Platinum-sensitive HGOC residual tumors share joint expression of CRYAB, CEACAM6, SOX2 genes with tumors that acquired resistance. Platinum-sensitive HGOC residual tumors share joint expression of CRYAB, CEACAM6, SOX2 genes with tumors that acquired resistance

Purpose: Most High-Grade Ovarian Carcinomas (HGOCs) are sensitive to carboplatin (CBP)-based chemotherapy but frequently recur within 24 months. Recurrent tumors remain frequently CBP-sensitive and acquire resistance after several CBP cycles. We developed Patient-Derived Xenografts (PDXs) that allow the study of these different stages of CBP-sensitive recurrence and acquisition of resistance. Experimental Design: We generated PDX models from CBP-sensitive HGOC. PDXs were CBP- or mock-treated and tumors were sampled, after treatment and at recurrence. We also isolated models with acquired-resistance from CBP-sensitive PDXs upon repeated CBP treatment. Tumors were characterized transcriptome levels by Affymetrix microarrays. Results: All PDX models reproduced treatment response seen in the patients. CBP-sensitive residual tumors contained non-proliferating tumor cells clusters embedded in a fibrotic mesh. This was absent in CBP-resistant tumors. Residual tumors had marked differences in gene expression when compared to naïve and recurrent tumors, indicating downregulation of cell cycle and proliferation and upregulation of interferon response and epithelial–mesenchymal transition. This gene expression pattern resembled that seen in embryonal diapause and ‘drug-tolerant persister’ states. Residual and acquired-resistance tumors share the overexpression of three genes – CEACAM6, CRYAB, and SOX2. Conclusions: In HGOC PDX, CBP-sensitive recurrences arise from a small population of quiescent, drug-tolerant, residual cells embedded in a fibrotic mesh. These cells overexpress CEACAM6, CRYAB and SOX2, a signature also associated with acquired resistance and poor patient prognosis Overall design: design 1 : To analyze residual cells after treatment of 3 CBP-sensitive Patient-Derived Xenografts (PDX), using Affymetrix microarrays, for a total of 12 samples (2 mock-treated biological duplicates and 2 CBP-treated biological duplicates X 3 PDX models). design 2: Patient-Derived Xenografts (PDX) were analyzed using Affymetrix microarrays,in naive(nai), after recurrence (regrowth=reg), or after acquired-resistance(resis) following several cycle of CBP treatments.