Fallopian tube/ovarian carcinosarcoma (FT-OCS) is a heterogeneous rare cancer containing both carcinomatous and sarcomatous components. This biphasic tumour is associated with high rates of metastatic disease and treatment poses significant challenges given the lack of evidence-based care, compounded by the rarity of the disease. For this reason, a genetically engineered mouse model (GEMM) emulating the underlying molecular biology of human FT-OCS would be extremely useful for investigating potential therapies.
We generated a fallopian tube-derived GEMM tumour exhibiting the classical histological features of FT-OCS. This FT-OCS arose after intra-bursal transplantation of a transgenic mouse fallopian tube (FT) over-expressing doxycyline-regulated Lin28b and SV40Tag, targeted by the Pax8 promoter to the FT secretory cells. Subsequently, an adherent cell line was generated from this FT-OCS. The FT-OCS responded poorly to standard platinum chemotherapy (cisplatin), both in vivo and in vitro. Excitingly, we observed impressive sensitivity of the FT-OCS cell line to the microtubule inhibitor, vinorelbine, which was further validated by in vivo treatment of three isogenic, yet distinct, FT-OCS lineages. Histological characterisation of the FT-OCS lineages demonstrated the selection of the sarcomatous component during transplantation. Gene expression profiling using RNA sequencing determined expression signatures that highlight differences between the GEMM cohort lineages, as well as the upregulation of genes characteristic of the human disease. As such, this model of FT-OCS may provide a versatile and essential resource that will aid in the repurposing and identification of therapies.