In this review, we highlight recent work that offers novel insights into mechanisms that can contribute to cluster formation and ascribe heightened metastatic potential to them.

We then focus on a highly aggressive disease—Inflammatory Breast Cancer (IBC)—that forms clustered lymphatic emboli as a major means of metastasis and note several lines of evidence suggesting distant metastases also occur via clusters.

b Conditions that can foster formation of CTC clusters—(i) state of individual cells to be able to both migrate and adhere (i.e., hybrid E/M phenotype), and (ii) cell-cell communication among these cells to spatially rearrange to form a cluster.

Although rare as compared to individually migrating CTCs, clusters of CTCs can individually form up to 50-times more metastases.

clearly suggesting that clustered migration provides emergent, i.e., or ‘whole is greater than sum of its parts’, advantage for metastasis.

Therefore, these tumor buds were proposed to exhibit a ‘partial EMT’ or a hybrid epithelial/mesenchymal (E/M) phenotype instead of a completely mesenchymal phenotype.

but the role of EMT in metastasis remains controversial because a genetic knockdown of two transcription factors inducing EMT—TWIST and SNAIL-in genetically engineered mouse models was recently shown to be dispensable for metastasis.

From a pathophysiological point of view, mastitis reflects a variety of underlying etiologies.

It can be due to non-infectious inflammation, infection (generally of bacterial origin) but can also be caused by inflammation resulting from malignant tumor growth.

The clusters of circulating tumor cells, although many fewer in number, possess much higher metastatic potential as compared to that of individual circulating tumor cells.

In this review, we highlight recent insights into molecular mechanisms that can enable the formation of these clusters—(a) hybrid epithelial/mesenchymal phenotype of cells that couples their ability to migrate and adhere, and (b) intercellular communication that can spatially coordinate the cluster formation and provide survival signals to cancer cells.

The prognostic value of CTC clusters can be gauged by clinical observations, where patients with CTC clusters circulating in their bloodstream have significantly worse overall and progression-free survival than those in whom only individually migrating single CTCs are found.

Therefore, identifying the molecular mechanisms that can form and maintain these clusters is of paramount importance in tackling metastasis.

Mastitis always manifests clinically by three cardinal signs of inflammation, which are redness, heat and pain.