RAI2 as novel suppressor of cancer cell homing and survival in the bone microenvironment

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Bone marrow (BM) is a common homing organ for disseminated tumor cells (DTCs, the seed of metastases) derived from various types of malignant epithelial tumors. We have shown that the presence of single DTCs in the BM is an independent predictor of metastatic relapse in many different solid tumors including breast cancer and identified genes, expression signatures and mechanisms associated with an early tumor cell dissemination to the BM. We identified retinoic acid–induced 2 (RAI2) as a novel metastasis suppressor gene significantly associated with both positive DTC status and poor prognosis in breast cancer. Furthermore, our functional studies showed that RAI2 sustains differentiation of ER-positive tumor cells, whereas loss of RAI2 induces hormone independent growth and activation of AKT signaling as an important mediator of dormancy control. Xenograft experiments performed during the first µBONE funding period showed an increased tumor dissemination (increased numbers of CTCs and DTCs) when RAI2 KO cells where injected orthotopically in Scid mice. Therefore, our results indicate that loss of RAI2 expression might represent a so far undiscovered key event for the onset of metastatic progression in the bone. The primary goal of this project is thus to better understand the precise role of RAI2 for the development of bone metastasis in breast cancer. Our recent drug screenings in the first project period identified a possible synthetic lethality associated with RAI2 expression in combination with drugs such as Aurora-A and AKT inhibitors. Thus, the role of RAI2 dependent AKT regulation in survival and dormancy will be analyzed in this application (WP1) as well as it suitability as a drug target in mouse models, including the suitability of Aurora-A kinase inhibition (WP2). We have also established a RAI2 KO (RAIKO) mouse, showing that RAI2 does not appear to be involved in initial tumor development. Here, we will cross RAIKO with a mouse model with spontaneous breast tumor formation (MMTV) to further analyze the involvement of RAI2 in early tumor dissemination and bone metastasis (WP2). Finally, we found that both the total conditioned media as well as the EV fraction from RAI2 KO cells was significantly increasing osteoclast differentiation. Thus, in the last WP3, we plan to analyze: (i) RAI2 dependent EV-related miRNA expression in bone modulation, and (ii) investigate of the role of RAI2 KO-derived secreted factors in tumor-bone crosstalk. In conclusion, the results obtained in this project will contribute to a better understanding of RAI2-mediated cancer dormancy and metastatic development in the BM microenvironment.