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

Abstract

Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer. 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-naïve 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 ALDH1A1) as compared to adherent growth-condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naïve 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-naïve tumours correlated with chemoresistance and reduced survival. In DSRT, 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.

Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness

“…Interestingly, in OC cells cultured in spheroid conditions (both cell lines and PDCs) we detected an increase in ALDH1A1 levels following DEX treatment, strongly suggesting the development of stemness phenotype mediated by this synthetic glucocorticoid. Our results are in corroboration with previous findings showing that modulation of ALDH1A1 expression is more easily detected in spheroid cultures 26 . ROR1-dependent upregulation of RhoA, YAP/TAZ, and BMI-1 was demonstrated by inducible shRNA targeting ROR1 expression in JHOS2 cells, which abrogated DEX-mediated increase in RhoA, YAP/TAZ, and BMI-1 expression (Fig.…”

ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer

“…To test and validate ZIP4 as a CSC marker, we conducted limiting dilution experiments using Since ALDH activity is one of the most common and best-described CSC markers for EOC [3,6,7,40,41], we tested ALDH activity as a CSC marker in PE04 cells in comparison to ZIP4 under the same conditions. ALDH + cell (10,000 cells/mouse) i.p.…”

The Presence and Potential Role of ALDH1A2 in the Glioblastoma Microenvironment

“…As mentioned above, there are two other ALDH1 family proteins, namely ALDH1A1 and ALDH1A3. Of these two, ALDH1A1 has been reported as a stem cell marker [ 39 , 40 , 41 ], while ALDH1A3 appears to have more tissue-specific expression, being highly expressed in the kidney, salivary glands, stomach, and breast [ 40 ]. These two genes were not expressed in our THP1 gene expression array ( Figure 2 C) and their corresponding proteins were absent in THP1 cells regardless of treatment or polarization state ( Figure 2 D).…”