Stromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor-initiated oncogenesis

Abstract

The androgen receptor (AR)-signaling pathways are essential for prostate tumorigenesis. Although significant effort has been devoted to directly targeting AR-expressing tumor cells, these therapies failed in most prostate cancer patients. Here, we demonstrate that loss of AR in stromal sonic-hedgehog Gli1-lineage cells diminishes prostate epithelial oncogenesis and tumor development using in vivo assays and mouse models. Single-cell RNA sequencing and other analyses identified a robust increase of insulin-like growth factor (IGF) binding protein 3 expression in AR-deficient stroma through attenuation of AR suppression on Sp1-regulated transcription, which further inhibits IGF1-induced Wnt/β-catenin activation in adjacent basal epithelial cells and represses their oncogenic growth and tumor development. Epithelial organoids from stromal AR-deficient mice can regain IGF1-induced oncogenic growth. Loss of human prostate tumor basal cell signatures reveals in basal cells of stromal AR-deficient mice. These data demonstrate a distinct mechanism for prostate tumorigenesis and implicate co-targeting stromal and epithelial AR-signaling for prostate cancer.

Unveiling Novel Double-Negative Prostate Cancer Subtypes Through Single-Cell RNA Sequencing Analysis

“…Raw data of 6 human studies in the SRA database were used to build HuPSA, including GSE210358 6 , GSE137829 13 , GSE193337 14 , GSE206962, GSE181294 15 , GSE185344 16 . Data of 12 mouse studies were used to build MoPSA, including GSE146811 39 , GSE164969 17 , GSE201956 40 , GSE216158 18 , GSE221755 19 , GSE171336 20 , GSE165741 21 , GSE174471 22 , GSE210358 6 , GSE163316 23 , GSE189307 24 , GSE158468 25 , GSE153701 26 (sTable4). All FASTQ files were downloaded using SRA-Toolkit fasterq-dump function and aligned to human (GRCh38 from NCBI) or mouse (GRCm38 from Ensembl) genome using Alevin-fry 41 .…”

Stromal-derived MAOB promotes prostate cancer growth and progression

“…To this end, we treated AR-expressing PrSC and PCF2 cells (26) with enzalutamide (ENZ), an AR inhibitor used clinically for CRPC management and able to induce a NE phenotype (27). Systemic administration of ENZ is considered to also modulate the stromal AR signaling that plays a role in PC tumorigenesis and progression as reported previously (28,29). PCF2 was selected as a representative primary human prostatic CAF cell line, which had the utmost MAOB up-regulation compared to its normal counterpart among three fibroblast pairs (Fig.…”

Antibody-Protein-Aptamer Electrochemical Biosensor based on Highly Efficient Proximity-Induced DNA Hybridization on Tetrahedral DNA Nanostructure for Sensitive Detection of Insulin-like Growth Factor-1

“…Consequently, it is vitally significant to quickly analyze and sensitively detect IGF-1. 8 In recent works, biosensors based on electrochemical luminescence, fluorescence, and electrochemical methods have been extensively researched for the quantitative analysis of IGF-1. 9−11 Noteworthily, out of all the above methods, the electrochemical approach has garnered the most attention for its wide linear range, high sensitivity, good reproducibility, and high sensitivity.…”

“…Human insulin-like growth factor-1 (IGF-1) is an important protein biomarker produced by the liver, which not only performs an extremely important role in regulating endocrine balance, nerve excitation conduction, and the growing development of humans − but is also related to neuropathic pain, growth hormone deficiency, prostate cancer, and other diseases. − Furthermore, because its aberrant expression levels have been connected to a variety of human illnesses, it is crucial in the early phases of clinical diagnosis and treatment. Consequently, it is vitally significant to quickly analyze and sensitively detect IGF-1 . In recent works, biosensors based on electrochemical luminescence, fluorescence, and electrochemical methods have been extensively researched for the quantitative analysis of IGF-1. − Noteworthily, out of all the above methods, the electrochemical approach has garnered the most attention for its wide linear range, high sensitivity, good reproducibility, and high sensitivity.…”