New screening system using Twist1 promoter activity identifies dihydrorotenone as a potent drug targeting cancer-associated fibroblasts

Abstract

Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells in tumor microenvironments. These cells strongly support tumor progression and are considered to be potent therapeutic targets. Therefore, drugs targeting CAFs have been developed, but most of them have failed in clinical trials. The discovery of additional drugs to inactivate or eliminate CAFs is thus essential. In this study, we developed a high-throughput screening system to find anti-CAF drugs using reporter cells that express Twist1 promoter-GFP. This screening system uses the activity of the Twist1 promoter as an indicator of CAF activation because Twist1 is known to be a central player in CAF activation. Using this screening system, we found that dihydrorotenone (DHR), an inhibitor of electron transfer chain complex 1 in mitochondria, can effectively deactivate CAFs. DHR-treated CAFs exhibited reduced expression of CAF-enriched markers, decreased capability of collagen gel contraction, and impaired ability to engage in tumor-promoting activities, such as facilitating the proliferation and colonization of cancer cells. Furthermore, conditioned media from DHR-treated CAFs attenuated tumor progression in mice grafted with MNK28 cells. In conclusion, DHR can be considered as a candidate drug targeting CAFs.

A comprehensive exploration of twist1 to identify a biomarker for tumor immunity and prognosis in pan-cancer

“…[ 44 ] Moreover, dihydrorotenone, a drug that deactivates cancer-associated fibroblasts through experimental targeting of twist1, has demonstrated efficacy in preclinical studies. [ 45 ] Moreover, our analysis also identified potential drugs that target twist1 and its interacting targets to combat tumorigenesis. Salinomycin was identified as a potent anti-tumor agent that primarily targets tumor stem cells.…”

PROX1 interaction with α-SMA-rich cancer-associated fibroblasts facilitates colorectal cancer progression and correlates with poor clinical outcomes and therapeutic resistance

“…They enhance chemoresistance and cancer progression [12,13] through multiple processes, such as compositing and remodelling of the ECM, as well as secretion of several soluble factors that likely can interact with the cancer cells, and disruption of immunity [14][15][16]. The inhibition of CAFs can be a promising treatment strategy for cancer [17,18], yet many challenges have arisen in its clinical practice.…”

PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression

“…Although CAF treatment and inhibition is a promising new cancer treatment strategy [8][9][10][11] , the clinical application of CAF inhibitors is lacking due to several challenges. One such challenge is the lack of fundamental knowledge on the heterogeneity of CAF populations.…”