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Lineage tracing of mutant granulosa cells reveals in vivo protective mechanisms that prevent granulosa cell tumorigenesis

ABSTRACT: In the current study, we combined a multi-fluorescent reporter mouse model with a conditional knockout mouse model, in which the tumor suppressor genes Pten and p27 were deleted in GCs, to perform cell lineage tracing of mutant GCs. We found that only 30% of ovaries with substantial mutant GCs developed into GCTs that derived from a single mutant GC. In-depth molecular analysis of the process of tumorigenesis demonstrated that up-regulation of immune evasion genes Cd24a and Cd47 led, in part, to the transition of mutant GCs to GCTs. Therefore, treatment with the Cd47 inhibitor RRX-001 was tested and found to efficiently suppress the growth of GCTs in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE220947 | GEO | 2023/05/10

REPOSITORIES: GEO

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Project description:Stable activation of the WNT signaling effector beta-catenin (CTNNB1(ex3) in ovarian granulosa cells results in the formation of premalignant lesions that develop into granulosa cell tumors (GCTs) spontaneously later in life. Loss of the tumor suppressor gene Pten accelerates GCT formation in the CTNNB1 strain. Conversely, expression of oncogenic KRASG12D causes the dramatic arrest of proliferation, differentiation and apoptosis in granulosa cells, and consequently, small abnormal follicle-like structures devoid of oocytes accumulate in the ovary. Because of the potent anti-proliferative effects of KRASG12D in granulosa cells, we sought to determine if KRASG12D would block precancerous lesion and tumor formation in follicles of the CTNNB1 mutant mice. Unexpectedly, transgenic Ctnnb1;Kras mutant mice developed early-onset GCTs leading to premature death in a manner similar to theCtnnb1;Pten mutant mice. Moreover, the GCTs in the Ctnnb1;Kras mutant mice exhibited increased GC proliferation, decreased apoptosis and impaired differentiation. Microarray and RT-PCR analyses revealed that ovaries from mice expressing dominant-stable CTNNB1 with either Pten loss or KRAS activation were unpredictably similar. Specifically, gene regulatory processes induced by CTNNB1 were mostly enhanced by either KRAS activation or Pten loss in remarkably similar patterns and degree. Furthermore, the concomitant activation of CTNNB1 and KRAS in Sertoli cells resulted in the development of granulosa cell tumors of the testis. RT-PCR studies showed a partial overlap in gene regulatory processes associated with tumor development in the ovary and testis. Together, these results suggest that KRAS activation and Pten loss induce GCT development from premalignant lesions via highly similar molecular mechanisms. four samples: average of two wild type samples (previously submitted as GSM403220 and GSM403221), beta-Catenin constitutively active mutant, beta-Catenin;Pten double mutant, and beta-Catenin;Kras(G12D) double mutant

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Lineage tracing of mutant granulosa cells reveals in vivo protective mechanisms that prevent granulosa cell tumorigenesis

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