Table 1.

Open questions in various areas of CTC cluster research

AreaOpen questions
  • Does breast density regulate “cell jamming” and CTC cluster formation?

  • Which tissue development/regeneration pathways support CTC cluster formation?

  • What multiple passive and/or active modalities of extracellular matrix, tumor microenvironment, and/or tumor cells support CTC cluster formation?

  • Are invadopodia-based and/or macrophage-dependent pathways involved in intravasation of CTC clusters into circulation?

  • Can disruption of CTC clusters in circulation prevent metastatic disease?

  • Are there any “druggable” and FDA-approved drugs that can dissociate CTC clusters?

  • What factors influence the structural plasticity (linear versus spherical) of CTC clusters and therefore their site of colonization?

Survival advantage
  • How does cellular plasticity confer survival advantage for CTC clusters? What are the molecular mechanism(s) that facilitate cellular plasticity within CTC clusters?

  • What are paracrine interactions between stromal/immune cells and tumor cells in heterotypic clusters? How are these interactions regulated?

  • What is the difference in cell metabolism between single CTCs and CTCs in clusters?

Metastatic potential
  • What is the expression of stem cell markers on CTCs within clusters? Where within CTC clusters are these potential tumor-initiating cells located?

  • What are the nontumor cell types (e.g. immune cells) within heterotypic CTC clusters? How do their interactions with tumor cells promote metastases?

  • Does the dormancy status of CTC clusters predict outcomes in patients/survivors?

  • How the CTC cluster–host interactions at the distant site facilitate metastasis?