Abstract 5538: Efferocytosis-induced HIF-1α enhances tumor vascularization and promotes osteoblastic bone remodeling in metastatic prostate cancer

Abstract

Abstract Metastatic prostate cancer (PCA) exhibits a predilection for bone metastasis, initiating a complex interplay with bone cells, leading to dysregulated remodeling and mixed-pathological bone alterations. Human PCA primarily yields osteoblastic bone lesions, linked to bone pain and an adverse prognosis. In this study, we explored the activation of HIF-1α in myeloid phagocytic cells by apoptotic cancer cells in the context of bone metastatic PCA. Our previous findings demonstrated HIF-1α stabilization in bone macrophages engulfing apoptotic PCA cells in vitro. This study extends our understanding to an in vivo setting using mouse prostate cancer cells designed to express inducible caspase 9, triggering apoptosis (and subsequent efferocytosis) when exposed to the dimerizer molecule AP20187 (AP). Our assessment of PCA tumor growth in bone utilized a syngeneic mouse model, introducing a loss-of-function Hif1a mutation into myeloid lineage cells using LysM-Cre mice crossed with Hif1a-floxed mice (Hif1amut (LysM-Cre+/- Hif1aflox)), compared with the LysM-Cre-/- Hif1aflox (WT). In the first model, cancer cells were inoculated into the tibiae of these mice and apoptosis was induced with AP on days 3 and 5 post-inoculation (AP model). Results were compared to a model where apoptosis was not induced after inoculation (No-AP). In the AP model, fractional bone volume (BV/TV) in the medullae was significantly higher in tumor-inoculated tibiae than in non-inoculated (No-tumor) contralateral bone, highlighting the predominance of osteoblastic lesions. Conversely, in the No-AP model, increased BV/TV significance was achieved in WT mice (tumor vs. No-tumor), but not in mutant mice. Trabecular thickness (Tb.Th) was increased in both models in the presence of tumor, regardless of the Hif1a phenotype. Importantly, significant differences in BV/TV and Tb.Th between WT and Hif1amut tumor tibiae were exclusively noted in the context of induced apoptosis. Histological differences between tumors in the AP model were observed by immunofluorescence (IF) staining, which revealed a reduced fractional F4/80+ area in Hif1amut vs. WT tumors, with no differences in TRAP+ (osteoclasts) lining bone surfaces. RNAseq analysis of HIF1amut vs. WT macrophages efferocytosing apoptotic cancer cells showed downregulated processes related to vasculature development and blood vessel morphogenesis (p< 10-5). In correlation, IF analysis with endomucin (EMCN) demonstrated a reduction in stained area (EMCN+) relative to tumor area in Hif1amut tibiae vs. WT, suggesting a role of efferocytosis-induced HIF-1α in tumor vascularization. This study unveils intricacies of metastatic tumor growth in bone and proposes a connection between efferocytosis-induced HIF-1α in myeloid phagocytic cells and the promotion of tumor vascularization, alongside the enhancement of osteoblastic bone remodeling. Citation Format: Gabriel G. Kleer, Maria Molina Sanchez, Veronica Mendoza-Reinoso, Amy J. Koh, John Rubin, Laurie K. McCauley, Hernan Roca. Efferocytosis-induced HIF-1α enhances tumor vascularization and promotes osteoblastic bone remodeling in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5538.