Wnt5a induces and maintains prostate cancer cells dormancy in bone

Abstract

In a substantial fraction of prostate cancer (PCa) patients, bone metastasis appears after years or even decades of latency. Canonical Wnt/β-catenin signaling has been proposed to be implicated in dormancy of cancer cells. However, how these tumor cells are kept dormant and recur under control of Wnt/β-catenin signaling derived from bone microenvironment remains unknown. Here, we report that Wnt5a from osteoblastic niche induces dormancy of PCa cells in a reversible manner in vitro and in vivo via inducing Siah E3 Ubiquitin Protein Ligase 2 (SIAH2) expression, which represses Wnt/β-catenin signaling. Furthermore, this effect of Wnt5a-induced dormancy of PCa cells depends on receptor tyrosine kinase-like orphan receptor 2 (ROR2), and a negative correlation of ROR2 expression with bone metastasis–free survival is observed in PCa patients. Therefore, these results demonstrate that Wnt5a/ROR2/SIAH2 signaling axis plays a crucial role in inducing and maintaining PCa cells dormancy in bone, suggesting a potential therapeutic utility of Wnt5a via inducing dormancy of PCa cells in bone.

SMAD3/SP1 complex‐mediated constitutive active loop between lncRNA PCAT7 and TGF‐β signaling promotes prostate cancer bone metastasis

“…D). Consistently, the positive correlation of PCAT7 with TGFBR1 and p‐SMAD3, and the negative correlation of PCAT7 with miR‐324‐5p were further clinically verified in primary PCa cells reported in our previous study (Ren et al , ) (Fig. E).…”

“…In order to determine the molecular mechanism that underlies the PCAT7/miR‐324‐5p axis in PCa bone metastasis, luciferase reporter assays were performed to assess the function of PCAT7 and miR‐324‐5p in multiple well‐known pathways that contribute to bone metastasis of PCa, including the Notch (Zayzafoon et al , ), TGF‐β (Dai et al , ), Wnt (Ren et al , ), and NF‐κB (Ren et al , ) pathways. As shown in Fig.…”

Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer

“…Inducer of ECM dormancy Wnt5a/ROR2/SIAH2 signaling axis is involved in the induction and maintenance of PCa cells dormancy in the bone. [65] TGFβ2/ GDF10…”

Premetastasis

“…If you define tumor-led predisposition of premetastatic organs as Paget-type, stochastic settlement of CTC with acquisition of the switching properties is of non-Paget-type. Hematopoietic stem cells (HSC) in bone marrow can be competitively evicted from the osteoblastic niche by metastasizing prostate cancer cells (Shiozawa et al 2011), and those cancer cells can stay dormant there by WNT5a repressing canonical WNT3a activity in a reversible manner (Ren et al 2019). Here the "lodge" is physiologically preestablished originally for HSC even before prostate cancer development.…”