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MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness

Abstract

The tumor microenvironment plays a critical role in prostate cancer (PC) development and progression. Inappropriate activation of the stroma potentiates the growth and transformation of epithelial tumor cells. Here, we show that upregulation of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, in stromal cells elevates production of reactive oxygen species, triggers an inflammatory response including activation of IL-6, and promotes tumorigenesis in vitro and in vivo. Mechanistically, MAOA enhances IL-6 transcription through direct Twist1 binding to a conserved E-box element at the IL-6 promoter. MAOA in stromal fibroblasts provides tumor cell growth advantages through paracrine IL-6/STAT3 signaling. Tissue microarray analysis revealed co-expression correlations between individual pairs of proteins of the stromal MAOA-induced Twist1/IL-6/STAT3 pathway in clinical specimens. Downstream of stromal MAOA, STAT3 also promotes cell stemness and transcriptionally activates expression of cancer stem cell marker CD44 in PC cells. MAOA inhibitor treatment effectively suppressed prostate tumor growth in mice in a stroma-specific targeted manner. Collectively, these findings characterize the contribution of MAOA to stromal activation in PC pathogenesis and provide a rationale for targeting MAOA in stromal cells to treat PC.

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Fig. 1: Increased MAOA levels in PC-associated stroma.
Fig. 2: Genetic silencing of MAOA in stromal cells reduces PC growth, migration, and invasion.
Fig. 3: MAOA promotes stromal cell reactivity and activates IL-6.
Fig. 4: MAOA upregulates IL-6 directly through Twist1 in prostate stromal cells.
Fig. 5: Stromal MAOA confers growth advantages on adjacent PC in a STAT3-dependent manner.
Fig. 6: Stromal MAOA/Twist1/IL-6 demonstrate co-expression correlations with adjacent tumor pSTAT3/STAT3 in PC tissue microarrays.
Fig. 7: MAOA in stromal cells promotes PC stemness via STAT3.
Fig. 8: Pharmacological inhibition of MAOA in stromal cells reduces PC growth in mice.

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Acknowledgements

We thank Yang Li (University of Southern California), Yanping Wang (CSMC), and Yidi Xu (Washington State University) for technical help, Leland W.K. Chung (CSMC) for comprehensive support of this study, and Gary Mawyer for editorial assistance. This work was supported by a Concern Foundation CONquer canCER Now Award, the Department of Defense Prostate Cancer Research Program grant W81XWH-15-1-0493, the NIH/NCI grant R37CA233658, and the WSU start-up fund to B.J.W.

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Conception and design: BJW. Development of methodology: JL, TP, LY, QL, and BJW. Acquisition of data: JL, TP, LY, QL, C-PL, and BJW. Analysis and interpretation of data: JL, TP, LY, QL, and BJW. Writing of the manuscript: BJW. Study supervision: BJW.

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Correspondence to Boyang Jason Wu.

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Li, J., Pu, T., Yin, L. et al. MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness. Oncogene 39, 3305–3321 (2020). https://doi.org/10.1038/s41388-020-1217-4

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