications

Tracking cancer progression: from circulating tumor cells to metastasis

Tracking cancer progression: from circulating tumor cells to metastasis

Heterogeneity of Circulating Tumor Cells in Breast Cancer: Identifying Metastatic Seeds

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

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