Rarg-Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer

Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling governs cell lineage identity is often missing. Here, leveraging prostate organoid technology, we show that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and specification of prostatic lumen. RA-dependent RAR activation promotes the expression of Foxa1, which synergizes with the androgen pathway for luminal expansion, cytoarchitecture and function. FOXA1 mutations are common in prostate and breast cancers, though their pathogenic mechanism is incompletely understood. Combining functional genetics with structural modeling of FOXA1 folding and chromatin binding analyses, we discover that FOXA1F254E255 is a loss-of-function mutation compromising its transcriptional function and luminal fate commitment of prostate progenitors. Overall, we define RA as an instructive signal for glandular identity in adult prostate progenitors. Importantly, we identify cancer-associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.

视黄酸（Retinoic acid, RA）信号通路是脊椎动物发育的主控调控通路，在体轴定向以及包括生殖系统在内的组织分化过程中发挥关键作用。但目前学界对RA信号通路如何调控细胞谱系特性的机制认知仍存在空白。本研究借助前列腺类器官技术，证实RA信号通路可协调成年小鼠前列腺祖细胞定向分化为腺体特性细胞、维持上皮屏障完整性，并特化前列腺腺腔。视黄酸依赖的视黄酸受体γ（RARγ）激活可促进叉头框蛋白A1（Foxa1）的表达，后者与雄激素通路协同调控腺腔扩张、细胞结构构建与功能维持。FOXA1突变在前列腺癌与乳腺癌中较为常见，但其致病机制尚未完全阐明。本研究将功能遗传学与FOXA1折叠结构建模、染色质结合分析相结合，发现FOXA1F254E255是一种功能丧失性突变，可损害其转录功能并削弱前列腺祖细胞的腺细胞命运定向能力。综上，本研究明确RA是成年小鼠前列腺祖细胞腺体特性形成的指导性信号。尤为重要的是，本研究鉴定出一类癌症相关的FOXA1插入缺失（indels）突变，这类突变会影响第254位残基F，属于功能丧失性突变，可促进成年小鼠前列腺祖细胞的去分化。