A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression

Abstract

As a key regulator of the DNA translesion synthesis (TLS) pathway, RAD18 is error-prone and contributes to the accumulation of DNA mutations. Our previous study showed that it plays an essential role in the progression of multiple tumors. However, the mechanism through which RAD18 influences triple-negative breast cancer (TNBC), especially the interaction between tumor cells and the tumor microenvironment, remains elusive. In this study, we showed that RAD18 expression is markedly higher in patients with high T stage TNBC and inversely correlated with prognosis. High expression of RAD18 facilitated a highly stem-cell phenotype through the Hippo/YAP pathway, which supports the proliferation of TNBC. In addition, the cytokine byproduct TGF-β activates macrophages to have an M2-like tumor-associated macrophage (TAM) phenotype. Reciprocally, TGF-β from TAMs activated RAD18 in TNBC to enhance tumor stemness, forming a positive feedback loop. Inhibition of YAP or TGF-β breaks this loop and suppresses cancer stemness and proliferation In nude mice, RAD18 promoted subcutaneous transplanted tumor growth and M2-type TAM recruitment. Collectively, the RAD18-YAP-TGF-β loop is essential for the promotion of the stemness phenotype by TNBC and could be a potential therapeutic target for TNBC.

Matrix stiffness‐induced α‐tubulin acetylation is required for skin fibrosis formation through activation of Yes‐associated protein

“…Our results displayed a connection between the nuclear YAP and the upregulation of TGF‐β1, which were in correspondence with previously published studies that knocked out of LATS1/2 could lead to decreased expression of phosphorylated YAP, which could cause increased expression of TGF‐β in mouse neuroepithelium and liver cells 49,50 . Other studies also showed that when the activity of YAP was inhibited with Verteporfin, the TGF‐β pathway was hindered in fibroblast, 51 and the secretion of TGF‐β by macrophages was diminished 52 . These results suggest a possible crosstalk between Hippo and TGF‐β pathways where dephosphorylated YAP could translocate into the nucleus to activate the TGF‐β signaling pathway.…”

Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy

“…JH-RE-06 also suppresses growth of A549 and H1299 lung cancer cells grown as xenografts in vivo ( 155 ). Further consistent with a role for TLS in sustaining tumors, RAD18 overexpression elevates colonization of esophageal cancer cells in the mice lung ( 156 ), while RAD18-deficient TNBC xenografts show reduced tumor volume ( 157 ). Taken together, these studies suggest that TLS is a cancer-dependency at least under select conditions.…”

“…Implanting cancer cells orthotopically in mice provides a convenient approach to study tumor growth in a physiologically relevant environment. Orthotopic injection of esophageal cancer cells overexpressing RAD18 increases colonization ( 156 ), while RAD18-deficient TNBC cell xenografts show reduced tumor growth ( 157 ). TLS inhibition by the REV1 inhibitor JH-RE-06 decreases colonization of lung cancer cells in mice ( 155 ).…”

Betulinic Acid Inhibits the Stemness of Gastric Cancer Cells by Regulating the GRP78-TGF-β1 Signaling Pathway and Macrophage Polarization

“…Moreover, BA dose-dependently inhibited the GRP78-mediated secretion of TGF-β, thereby suppressing macrophage polarization, IL-6 secretion, and IL-6-mediated gastric cancer stemness ( Figure 6 ). In a previous study, TGF-β signaling was reported to involve a positive feedback loop in the regulation of triple-negative breast cancer and macrophage-mediated cancer stemness and progression [ 41 ]. The results also indicated that BA-induced downregulation of TGF-β through the GRP78-mediated pathway may inhibit the positive feedback loop between gastric cancer cells and macrophage-mediated cancer stemness and tumor progression.…”