Abstract
The Cancer Genome Atlas network has revealed that the ‘mesenchymal’ epithelial ovarian cancer (EOC) subtype represents the poorest outcome, indicating a crucial role of stromal cancer-associated fibroblasts (CAFs) in disease progression. The cooperative role of CAFs in EOC metastasis has long been recognized, but the mechanisms of stromal CAFs activation are still obscure. Therefore, we carried out an integrative analysis to identify the regulator genes that are responsible for CAFs activation in microdissected tumor stroma profiles. Here, we determined that myristoylated alanine-rich C-kinase substrate (MARCKS) was highly expressed in ovarian stroma, and was required for the differentiation and tumor promoting function of CAFs. Suppression of MARCKS resulted in the loss of CAF features, and diminished role of CAFs in supporting tumor cell growth in 3D organotypic cultures and in murine xenograft model. Mechanistically, we found that MARCKS maintained CAF activation through suppression of cellular senescence and activation of the AKT/Twist1 signaling. Moreover, high MARCKS expression was associated with poor patient survival in EOC. Collectively, our findings identify the potential of MARCKS inhibition as a novel stroma-oriented therapy in EOC.
Highlights
High-grade epithelial ovarian cancer (EOC) remains the most lethal gynecological cancer and exhibits considerable heterogeneity [1]
To explore the regulatory molecules that drive gene expression representative of cancer-associated fibroblasts (CAFs) features in EOC, we carried out an integrative analysis to identify genes that are important for CAF activation and upregulated in tumor stroma
Suppression of myristoylated alanine-rich C-kinase substrate (MARCKS) resulted in fibroblast senescence and the loss of the CAF phenotype through the attenuation of the AKT/Twist1 cascade signaling, which contributes to the maintenance of stromal CAF activity
Summary
High-grade epithelial ovarian cancer (EOC) remains the most lethal gynecological cancer and exhibits considerable heterogeneity [1]. A subsequent follow-up study determined that patients with the “mesenchymal” subtype presented the worst prognosis [7]. These newly emerged classification schemes based on molecular profiling facilitate our understanding of EOC heterogeneity and the development of personalized treatment strategies [8,9,10]. This advantageous stratification emphasized the importance of tumor microenvironment, especially in terms of the stromal infiltrating components in EOC patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
