WNT and inflammatory signaling distinguish human Fallopian tube epithelial cell populations.

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.

Gastric squamous-columnar junction contains a large pool of cancer-prone immature osteopontin responsive Lgr5-CD44+ cells.

Areas of a junction between two types of epithelia are known to be cancer-prone in many organ systems. However, mechanisms for preferential malignant transformation at the junction areas remain insufficiently elucidated. Here we report that inactivation of tumor suppressor genes Trp53 and Rb1 in the gastric squamous-columnar junction (SCJ) epithelium results in preferential formation of metastatic poorly differentiated neoplasms, which are similar to human gastroesophageal carcinoma. Unlike transformation-resistant antral cells, SCJ cells contain a highly proliferative pool of immature Lgr5-CD44+ cells, which are prone to transformation in organoid assays, comprise early dysplastic lesions, and constitute up to 30% of all neoplastic cells. CD44 ligand osteopontin (OPN) is preferentially expressed in and promotes organoid formation ability and transformation of the SCJ glandular epithelium. OPN and CD44 overexpression correlate with the worst prognosis of human gastroesophageal carcinoma. Thus, detection and selective targeting of the active OPN-CD44 pathway may have direct clinical relevance.