Clinical Stratification of High-Grade Ovarian Serous Carcinoma Using a Panel of Six Biomarkers

Abstract

Molecular stratification of high-grade serous ovarian carcinoma (HGSC) for targeted therapy is a pertinent approach in improving prognosis of this highly heterogeneous disease. Enabling the same necessitates identification of class-specific biomarkers and their robust detection in the clinic. We have earlier resolved three discrete molecular HGSC classes associated with distinct functional behavior based on their gene expression patterns, biological networks, and pathways. An important difference revealed was that Class 1 is likely to exhibit cooperative cell migration (CCM), Class 2 undergoes epithelial to mesenchymal transition (EMT), while Class 3 is possibly capable of both modes of migration. In the present study, we define clinical stratification of HGSC tumors through the establishment of standard operating procedures for immunohistochemistry and histochemistry based detection of a panel of biomarkers including TCF21, E-cadherin, PARP1, Slug, AnnexinA2, and hyaluronan. Further development and application of scoring guidelines based on expression of this panel in cell line-derived xenografts, commercial tissue microarrays, and patient tumors led to definitive stratification of samples. Biomarker expression was observed to vary significantly between primary and metastatic tumors suggesting class switching during disease progression. Another interesting feature in the study was of enhanced CCM-marker expression in tumors following disease progression and chemotherapy. These stratification principles and the new information thus generated is the first step towards class-specific personalized therapies in the disease.

Functional balance between Tcf21–Slug defines cellular plasticity and migratory modalities in high grade serous ovarian cancer cell lines

“…Our findings also pose imminent questions regarding the epigenetic landscapes of the E -M spectrum with respect to this axis; cellular compartment specific interacting partners of these TF s that assist their activity; mechanisms linking Tcf21-S lug to specific migratory modes; biochemical evaluation of protein domains responsible for differential sub-cellular localization and TF activity, etc. A retrospective pre-clinical study from our group has further established Tcf21-S lug as potential biomarkers for HGS C tumor stratification and implied the adoption of tumor class -specific therapeutic regimes to effectively target the disease(54). Our report, thus supports this study and presents Tcf21-S lug as a crucial axis in HGS C cellular plasticity with genuine clinical implications.…”

A monoclonal antibody against annexin A2 targets stem and progenitor cell fractions in tumors

“…IHC was performed on xenografts as described earlier [20] . Briefly, 5 µm sections were fixed at 60 °C for 1 h, deparaffinized in xylene, hydrated in ethanol-distilled water gradient and incubated for 30 min at pH 6 for heat-induced epitope retrieval (HIER).…”

A Multistep Tumor Growth Model of High-Grade Serous Ovarian Carcinoma Identifies Hypoxia-Associated Signatures

“…As previously described, the hyaluronic acid (HA) content of tumors was detected by Alcian blue staining (Sigma-Aldrich, A5268; pH -2.5) [Kamble et al, 2019]. Alcian blue stains ECM components such as HA and mucin fibers (blue color) in the enzymatic undigested tissue sections, while HA expression is eliminated in the consecutive hyaluronidase-digested tumor sections.…”

“…We previously identified from a panel of HGSC cell lines that A4 cells exhibit an inherent capacity to form aggressive tumors over a short latency period and recapitulate clinically relevant disease progression features. Hence, we focused our efforts on comprehending HGSC tumor growth with xenograft models derived from A4 cells [Bapat et al, 2005;Bapat et al, 2010;Kalra and Bapat, 2013;Gardi et al, 2014;Singh et al, 2015;Naik et al, 2016a, c;Kamble et al, 2019;Varankar et al, 2020]. Xenograft growth models were histopathologically evaluated, and in vivo bioluminescence imaging was utilized in the o.t model to successfully track tumor progression and distant-organ metastasis.…”