Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis

Aceto, Nicola; Bardia, Aditya; Miyamoto, David T.; Donaldson, Maria C.; Wittner, Ben S.; Spencer, Joel A.; Yu, Min; Pely, Adam; Engstrom, Amanda; Zhu, Huili; Brannigan, Brian W.; Kapur, Ravi; Stott, Shannon L.; Shioda, Toshi; Ramaswamy, Sridhar; Ting, David T.; Lin, Charles P.; Toner, Mehmet; Haber, Daniel A.; Maheswaran, Shyamala

doi:10.1016/j.cell.2014.07.013

Cited by 2,086 publications

(2,571 citation statements)

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“…Interestingly, the circulating clusters in breast cancer also show enhanced signaling through catenin (24), a molecule also activated in several of our metastases. The phenomenon reported here in human melanoma patients may explain certain patterns of disease relapse of patients treated with targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination

Sanborn¹,

Chung

Purdom

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

155

133

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Melanoma is difficult to treat once it becomes metastatic. However, the precise ancestral relationship between primary tumors and their metastases is not well understood. We performed whole-exome sequencing of primary melanomas and multiple matched metastases from eight patients to elucidate their phylogenetic relationships. In six of eight patients, we found that genetically distinct cell populations in the primary tumor metastasized in parallel to different anatomic sites, rather than sequentially from one site to the next. In five of these six patients, the metastasizing cells had themselves arisen from a common parental subpopulation in the primary, indicating that the ability to establish metastases is a late-evolving trait. Interestingly, we discovered that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct. Such establishment of metastases by multiple tumor subpopulations could help explain why identical resistance variants are identified in different sites after initial response to systemic therapy. One primary tumor harbored two subclones with different oncogenic mutations in CTNNB1, which were both propagated to the same metastasis, raising the possibility that activation of wingless-type mouse mammary tumor virus integration site (WNT) signaling may be involved, as has been suggested by experimental models.A s in many other solid tumors, melanoma metastases often first present in lymph nodes in the draining area of the primary, whereas distant metastases tend to appear later (1). The conclusion that melanoma follows a linear progression from primary tumor to regional to distant metastases has supported preemptive surgical removal of regional lymph nodes with curative intent (2). However, several observations suggest that distant metastases are seeded early, contemporaneously with regional metastases. Patients who undergo resection of lymph node basins harboring metastasis do not experience a significantly extended life expectancy (3, 4). Furthermore, circulating melanoma cells were detected in the blood of 26% of patients who only have metastases detected regionally (5, 6).Melanoma, like other cancers, arises and evolves through the accumulation of genetic alterations within tumor cells (7-9). Comparing somatic mutations in primary tumor and regional and distant metastases from the same patient can provide insight into the phylogenetic relationships between these distinct tumor cell populations and the order of metastatic dissemination (8, 10). These analyses may also establish whether cells in the primary tumor that metastasize acquired this ability to disseminate and seed other anatomic sites by a newly acquired genetic alteration, or whether metastatic colonization is simply a stochastic process of which all cells in the primary are capable but few succeed.Using whole-exome sequencing (for discovery) and targeted sequencing (for validation), we analyzed mutation patterns of primary melanomas and two or more metastases in each of e...

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Section: Discussionmentioning

confidence: 99%

Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination

Sanborn¹,

Chung

Purdom

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

155

133

View full text Add to dashboard Cite

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“…Specifically, we expect that Notch-Jagged signaling between these cells helps them to maintain that otherwise metastable hybrid epithelial/mesenchymal (E/M) phenotype. As has been recently observed in clusters of circulating tumor cells (CTCs), these hybrid E/M cells mediate tumor aggression and invasion (58), and can have more metastatic potential than the CTCs moving individually (59,60). Future theoretical studies should investigate the coupling of EMT and Notch-Delta-Jagged signaling to explore this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

Boareto

Jolly

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

141

226

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Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.

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“…18,19 Analysis of circulating tumor cells from blood samples and surgically removed samples often reveal circulating tumor cell clusters in addition to single migratory cells. 20 Circulating or migrating tumor cells need to undertake survival programs during and after migration through blood, lymphatic vessels or other conduits, followed by the need to proliferate and often reconfigure the microenvironment in a new location. 21 By what molecular mechanism does stabilization of E-cadherin influence migration?…”

Section: E969112-4mentioning

confidence: 99%

Loss of E-cadherin and epithelial to mesenchymal transition is not required for cell motility in tissues or for metastasis

et al. 2014

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Loss of E-cadherin has been long considered to be a major hallmark of epithelial-mesenchymal transition (EMT) and has been reported in various cancers. P120 catenin regulates E-cadherin stability on the cell surface and also plays a role in intracellular signaling by modulating nuclear transcription. We recently characterized the nature of interactions between p120 catenin and Mucin 1 (MUC1) in pancreatic cancer. Expression of different p120 catenin isoforms with and without MUC1 induced distinct morphologies, cell adhesion, and dynamic properties of motility along with different metastatic properties in vivo. Re-expression of p120 catenin isoform 3A in the context of MUC1 expression in a p120 catenin-deficient cell line stabilized expression of E-cadherin. However, orthotopic implantation of tumors using this stable cell line produced large metastatic lesions to the liver, which exceeded the volume of the primary tumor, suggesting down regulation of E-cadherin is not required for tumor metastasis. Here we extend those studies by showing that ectopic expression of E-cadherin does not block in vitro invasion of the pancreatic cancer cells, and instead accelerated the rate of tumor invasion. Furthermore, results from 23 cases of human pancreatic primary tumor specimens revealed that most tumors exhibiting metastatic activity retained epithelial morphology and E-cadherin gene expression. Our results indicate that loss of E-cadherin and EMT are not required for metastasis and that an epithelial morphology can be maintained during the process of tumor cell movement.

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Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis

Cited by 2,086 publications

References 50 publications

Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination

Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination

Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

Loss of E-cadherin and epithelial to mesenchymal transition is not required for cell motility in tissues or for metastasis

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