Poster Presentation 36th Lorne Cancer Conference 2024

Characterising epithelial-to-mesenchymal transition in ovarian carcinosarcoma preclinical models to identify new targets for treatment (#120)

Anthony Hadla 1 2 , Casey Anttila 3 , Daniel Brown 2 3 , Ling Ling 3 , Daniela Zalcenstein 2 3 , Rory Bowden 3 , Alexandra Garnham 4 , Gayanie Ratnayake 5 , Silvia Stoev 1 , Kathy Barber 1 , Tony Papenfuss 2 6 , Cassandra Vandenberg 1 2 , Holly Barker 1 2 , Clare Scott AM 1 2 5 7
  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. Bioinformatics Support Facility, Walter and Eliza Hall Institute (WEHI), Melbourne, Victoria, Australia
  5. The Royal Women’s Hospital, Melbourne, Victoria, Australia
  6. Bioinformatics, Walter and Eliza Hall Institute (WEHI), Melbourne, Victoria, Australia
  7. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Ovarian carcinosarcoma (OCS) is a rare and aggressive subtype of ovarian cancer, characterised by the presence of both epithelial (carcinomatous) and mesenchymal (sarcomatous) components(1). We and others have produced data supporting the conversion theory of development, where the sarcoma component arises from the carcinoma component via epithelial-to-mesenchymal transition (EMT)(2-4). Platinum- and taxane-based chemotherapy is not as effective against OCS, compared to high grade serous ovarian carcinoma (HGSOC), the most common subtype of ovarian cancer. As OCS and HGSOC have similar aberrations, it is likely that the sarcoma component in OCS causes the disparity in treatment response(5).

Partial EMT (pEMT), where cells gain characteristics associated with mesenchymal cells whilst retaining expression of epithelial markers, is believed to be more common in cancer than a full EMT(6). Cells in this state have also been shown to contribute more significantly to metastasis, compared to full EMT cells, and have an increased capacity to revert to an epithelial state via a mesenchymal-to-epithelial transition (MET), making them ideal targets for treatment strategies(6,7). Therefore, we are using single nuclear RNA sequencing (snRNAseq) and spatial transcriptomics to study patient-derived xenograft (PDX) models of OCS, to analyse gene expression differences between the carcinomatous and sarcomatous regions with a particular focus on the cells transitioning between carcinoma and sarcoma. We have completed a pilot study of four PDX tumours and are using common epithelial and mesenchymal markers, such as CDH1, CDH2, VIM, ZEB1 and SNAI1, to distinguish more carcinomatous and sarcomatous regions of the tumour in the spatial transcriptomics data. We will then use snRNAseq data to identify genes highly expressed in the pEMT cells. Concurrently, we have been analysing the expression of pEMT markers identified in other cancer types in our OCS models using flow cytometry(8). Western blotting and in vitro functional assays are being carried out on these sorted subpopulations to further characterise this process in OCS.  

By targeting the key elements involved in the development of the sarcomatous component of OCS we hope to increase the epithelial nature of the tumour. This may make the tumour more susceptible to standard first-line platinum- and taxane-based chemotherapy.  

  1. Barker, H. E., & Scott, C. L. (2020, April). Genomics of gynaecological carcinosarcomas and future treatment options. In Seminars in cancer biology (Vol. 61, pp. 110-120). Academic Pre
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  3. del Carmen, M. G., Birrer, M., & Schorge, J. O. (2012). Carcinosarcoma of the ovary: a review of the literature. Gynecologic oncology, 125(1), 271-277.
  4. Schipf, A., Mayr, D., Kirchner, T., & Diebold, J. (2008). Molecular genetic aberrations of ovarian and uterine carcinosarcomas—a CGH and FISH study. Virchows Archiv, 452, 259-268.
  5. Hollis, R. L., Croy, I., Churchman, M., Bartos, C., Rye, T., Gourley, C., & Herrington, C. S. (2022). Ovarian carcinosarcoma is a distinct form of ovarian cancer with poorer survival compared to tubo-ovarian high-grade serous carcinoma. British Journal of Cancer, 127(6), 1034-1042.
  6. Lüönd, F., Sugiyama, N., Bill, R., Bornes, L., Hager, C., Tang, F., ... & Christofori, G. (2021). Distinct contributions of partial and full EMT to breast cancer malignancy. Developmental cell, 56(23), 3203-3221.
  7. Burkhardt, D. B., San Juan, B. P., Lock, J. G., Krishnaswamy, S., & Chaffer, C. L. (2022). Mapping phenotypic plasticity upon the cancer cell state landscape using manifold learning. Cancer discovery, 12(8), 1847-1859.
  8. Pastushenko, I., Brisebarre, A., Sifrim, A., Fioramonti, M., Revenco, T., Boumahdi, S., ... & Blanpain, C. (2018). Identification of the tumour transition states occurring during EMT. Nature, 556(7702), 463-468.