Tumor recurrence fueled by residual tumor cells having survived chemotherapy represents the princ... more Tumor recurrence fueled by residual tumor cells having survived chemotherapy represents the principal cause of breast cancer treatment failure. Triple-negative breast cancer (TNBC) is a heterogeneous disease at both molecular and cellular level, and the presence of different tumor cell sub-populations is likely the reason for this heterogeneity and for the incomplete response to neoadjuvant chemotherapy observed for most TNBC. To identify and isolate tumor cell sub-populations that resist to chemotherapy, we used a panel of 45 antibody fluorochrome conjugates in combination with multi-parameter flow cytometry to screen for the expression of a set of cell surface markers during the course of tumor chemotherapy. This set of markers represented both proteins involved in stem cell function and proteins known to be over-expressed in stem cells or cancer stem cell sub-populations. As a source of tumor samples, we used a panel of TNBC patient-derived xenografts (PDXs). These tumor models a...
Trastuzumab is the standard treatment for HER2+ breast cancer (BC) patients, and even though it s... more Trastuzumab is the standard treatment for HER2+ breast cancer (BC) patients, and even though it significantly improved their clinical outcome, 50% of them do not benefit from this drug and disease recurs, underlining the need of reliable predictive biomarkers and new therapeutic strategies. Strikingly, despite all the molecular analyses performed to identify the escape mechanisms behind this resistance, it still represents a question point. MiRNAs have been correlated with occurrence and progression of human cancer, and their potential as clinical tools has emerged in the last years. We previously reported that oncosuppressive miR-205 targets HER3, thus increasing the responsiveness to TKIs lapatinib and gefitinib in preclinical models. Here we demonstrate that HER3 inhibition by miR-205 ectopic expression or siRNA-mediated silencing improves the responsiveness to Trastuzumab in HER2+ BC cell lines, and that this effect is exerted through impairment of AKT-mediated pathway. Moreover...
Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. Howev... more Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer. Gene and protein expression profiles were analysed in a panel of ER- breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively. The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated ...
Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk ... more Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk of metastasis and early relapse in breast cancer. The aim of this study was to identify and evaluate biomarkers of treatment-resistant tumor cells. We performed a cell surface marker screen in triple-negative breast cancer patient-derived xenograft models treated with standard care genotoxic chemotherapy. Global expression profiling was used to further characterize the identified treatment-resistant subpopulations. High expression of sialyl-glycolipid stage-specific embryonic antigen 4 (SSEA4) was found in residual tumor cells surviving chemotherapy and in samples from metastatic patients who relapsed after neoadjuvant chemotherapy. Gene and microRNA (miRNA) expression profiling linked SSEA4 positivity with a mesenchymal phenotype and a deregulation of drug resistance pathways. Functional assays demonstrated a direct link between epithelial-mesenchymal transition (EMT) and SSEA4 expressi...
Tumor recurrence fueled by residual tumor cells having survived chemotherapy represents the princ... more Tumor recurrence fueled by residual tumor cells having survived chemotherapy represents the principal cause of breast cancer treatment failure. Triple-negative breast cancer (TNBC) is a heterogeneous disease at both molecular and cellular level, and the presence of different tumor cell sub-populations is likely the reason for this heterogeneity and for the incomplete response to neoadjuvant chemotherapy observed for most TNBC. To identify and isolate tumor cell sub-populations that resist to chemotherapy, we used a panel of 45 antibody fluorochrome conjugates in combination with multi-parameter flow cytometry to screen for the expression of a set of cell surface markers during the course of tumor chemotherapy. This set of markers represented both proteins involved in stem cell function and proteins known to be over-expressed in stem cells or cancer stem cell sub-populations. As a source of tumor samples, we used a panel of TNBC patient-derived xenografts (PDXs). These tumor models a...
Trastuzumab is the standard treatment for HER2+ breast cancer (BC) patients, and even though it s... more Trastuzumab is the standard treatment for HER2+ breast cancer (BC) patients, and even though it significantly improved their clinical outcome, 50% of them do not benefit from this drug and disease recurs, underlining the need of reliable predictive biomarkers and new therapeutic strategies. Strikingly, despite all the molecular analyses performed to identify the escape mechanisms behind this resistance, it still represents a question point. MiRNAs have been correlated with occurrence and progression of human cancer, and their potential as clinical tools has emerged in the last years. We previously reported that oncosuppressive miR-205 targets HER3, thus increasing the responsiveness to TKIs lapatinib and gefitinib in preclinical models. Here we demonstrate that HER3 inhibition by miR-205 ectopic expression or siRNA-mediated silencing improves the responsiveness to Trastuzumab in HER2+ BC cell lines, and that this effect is exerted through impairment of AKT-mediated pathway. Moreover...
Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. Howev... more Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer. Gene and protein expression profiles were analysed in a panel of ER- breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively. The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated ...
Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk ... more Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk of metastasis and early relapse in breast cancer. The aim of this study was to identify and evaluate biomarkers of treatment-resistant tumor cells. We performed a cell surface marker screen in triple-negative breast cancer patient-derived xenograft models treated with standard care genotoxic chemotherapy. Global expression profiling was used to further characterize the identified treatment-resistant subpopulations. High expression of sialyl-glycolipid stage-specific embryonic antigen 4 (SSEA4) was found in residual tumor cells surviving chemotherapy and in samples from metastatic patients who relapsed after neoadjuvant chemotherapy. Gene and microRNA (miRNA) expression profiling linked SSEA4 positivity with a mesenchymal phenotype and a deregulation of drug resistance pathways. Functional assays demonstrated a direct link between epithelial-mesenchymal transition (EMT) and SSEA4 expressi...
Uploads
Papers by Olivier Déas