Poster Presentation 37th Lorne Cancer Conference 2025

Characterising epithelial-to-mesenchymal transition in ovarian carcinosarcoma preclinical models to identify new targets for treatment (#149)

Anthony Hadla 1 2 , Casey Anttila 3 , Daniela Zalcenstein 2 3 , Rory Bowden 3 , Silvia Stoev 1 , Kathy Barber 1 , Yunshun Chen 1 2 , Xueyi Dong 1 , Tony Papenfuss 2 4 , Andrew Farrell 1 , Cassandra Vandenberg 1 2 , Holly Barker 1 2 , Clare Scott AM 1 2 5 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. Bioinformatics, Walter and Eliza Hall Institute (WEHI), Melbourne, Victoria, Australia
  5. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  6. The Royal Women’s Hospital, 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 components1. We, and others, have provided recent evidence that these tumours arise from a single progenitor cell, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT)2-4. We found that the carcinomatous cells of OCS exhibited increased expression of EMT-related genes compared to epithelial ovarian cancers, indicating that these cells were primed to undergo EMT2. First-line treatment options, including cytoreductive surgery and platinum- and taxane-based chemotherapy have showed reduced effectiveness against OCS, compared to high grade serous ovarian carcinoma (HGSOC), the most common subtype of ovarian cancer5. As these tumour types have similar genetic aberrations, it is likely the unique sarcomatous component of OCS that majorly contributes to the observed disparity in treatment response.  

We have used single cell RNA sequencing (scRNAseq) and spatial transcriptomics on patient-derived xenograft (PDX) models of OCS to determine key genes expressed in the carcinomatous and sarcomatous components. This has enabled us to develop OCS-specific gene expression signatures for these two regions. As 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 and is thought to involve the most likely cells to metastasise, we have identified potential genes involved in this process6-7. By then annotating regions of epithelial, pEMT, and mesenchymal cells within our tumours using spatial transcriptomics, we can also identify genes that show an expression pattern expected of a typical EMT program (i.e., low expression in epithelial regions, intermediate expression in pEMT regions, and high expression in mesenchymal regions). These genes would be ideal candidates for further interrogation of the processes mediating the sarcomatous transformation of epithelial carcinomatous cells.

By targeting these key genetic 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 treatment options, including 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
  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. 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.