Abstract B42: Autocrine/paracrine RANKL-RANK signaling promotes cancer bone metastasis and establishes premetastatic niche recruiting bystander cancer cells to participate in the metastatic process
Authors: Chu Gina Chia-Yi , Zhau Haiyen E. , Wang Ruoxiang , Chung. Leland W.K. 
Published: May 2019

RANKL-elicited RANK activity plays critical roles in many biological and pathological conditions, including osteoclast differentiation/bone remodeling, lymph node/thymic development, central thermoregulation and progesterone-driven mammary gland maturation, differentiation and carcinogenesis. RANKL can be derived from osteoblasts, infiltrating inflammatory cells and stromal fibroblasts. We previously showed that malignant prostate cancer (PCa) cells expressed RANKL and that its expression was correlated with clinical PCa progression and bone metastasis. RANKL expression at the single cell level in primary PCa specimens predicts PCa patient survival. We demonstrated RANKL overexpression promoted epithelial-to-mesenchymal transition (EMT), stem cells, and neuroendocrine (NE) phenotypes of PCa cells through transactivation of c-Myc/Max and AP4 via RANK-mediated signaling and conferred PCa bone and soft tissue metastases in mice. Blockade of RANKL-RANK signaling as well as their downstream regulators abolished the metastasis of PCa induced by RANKL. Furthermore, recombinant RANKL protein alone is sufficient to induce bone colonization and growth of RANKL- and non-metastatic PCa and breast cancer cells. Even a few RANKL+ PCa cells are sufficient to initiate the in vivo metastatic cascade by recruiting non-tumorigenic RANKL- PCa cells to participate in the metastatic process via downstream signaling amplification, implicating metastasis-initiating properties of RANKL-expressing PCa cells. Recently, we further demonstrated that RANKL rendered metastatic potential to breast, lung, renal, and liver cancer cells and promote their metastases to bone and other soft tissues in mice. Collectively, these results demonstrated RANKL is a uniform factor that drives bone metastasis of many different cancers, including prostate, breast, lung, renal, and liver cancers. The autocrine/paracrine RANKL-RANK signaling in cancer cells establishes a premetastatic niche through a “vicious cycle”, inducing RANKL and c-Met expression via activation of c-Myc/Max, and this promotes PCa EMT progression, stem and NE cell properties, and bone and soft tissue metastases. RANKL-expressing cancer cells possess metastasis-initiating potential that recruits and reprograms bystander non-tumorigenic cells to participate in the metastatic process. RANKL expression status therefore offers new insights for dissecting the mechanism by which PCa cells exhibit propensity for bone colonization/metastasis.

Citation Format: Gina Chia-Yi Chu, Haiyen E. Zhau, Ruoxiang Wang, Leland W.K. Chung. Autocrine/paracrine RANKL-RANK signaling promotes cancer bone metastasis and establishes premetastatic niche recruiting bystander cancer cells to participate in the metastatic process. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B42.