Abstract 1548: Olfactomedin 4 deficiency promote de novo progression of prostate cancer in TRAMP mouse model

Abstract

Abstract Prostate cancer is the most diagnosed solid tumor and the second leading cause of cancer-related death in American men. Olfactomedin (OLFM4) plays tumor suppressor roles and is associated with the initiation, growth, and clinical outcome of human prostate cancer. Olfm4-null mouse sporadically developed prostate epithelial neoplasia through up-regulated hedgehog signaling pathways. In this study, we have generated Olfm4+/+/GFP/TRAMP and Olfm4−/−/TRAMP mouse models to investigate Olfm4 gene biological functions underlying prostate cancer de novo progression. We have observed that Olfm4−/−/TRAMP mice developed more advanced prostate cancer at 47.6% (20/42) compared to Olfm4+/+/TRAMP at 11.9 % (5/42) and had poor survival compared to Olfm4+/+/TRAMP mice (P<0.01). Histopathological and immunofluorescent staining revealed that tumor tissues containing more heterogeneous cells such as Ar+/Ck8+ epithelial or Syn+ neuroendocrinal cells or Vim+/Ck8+ epithelium mesenchymal transition cells in the primary tumors obtained from Olfm4−/−/TRAMP mouse. We found more tumor angiogenesis and metastases into lymph nodes, liver, lung, kidney, and soft tissues in Olfm4−/−/TRAMP mice. The accumulations of the dendritic cell population in primary tumor and lung metastasis tumors were detected. The primary tumor was sensitive to androgen deprivation therapy by using castration with both Olfm4+/+/GFP/TRAMP and Olfm4−/−/TRAMP mice. However, castration-resisted EMT tumor cells or expressing neuroendocrine marker cells regrew after castration 7-8 months in both Olfm4+/+/GFP/TRAMP and Olfm4−/−/TRAMP mice. Furthermore, we tested JQ1, a BET bromodomain inhibitor, as an epigenetic targeted therapy reagent and found that JQ1 significantly inhibited tumor cell growth of Olfm4−/−/TRAMP mouse tumor in the organoids culture. Taken together, we have provided novel evidence that Olfm4 plays a tumor-suppressing role during prostate cancer de novo progression. Citation Format: Hongzhen Li, Wenli Liu, Jianqiong Zhu, Kyung Chin, Griffin P. Rodgers. Olfactomedin 4 deficiency promote de novo progression of prostate cancer in TRAMP mouse model [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 1548.