Ovarian carcinoma patient derived xenografts reproduce their tumor of origin and preserve an oligoclonal structure

Advanced Epithelial Ovarian Cancer (EOC) patients frequently relapse by 24 months and develop resistant disease. Research on EOC therapies relies on cancer cell lines established decades ago making Patient Derived Xenografts (PDX) attractive models, because they are faithful representations of the original tumor. We established 35 ovarian cancer PDXs resulting from the original graft of 77 EOC samples onto immuno-compromised mice. PDXs covered the diversity of EOC histotypes and graft take was correlated with early patient death. Fourteen PDXs were characterized at the genetic and histological levels. PDXs reproduced phenotypic features of the ovarian tumors of origin and conserved the principal characteristics of the original copy number change (CNC) profiles over several passages. However, CNC fluctuations in specific subregions comparing the original tumor and the PDXs indicated the oligoclonal nature of the original tumors. Detailed analysis by CGH, FISH and exome sequencing of one case, for which several tumor nodules were sampled and grafted, revealed that PDXs globally maintained an oligoclonal structure. No overgrowth of a particular subclone present in the original tumor was observed in the PDXs. This suggested that xenotransplantation of ovarian tumors and growth as PDX preserved at least in part the clonal diversity of the original tumor. We believe our data reinforce the potential of PDX as exquisite tools in pre-clinical assays.


O-2055
Poorly differentiated SOC (grade 3) containing moderately differentiated areas (25%) characterized by papillary and micro-papillary structures with psammoma bodies. Undifferentiated areas show packed tumor cells, nuclear atypias and vacuolar degeneration. The mean mitotic count is 10 mitoses/10 high-power fields (400x). The PDXs recapitulate the morphology and the heterogeneity of the primary tumor with moderatly and poorly differentiated areas.

O-2146
High-grade SOC with papillary structures and diffuse/solid highly cellular growth pattern., marked nuclear atypias. Mitotic count is greater than 10 (400x).

O-2815
Mixed Müllerian tumor (MMT) or carcinosarcoma displaying epithelial portions with solid pattern, numerous mitoses and large necrotic areas. Papillary architecture is observed in the primary tumor. Within the epithelial component, chondrosarcomatous areas are identified. Poorly differentiated areas and the sarcomatous component predominate in tumor deposits sampled from the great omentum. PDXs recapitulate the heterogeneous morphology with solid architecture and large necrotic areas, papillary morphologies as well as dispersed chondrosarcomatous areas.

O-2878 and 0005D/0005S
Moderately differentiated (grade 2) SOC containing 25% of poorly differentiated areas. Cellular atypias with high mitotic activity as well as psammoma bodies are present on peritoneal and pelvic deposits. Necrotic areas are absent on sampled sections. Suprarenal and diaphragmatic post-CT nodules (O-0005S and O-0005D) sampled at interval surgery after chemotherapy conserve this moderately differentiated serous architecture, associated with solid areas and cellular atypias and intense mitotic activity. PDX derived from the primary tumour reproduce the serous papillary and micro-papillary architecture and necrotic nucleus. PDXs derived from 0005S and 0005D bear comparable papillary architecture. O-3312 SOC presenting moderately and poorly differentiated areas (50%) and extended necrotic areas. Few psammoma bodies are observed within the primary ovarian tumor. PDXs derived from this primary serous ovarian cancer recapitulate this morphology either at low or at advanced passages. Large necrotic areas are also present.

O-1217
Mixed Müllerian tumors (MMT) or carcinosarcoma. Within the epithelial component, chondrosarcomatous and osteosarcomatous components are observed containing large necrotic areas. Corresponding PDXs bear a similar morphology with serous aspects associated with chondrosarcomatous areas.

O-1106
Heterogeneous primary SOC with moderately and poorly differentiated portions containing solid and cribriform structures, important nuclear atypias and elevated mitotic counts. Numerous psammoma bodies are observed with necrotic and inflammatory reaction within the stroma. PDXs derived from this tumor recapitulate this morphology including psammoma bodies.

O-3006
High grade SOC. Note the absence of papillary structures and extended necrotic areas. PDXs reiterate this undifferentiated morphology and large necrotic areas.

O-1912
Heterogeneous ovarian carcinoma combining a moderately differentiated SOC and areas of clear-cell carcinoma. Papillary structures are bordered by cancerous cells with numerous mitoses and cellular atypias and necrotic areas. Psammoma bodies are observed. PDXs derived from this tumor recapitulate this heterogeneity with the presence of both papillary architecture and areas of clear-cell carcinoma.

O-0822
Ov-0822 is a primary high-grade serous ovarian carcinoma. Papillae structures are identified with connective-vascular tissues axes. Necrotic areas are rare and Psammoma bodies absent. This tumor is also heterogeneous with the identification of undifferentiated areas with solid aspect and higher cellularity. PDXs stemming from this tumor maintain this architecture and this heterogeneity. Some of them respect the papillary architecture with various percentages of undifferentiated and solid areas. After the third passage, PDXs examined are undifferentiated with large necrotic areas and high mitotic count.

O-1458
High-grade SOC with moderately and poorly differentiated areas. Psammoma bodies are absent and papillae structures coexist with more solid and undifferentiated parts containing large necrotic areas. PDXs maintain the heterogeneity with identification of rare papillary structures and predominant undifferentiated and solid areas.

O-1741
Moderately differentiated SOC with papillary and micro-papillary structures, some rare necrotic areas and psammoma bodies. Portions of undifferentiated are found. PDXs have a similar morphology with moderately differentiated andpapillary and micropapillary structures. Necrotic areas, high mitotic count, psammoma bodies are identified.

Case 2781
Primary mucinous carcinoma with glandular structures within a connective stroma. Cancerous cells are expanded by the mucus material that is observed also in extracellular position. Corresponding PDX displays similar morphology with tumoral glands dispersed within a connective stroma. Mucus materials are visualized in intra and extracellular position.