The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. It is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors.
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Circulating tumor cells are cancer cells that detach from the primary tumor and enter the blood circulation, on their way to initiate a metastasis at a distant site. When traveling in the blood as clusters, circulating tumor cells are endowed with an extraordinary potential to efficiently initiate a metastasis. While very rare compared to blood cells in the bloodstream (1 circulating tumor cell per billion blood cells), capturing of circulating tumor cell clusters is now possible through the use of specialized microfluidic technologies, thus enabling scientists to study their biology and vulnerabilities.
S. Gkountela et al. Cell. 2019 Jan 10;176(1-2):98-112.e14.
Summary of the findings
A better understanding of the molecular features that characterize metastatic cancer cells is of exceptional importance for the development of new cancer therapies. We set out to perform a genome-wide DNA methylation analysis of circulating tumor cells (CTCs) from both breast cancer patients and mouse models, aiming to define the methylation landscape of metastatic precursors in circulation. Surprisingly, when comparing the methylome of single and clustered CTCs, we found that highly metastatic CTC clusters display hypomethylation at binding sites for critical stemness- and proliferation-associated transcription factors such as OCT4, SOX2, NANOG and SIN3A. These results suggest that CTC clustering is linked to DNA methylation remodeling, with significant impact on metastasis-seeding ability. Importantly, when dissociating CTC clusters through CRISPR-mediated cell-cell junction knockout or treatment with CTC cluster-dissociating compounds (identified through a screen with 2’486 FDA-approved molecules), we observed re-methylation of critical transcription factor binding sites and suppression of metastasis-forming ability in mouse models. Our findings clearly link cell-cell junction formation with changes in DNA methylation that promote stemness and metastasis, and highlight an opportunity for anti-cluster therapies in the treatment of metastatic cancers. These results are rapidly translating into the clinical setting, as we conducting a proof-of-concept clinical trial to evaluate CTC cluster dissociation approaches in breast cancer patients.
