Innate immunity and Nfkb pathway control prostate stem cell plasticity, reprogramming and tumor initiation

Prostate epithelium develops from multipotent stem cells (SCs) which are replaced in adult life by different lineage-restricted basal and luminal unipotent SCs that sustain the homeostasis in a regionalized manner. Deletion of Pten re-induces multipotency in basal cells (BC). However, the molecular mechanisms regulating cell plasticity and tumor initiation are poorly understood. Here, we showed that Pten deletion in BCs led to distinct cell fate reprograming and tumor initiation in a regionalized manner. In anterior and dorsal prostates, BCs were reprogrammed into a Hillock like state that progressed into a basal-luminal hybrid state, which further transitioned into a proximal-like luminal state before progressing to tumorigenesis. In the ventral prostate, BC expressing Nkx3.1 gave rise to distal-like luminal state that are less plastic and progress more slowly to tumorigenesis. Single-cell sequencing and ATAC-seq analysis showed that the reprograming into hillock and proximal states induced activation of the innate immunity pathway during the cellular reprograming and tumor formation. Targeting Il-1, JAK/STAT and Nfkb inhibits Pten-induced cell plasticity and oncogenic reprograming, opening new opportunities in the prevention and treatment of prostate cancer. Overall design: To unravel the chromatin remodeling and gene regulatory networks associated with oncogenic hits induced BC multipotency in the prostate, we performed bulk ATAC-seq of FACS isolated BCs and LCs from WT mice and BCs 6 weeks following Pten deletion in BC.

前列腺上皮（prostate epithelium）起源于多能干细胞（multipotent stem cells, SCs），成年后这类细胞会被不同的谱系受限基底与腔面单能干细胞替代，后者以区域特异性方式维持组织稳态。敲除Pten（phosphatase and tensin homolog, Pten）可重新诱导基底细胞（basal cells, BC）恢复多能性。然而，调控细胞可塑性与肿瘤起始的分子机制仍有待深入阐明。
本研究证实，在基底细胞中敲除Pten会以区域特异性方式引发独特的细胞命运重编程与肿瘤起始过程。在前列腺前叶与背叶中，基底细胞会被重编程为丘状样状态（Hillock-like state），随后进展为基底-腔面杂合状态（basal-luminal hybrid state），并在进展为肿瘤发生（tumorigenesis）前进一步过渡为近端样腔面状态（proximal-like luminal state）。在前列腺腹叶中，表达Nkx3.1（NK3 homeobox 1, Nkx3.1）的基底细胞会分化为远端样腔面状态（distal-like luminal state），这类细胞可塑性更低，肿瘤发生进展速度更缓慢。
单细胞测序（single-cell sequencing）与ATAC-seq（assay for transposase-accessible chromatin sequencing）分析显示，在细胞重编程与肿瘤形成过程中，向丘状样与近端样状态的重编程会激活先天免疫通路（innate immunity pathway）。靶向干预IL-1（interleukin 1）、JAK/STAT（Janus kinase/signal transducer and activator of transcription）与NF-κB（nuclear factor kappa B）可抑制Pten诱导的细胞可塑性与致癌重编程（oncogenic reprograming），为前列腺癌的预防与治疗提供了新的思路。
实验设计（Overall design）：为阐明与前列腺中致癌打击诱导的基底细胞多能性相关的染色质重塑（chromatin remodeling）与基因调控网络（gene regulatory networks），我们对野生型（wild-type, WT）小鼠中经荧光激活细胞分选（fluorescence-activated cell sorting, FACS）分离得到的基底细胞与腔面细胞（luminal cells, LCs），以及在基底细胞中敲除Pten 6周后的基底细胞进行了批量ATAC-seq（bulk ATAC-seq）检测。