Poster Presentation 35th Lorne Cancer Conference 2023

Characterising epithelial-to-mesenchymal transition in ovarian carcinosarcoma preclinical models to identify new targets for treatment (#156)

Anthony Hadla 1 2 , Daniel Brown 2 3 , Casey Anttila 3 , Ling Ling 3 , Daniela Zalcenstein 2 3 , Rory Bowden 3 , Gayanie Ratnayake 4 , Silvia Stoev 1 , Kathy Barber 1 , Tony Papenfuss 2 5 , Ramyar Molania 2 5 , Genevieve Dall 6 , Cassandra Vandenberg 1 2 , Holly Barker 1 2 , Clare Scott 1 2 4 6
  1. ACRF Cancer Biology and Stem Cells, Walter and Eliza Hall Institute (WEHI) , Melbourne, Victoria, Australia
  2. Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
  3. WEHI Advanced Genomics Facility, Walter and Eliza Hall Institute (WEHI), Melbourne, Victoria, Australia
  4. The Royal Women’s Hospital, Melbourne, Victoria, Australia
  5. Bioinformatics, Walter and Eliza Hall Institute (WEHI), Melbourne, Victoria, Australia
  6. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Ovarian carcinosarcoma (OCS) is a rare and aggressive subtype of ovarian cancer characterised by both epithelial carcinomatous and mesenchymal sarcomatous components1. The conversion theory of OCS posits that this biphasic nature arises via a sarcomatous transformation of carcinomatous cells. Support for the conversion theory comes from the elevated epithelial-to-mesenchymal transition (EMT) scores exhibited by OCS, compared to epithelial ovarian cancers, leading to EMT being identified as a potential driver of this sarcomatous transformation2.   

 A recent investigation using a skin squamous cell carcinoma mouse model identified six subpopulations that represented intermediate states of EMT. All six subpopulations co-expressed epithelial and mesenchymal markers and had unique functional characteristics3. These findings were conserved in a genetically engineered mouse model of OCS developed in our lab, with the six subpopulations able to be categorised into two groups: intermediate epithelial (IE) and intermediate mesenchymal (IM). IM cells displayed elevated spheroidogenic and clonogenic potentials when compared to IE cells, as would be expected of mesenchymal-like subpopulations. Interestingly, IM cells also exhibited increased sensitivity to eribulin mesylate, a chemotherapeutic known to reverse EMT2,4,5. Eribulin treatment resulted in a reduction of the spheroidogenic and clonogenic capacity of IM cells, shifting their functional potential away from that of a typical mesenchymal-like cell, characteristic of a mesenchymal-to-epithelial transition.  

 This investigation will utilise patient-derived xenografts (PDX) models of OCS to further elucidate the differences between the carcinomatous and sarcomatous components via single nuclear RNA (snRNA) sequencing and spatial transcriptomics. Moreover, the subpopulations representing EMT transition states in OCS will also be characterised through proteomic analysis and functional assays. This will identify signalling pathways that drive the sarcomatous transformation in OCS and the potential of targeting these genetic elements to disrupt OCS development will then be validated. Targeting these elements may result in a more epithelial tumour that exhibits increased susceptibility to standard first-line therapeutics, including chemotherapy.   

  1. Barker HE, Scott CL: Genomics of gynaecological carcinosarcomas and future treatment options. In: Seminars in cancer biology: 2020. Elsevier: 110-120.
  2. Ho, G. Y., Kyran, E. L., Bedo, J., Wakefield, M. J., Ennis, D. P., Mirza, H. B., ... & Barker, H. E. (2022). Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin. Cancer Research, 82(23), 4457-4473.
  3. Pastushenko I, Brisebarre A, Sifrim A, Fioramonti M, Revenco T, Boumahdi S, Van Keymeulen A, Brown D, Moers V, Lemaire S. (2018) Identification of the tumour transition states occurring during EMT. Nature. 556(7702):463-468.
  4. Kaul R, Risinger AL, Mooberry SL. (2019) Eribulin rapidly inhibits TGF-β-induced Snail expression and can induce Slug expression in a Smad4-dependent manner. British journal of cancer. 121(7):611-621.
  5. Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, Uesugi M, Agoulnik S, Taylor N, Funahashi Y. (2014) Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial–mesenchymal transition (EMT) to 79 mesenchymal–epithelial transition (MET) states. British journal of cancer. 110(6):1497-1505.