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Abstract Keratins are an integral part of cell structure and function. Here, it is shown that ectopic expression of a truncated isoform of keratin 81 (tKRT81) in breast cancer is upregulated in metastatic lesions compared to primary tumors and patient‐derived circulating tumor cells, and is associated with more aggressive subtypes. tKRT81 physically interacts with keratin 18 (KRT18) and leads to changes in the cytosolic keratin intermediate filament network and desmosomal plaque formation. These structural changes are associated with a softer, more elastically deformable cancer cell with enhanced adhesion and clustering ability leading to greater in vivo lung metastatic burden. This work describes a novel biomechanical mechanism by which tKRT81 promotes metastasis, highlighting the importance of the biophysical characteristics of tumor cells.

Using previously established CTC lines from breast cancer patients, we identified different morphometric subgroups of CTCs with one of them having the highest tumorigenic potential in vivo despite the slowest cell proliferation in vitro. This subgroup represents 32% of all cells and contains cells with small cell volume, large nucleus to cell, dense nuclear areas to the nucleus, mitochondria to cell volume ratios and rough texture of cell membrane and termed “Small cell, Large mitochondria, Rough membrane” (SLR). RNA-seq analyses showed that the SLR group is enriched in pathways and cellular processes related to DNA replication, DNA repair and metabolism. SLR upregulated genes are associated with poor survival in patients with ER+ breast cancer based on the KM Plotter database. The high tumorigenic potential, slow proliferation, and enriched DNA replication/repair pathways suggest that the SLR subtype is associated with stemness properties. Our new findings provide a simple image-based identification of CTC subpopulations with elevated aggressiveness, which is expected to provide a more accurate prediction of patient survival and therapy response than total CTC numbers. The detection of morphometric and transcriptomic profiles related to the SLR subgroup of CTCs also opens opportunities for potential targeted cancer treatment.