Ovarian carcinosarcoma (OCS) is an aggressive subtype of ovarian cancer characterised by epithelial carcinomatous and mesenchymal sarcomatous components1. The conversion theory of OCS development posits the existence of a single progenitor cell giving rise to solely carcinomatous cells, which then undergo an independent transdifferentiation process to establish the biphasic tumour. Epithelial-to-mesenchymal transition (EMT) may be implicated in this sarcomatous transformation2.
Previous investigations analysing other cancer models identified numerous EMT transition states with unique functional potentials3. As such, I attempted to identify these subpopulations in OCS and characterise their expression of epithelial and mesenchymal markers, as well as their clonogenic capacities. Moreover, the microtubule inhibitor, Eribulin mesylate, shown by others to reverse EMT, was used to determine the functional effects of EMT inhibition on the different subpopulations representing EMT transition states in OCS4. EMT inhibition was expected to shift the more mesenchymal subpopulations towards epithelial phenotypes, resulting in reduced clonogenicity and cell migration.
This investigation, using tumours derived from a genetically engineered mouse model (GEMM) of OCS, identified six subpopulations representing various EMT transition states. Rather than being characterised as existing on a sliding scale of more epithelial to more mesenchymal as expected, the six subpopulations could be categorised into two groups: intermediate epithelial (IE) and intermediate mesenchymal (IM). Eribulin treatment reduced the spheroidogenic and clonogenic potential of IM cells, whereas IE cells were relatively unaffected. Eribulin was also found to reduce the formation of cellular protrusions associated with migration, indicative of an inhibitory effect on this aspect of cancer metastasis. Overall, these data indicate that targeting the mesenchymal components of OCS may be an effective therapeutic strategy.