Spatial Transcriptomic Analysis of Ovarian Cancer Precursors Reveals Reactivation of IGFBP2 during Pathogenesis

Elucidating the earliest pathogenic steps in cancer develop-ment is fundamental to improving its early detection and pre-vention. Ovarian high-grade serous carcinoma (HGSC), a highly aggressive cancer, mostly originates from the fallopian tube epithelium through a precursor stage, serous tubal intraepithelial carcinoma (STIC). In this study, we performed spatial transcrip-tomic analysis to compare STICs, carcinoma, and their matched normal fallopian tube epithelium. Several differentially expressed genes in STICs and carcinomas were involved in cancer metab-olism and detected in a larger independent transcriptomic data -set of ovarian HGSCs. Among these, insulin-like growth factor binding protein-2 (IGFBP2) was found to undergo DNA hypo-methylation and to be increased at the protein level in STICs. Pyrosequencing revealed an association of IGFBP2 expression with the methylation state of its proximal enhancer, and 5-aza-cytidine treatment increased IGFBP2 expression. In postmeno-pausal fallopian tubes, where most STICs are detected, IGFBP2 immunoreactivity was detected in all 38 proliferatively active STICs but was undetectable in morphologically normal tubal epithelia, including those with TP53 mutations. In premenopaus-al fallopian tubes, IGFBP2 expression was limited to the secretory epithelium at the proliferative phase, and estradiol treatment increased IGFBP2 expression levels. IGFBP2 knockdown sup-pressed the growth of IGFBP2-expressing tubal epithelial cells via inactivation of the AKT pathway. Taken together, demethylation of the proximal enhancer of IGFBP2 drives tumor development by maintaining the increased IGFBP2 required for proliferation in an otherwise estrogen-deprived, proliferation-quiescent, and postmenopausal tubal microenvironment.Significance: Molecular studies of the earliest precursor lesions of ovarian cancer reveal a role of IGFBP2 in propelling tumor initiation, providing new insights into ovarian cancer development.

Automated summary

By analyzing the precursor stage and cancer tissue of high-grade serous carcinoma (HGSC) in the ovary, researchers have identified the role of IGFBP2 in driving tumor initiation, providing new insights into ovarian cancer development.