WNT and inflammatory signaling distinguish human Fallopian tube epithelial cell populations

Abstract

Many high-grade serous carcinomas (HGSCs) likely originate in the distal region of the Fallopian tube’s epithelium (TE) before metastasizing to the ovary. Unfortunately, molecular mechanisms promoting malignancy in the distal TE are obfuscated, largely due to limited primary human TE gene expression data. Here we report an in depth bioinformatic characterization of 34 primary TE mRNA-seq samples. These samples were prepared from proximal and distal TE regions of 12 normal Fallopian tubes. Samples were segregated based on their aldehyde dehydrogenase (ALDH) activity. Distal cells form organoids with higher frequency and larger size during serial organoid formation assays when compared to proximal cells. Consistent with enrichment for stem/progenitor cells, ALDH+ cells have greater WNT signaling. Comparative evaluation of proximal and distal TE cell population’s shows heightened inflammatory signaling in distal differentiated (ALDH−) TE. Furthermore, comparisons of proximal and distal TE cell populations finds that the distal ALDH+ TE cells exhibit pronounced expression of gene sets characteristic of HGSC sub-types. Overall, our study indicates increased organoid forming capacity, WNT/inflammatory signaling, and HGSC signatures underlie differences between distal and proximal regions of the human TE. These findings provide the basis for further mechanistic studies of distal TE susceptibility to the malignant transformation.

Organoids of the Female Reproductive Tract: Innovative Tools to Study Desired to Unwelcome Processes

“…Notch inhibition by use of a γ-secretase inhibitor propelled ciliogenesis (Kessler et al, 2015), as later also found in endometrial organoids (Haider et al, 2019). It was also demonstrated that the fimbrial ends of the oviducts possess the highest organoid-forming capacity, both in mouse (Xie et al, 2018) and human (Rose et al, 2020), and that human fimbrial ALDH+ cells replicate with higher frequency and form larger structures (Rose et al, 2020). Co-culturing of FT epithelial cells with FT stromal cells and endothelial (HUVEC) cells formed more complex organoid structures (Chang et al, 2020).…”

Quantitative clonal analysis reveals vast heterogeneity among fallopian tube cells for ovarian cancer-initiation and progression

“…The distal FT preference and high clonogenic potential of the founder cells for large clones raised the possibility that these cells might represent a more primitive population (Fuchs and Segre, 2000; Ghosh et al, 2017; Paik et al ., 2012; Rose et al ., 2020; Wang et al, 2012; Xie et al, 2018). Speculating that a portion of the cells within the large clones might retain the primitive property of the clonal founders, we hypothesized that the large clones maintain a more primitive status than the small clones.…”

“…However, recent studies suggest heterogeneity among FT Pax8+ cells. As in vitro cultures of isolated FT epithelial cells, Pax8+ cells have a heterogeneous ability to form organoids and self-renew, indicating the existence of a more primitive subset (Paik et al, 2012; Rose et al, 2020). Although in vivo data are lacking, these findings raise the question of whether all or only specific subsets of Pax8+ cells possess the cancer-initiating capacity in vivo.…”

In vitro modelling of the physiological and diseased female reproductive system

“…Further exploration using these organoids revealed the involvement of Notch and WNT signalling in maintaining stemness and in differentiation to ciliated and secretory cells. FTderived organoids were also instrumental in documenting the existence of tissue regional (proximal versus distal) differences in stem cell abundance, phenotype (cancer proneness), and regulation by WNT and inflammatory signals [288]. Chronic Chlamydia infection causes FT scarring and can lead to infertility.…”

“…Recapitulates proximal and distal epitehlium [288] Pathogen infection studies: Chlamydia infection [289] Matrigel [289]…”