Dual inhibition of Wnt and Yes‐associated protein signaling retards the growth of triple‐negative breast cancer in both mesenchymal and epithelial states

Abstract

Triple‐negative breast cancer (TNBC), the most refractory subtype of breast cancer to current treatments, accounts disproportionately for the majority of breast cancer‐related deaths. This is largely due to cancer plasticity and the development of cancer stem cells (CSCs). Recently, distinct yet interconvertible mesenchymal‐like and epithelial‐like states have been revealed in breast CSCs. Thus, strategies capable of simultaneously inhibiting bulk and CSC populations in both mesenchymal and epithelial states have yet to be developed. Wnt/β‐catenin and Hippo/YAP pathways are crucial in tumorigenesis, but importantly also possess tumor suppressor functions in certain contexts. One possibility is that TNBC cells in epithelial or mesenchymal state may differently affect Wnt/β‐catenin and Hippo/YAP signaling and CSC phenotypes. In this report, we found that YAP signaling and CD44high/CD24−/low CSCs were upregulated while Wnt/β‐catenin signaling and ALDH+ CSCs were downregulated in mesenchymal‐like TNBC cells, and vice versa in their epithelial‐like counterparts. Dual knockdown of YAP and Wnt/β‐catenin, but neither alone, was required for effective suppression of both CD44high/CD24−/low and ALDH+ CSC populations in mesenchymal and epithelial TNBC cells. These observations were confirmed with cultured tumor fragments prepared from patients with TNBC after treatment with Wnt inhibitor ICG‐001 and YAP inhibitor simvastatin. In addition, a clinical database showed that decreased gene expression of Wnt and YAP was positively correlated with decreased ALDH and CD44 expression in patients’ samples while increased patient survival. Furthermore, tumor growth of TNBC cells in either epithelial or mesenchymal state was retarded, and both CD44high/CD24−/low and ALDH+ CSC subpopulations were diminished in a human xenograft model after dual administration of ICG‐001 and simvastatin. Tumorigenicity was also hampered after secondary transplantation. These data suggest a new therapeutic strategy for TNBC via dual Wnt and YAP inhibition.

Up-regulation of THY1 attenuates interstitial pulmonary fibrosis and promotes lung fibroblast apoptosis during acute interstitial pneumonia by blockade of the WNT signaling pathway

“…In addition to this information, YAP is a main player in Hippo and both WNT and Hippo pathways participate in various cellular developments of many diseases [34]. It was recently demonstrated that the YAP mediated by E-cadherin could be included in the destruction complex of β-catenin in order to orchestrate WNT signaling [35]. In this study, experimental results were consistent with the aforementioned studies that the mRNA and protein levels of β-catenin were increased in AIP lung fibroblasts.…”

A mechanism-based computational model to capture the interconnections among epithelial-mesenchymal transition, cancer stem cells and Notch-Jagged signaling

“…This prediction is supported by our analysis of gene expression profiles of CSCs belonging to different cancer subtypes, and report the presence of epithelial, hybrid E/M and mesenchymal CSCs. Recent experimental studies have identified such heterogeneity in EMT status of different CSCs across cancer subtypes [10,12,36,[54][55][56][57], supporting the idea about a dynamic 'stemness window' [13] along the 'EMT axis'. Moreover, a recent clinical study identified different subsets of CTCs -those that expressed EMT markers but not stemness ones, those that expressed stemness markers but not EMT, those that expressed both EMT and stemness markers, and those that expressed neither.…”

Phenotypic Plasticity, Bet-Hedging, and Androgen Independence in Prostate Cancer: Role of Non-Genetic Heterogeneity

“…Similarly, Deb et al ( 163 ) identified two mutually exclusive clonal subpopulations in altered signaling states—one with upregulated pSTAT3 and the other with downregulated SMAD2/3—and targeted STAT3 and BCL6 (a transcription factor downstream of SMAD2/3) in a combinatorial manner to overcome non-genetic heterogeneity. Furthermore, dual inhibition of Wnt and Yes-associated protein (YAP) signaling can restrict the population of both epithelial-like and mesenchymal-like CSCs ( 164 ). These combinatorial therapies are reminiscent of combinations of drug pyrazinamide (that specifically targets M. tuberculosis persisters) with other canonical treatments ( 165 ).…”