Abstract B024: TBX2highmiR-375-3plowRBPJhigh signaling drives prostate cancer bone metastatic phenotype via exosomes

Abstract

Abstract Recent studies have shown that exosome secretion by prostate cancer (PCa) cells fosters multiple facets of PCa progression and metastasis, mediated in particular through exosomal micro RNAs (miRs) that dictate gene expression changes. However, the molecular mechanisms through which exosomal miRs orchestrate bone remodeling that facilitates the establishment of a pre-metastatic niche (PMN) at the distant metastatic site i.e. bone remain elusive. We have identified that TBX2, a transcription factor that we previously reported plays a key role in PCa metastasis, represses miR-375-3p thereby resulting in de-repression/upregulation of its target RBPJ, an effector of Notch signaling and an established driver of PCa metastasis. Further, the unbiased identification of miR-375-3p as the topmost miR repressed by TBX2, in combination with experiments that genetically manipulate miR-375-3p in the context of TBX2 modulation, point to a crucial biological function of miR-375-3p as a key mediator in RBPJ regulation exerted by TBX2. In addition, the study highlights a dual level of RBPJ regulation by TBX2/miR-375-3p signaling i.e. via: a) gene expression changes at the intra-cellular or autocrine level, and b) gene expression changes at the distant site of bone metastasis through inter-cellular/endocrine communication via exosomes. Further, the study implicates TBX2high primary PCa cells in directing bone remodeling activity at the distant metastatic site in a paracrine mode via exosomes in addition to our previously reported role of TBX2 in mediating bone remodeling in an autocrine mode that occurs following metastatic dissemination. Taken together, our study unravels the role of TBX2/miR-375-3p/RBPJ signaling in PCa bone metastatic progression. Citation Format: Girijesh Kumar Patel, Sayanika Dutta, Hamed Khedmatgozar, Manisha Tripathi, Srinivas Nandana. TBX2highmiR-375-3plowRBPJhigh signaling drives prostate cancer bone metastatic phenotype via exosomes [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B024.