Abstract 2151: Neuroendocrine cancer cells have changed HOX code during trans-differentiation

Abstract Background: HOX genes encode Homeobox-containing proteins. There are 39 HOX genes organized into 4 clusters in human. The nested and partially overlapping expression of HOX genes in an anatomic region can determine its tissue specificity, which is termed as “HOX code”. In this study, we examined the expression of HOX genes in neuroendocrine prostate cancer (NEPCa), an aggressive subtype prostate cancer that arises from prostate adenocarcinoma (AdPCa) trough trans-differentiation. Methods: The HOX genes expression data were extracted from Cancer Cell Line Encyclopedia (CCLE) dataset. All in silico analysis were performed by using R language. Immunohistochemistry (IHC), dual immunofluorescence staining, Western blot and RT-qPCR were conducted to access the expression of HOXs. Results: Using the HOXs' mRNA expression data from CCLE, we generated HOX codes for 25 different types of tissues. These HOX codes were validated in TCGA pan cancer. By calculating the Pearson correlation, we were able to use 9 HOX codes including prostatic HOX code to identify the tissue origins of the cancer samples. Further, we found that in prostate cancer, the NEPCa samples have lost prostatic HOX code while majority of the AdPCa samples maintain the prostatic HOX code. The expression of HOXB13, the most prominent HOX expressed in prostatic tissues, was increased in AdPCa along with PCa progression but was decreased in NEPCa. Similarly, we found that in breast cancer, a sub-group of samples correlated well with the HOX code of mammary gland, but the rest did not. By comparing the differentially expressed genes in these two subgroups of samples, we found that the neuroendocrine markers including CHGA, CHGB and SYP were higher in HOX code-negative samples compared with HOX code-positive ones. Additionally, we observed a similar phenomenon in colorectal cancer samples: The expression of neurogenesis genes were enriched in HOX code-negative subgroup. Conclusions: 1) The expression of HOXB13 is decreased in NEPCa. 2) NEPCa has changed HOX code, suggesting the loss of prostatic identity in these samples. 3) The association of neuroendocrine phenotype with the changes in HOX code is not limited to prostate cancer but also is observed in other types of cancer. Significance: The HOX codes we established can be used in pan cancer research to identify the tissue origins of cancer samples and to study the trans-differentiation of cancer cells. Funding: This study is supported by: The LSUHS Office of Research SEED awards, NIH R01 CA226285 and Feist-Weiller Cancer Center. Citation Format: Siyuan Cheng, Shu Yang, Yingli Shi, Runhua Shi, Yunshin Yeh, Xiuping Yu. Neuroendocrine cancer cells have changed HOX code during trans-differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2151.