Abstract 1781: Correlates of androgen deprivation and gut microbiome in mouse Pten-deficient prostate cancer
Authors: De Velasco Marco A. , Sakai Kazuko , Kura Yurie , Banno Eri , Ando Naomi , Sako Noriko , Shimizu Nobutaka , Fujita Kazutoshi , Nozawa Masahiro , Yoshimura Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: July 2021

Abstract
Androgen receptor (AR) signaling plays a key role in the progression of prostate cancer and androgen deprivation therapy (ADT) is one the standard of care for men with advanced prostate cancer. However, AR also exerts effects on androgen responsive tissues and accumulating data indicates that AR is implicated in influencing gut flora. Commensal bacteria are essential for maintaining a healthy immune system which plays a major role in cancer surveillance. Moreover, cancer is known to promote commensal dysbiosis which can further impair immune function. Here, we investigate associations between commensal fecal bacteria and androgen deprivation in an immunocompetent transgenic mouse model of Pten-deficient prostate cancer. 16S rRNA amplicon sequencing was used to comprehensive profile and compare the fecal microbiomes of bearing conditional Pten-knockout mice with those of mice 5 weeks after surgical castration. Tumor burden in surgically castrated mice was significantly lower compared to that of intact mice, 57.45%, P&lt;0.001. With regards to fecal microbial composition, ADT via surgical castration enhanced alpha diversity (Shannon index, P=0.006). Moreover, microbial communities differed between castrated and intact mice (PERMANOVA, P=0.003, NMDS stress=0.042). Notably, an individual mouse with a strong response to ADT showed marked differences in fecal microbe composition compared to other mice in the cohort. Taxa associated with ADT included Dorea, Oscillospora, Sutturella, Dehalobacterium, Akkermansia muciniphila, and Flexispira while Prevoltella, Allobacalum, Ruminococcus flavefaciens, Candidatus Arthromitus and Bacteroides. Dehalobacterium, Coprococcus and Ruminococcus gnavus were more abundant in fecal samples from castrated, low tumor burden mouse. Overall, Bacteriodes and Parabacteriodes were positively correlated to tumor burden. Taxon enrichment analysis (TSEA) revealed functional enrichments of lipid translocation, carbohydrate transport, amino acid transport and proteoglycans in cancer in castrated mice, whereas, enrichment of low-density lipoprotein particle binding, extracellular matrix assembly, inflammatory response to antigenic stimulus and ADP metabolic process. Functional profiles inferred from metagenomic 16S rRNA data revealed enrichment of glyoxylate and dicarboxylate metabolism, carbon metabolism and geraniol metabolism in castrated mice. In intact mice, lipopolysaccharide biosynthesis, streptomycin biosynthesis and amino sugar and nucleotide sugar metabolism were enriched. Notably, lower tumor burden was associated with porphyrin and chlorophyll metabolism, propanoate metabolism, and valine, leucine and isoleucine degradation. This study models ADT in a preclinical model of prostate cancer and provides a broad characterization of the gut microbiome and its association to androgen deprivation.
Citation Format: Marco A. De Velasco, Kazuko Sakai, Yurie Kura, Eri Banno, Naomi Ando, Noriko Sako, Nobutaka Shimizu, Kazutoshi Fujita, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Correlates of androgen deprivation and gut microbiome in mouse Pten-deficient prostate cancer [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 1781.