ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors

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Kaipio , K , Chen , P , Roering , P , Huhtinen , K , Mikkonen , P , Östling , P , Lehtinen , L , Mansuri , N , Korpela , T , Potdar , S , Hynninen , J , Auranen , A , Grénman , S , Wennerberg , K , Hautaniemi , S & Carpén , O 2020 , ' ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors ' , Journal of Pathology , vol. 250 , no. 2 , pp. 159-169 . https://doi.org/10.1002/path.5356

Title: ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors
Author: Kaipio, Katja; Chen, Ping; Roering, Pia; Huhtinen, Kaisa; Mikkonen, Piia; Östling, Päivi; Lehtinen, Laura; Mansuri, Naziha; Korpela, Taina; Potdar, Swapnil; Hynninen, Johanna; Auranen, Annika; Grénman, Seija; Wennerberg, Krister; Hautaniemi, Sampsa; Carpén, Olli
Contributor organization: Institute for Molecular Medicine Finland
Precision Systems Medicine
Helsinki Institute of Life Science HiLIFE
University of Helsinki
HTB
Bioinformatics
Department of Biochemistry and Developmental Biology
Research Programs Unit
Faculty of Medicine
Medicum
HUSLAB
Precision Cancer Pathology
Department of Pathology
Date: 2020-02
Language: eng
Number of pages: 11
Belongs to series: Journal of Pathology
ISSN: 0022-3417
DOI: https://doi.org/10.1002/path.5356
URI: http://hdl.handle.net/10138/320153
Abstract: Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer (HGSC). Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient-derived cell lines, correlate stemness markers with clinical outcome and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment-naive and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth condition HGSC cells showed increased stemness marker expression (including aldehyde dehydrogenase isoform I; ALDH1A1) as compared with adherent growth condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naive tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment-naive tumours correlated with chemoresistance and reduced survival. In drug sensitivity and resistance testing, five compounds, including two PI3K-mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells. Our results identify stemness markers in HGSC that are associated with a decreased response to conventional chemotherapy and reduced survival if expressed by treatment-naive tumours. EGFR, mTOR-PI3K and aurora kinase inhibitors are candidates for targeting this cell population. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Subject: 3122 Cancers
Ovarian cancer
stem-like cell
patient derived cell line
survival
drug sensitivity
CELLS
CONTRIBUTE
BMI-1
ovarian cancer
ALDEHYDE DEHYDROGENASE
MARKER
IDENTIFICATION
patient-derived cell line
MICROENVIRONMENT
EXPRESSION
EPITHELIAL OVARIAN
AURORA
Peer reviewed: Yes
Rights: unspecified
Usage restriction: openAccess
Self-archived version: acceptedVersion


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