Biallelic Dicer1 Loss Mediated by aP2-Cre Drives Angiosarcoma

Abstract

Angiosarcoma is an aggressive vascular sarcoma with an extremely poor prognosis. Due to the relative rarity of this disease, its molecular drivers and optimal treatment strategies are obscure. DICER1 is an RNase III endoribonuclease central to microRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types. Here we show that biallelic Dicer1 deletion with aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/−mice histologically and genetically resemble human angiosarcoma. MicroRNA-23 target genes including the oncogenes Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis were enriched in mouse and human angiosarcoma. These studies illustrate that Dicer1 can function as a traditional loss-of-function tumor suppressor gene, and they provide a fully penetrant animal model for the study of angiosarcoma development and metastasis.

Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis

“…However, other studies indicate that DICER1 hotspot mutations are biallelic in cancer, and act in trans to nonsense or inactivating alleles of DICER1 20,21,37 . Surprisingly, certain murine cancer models are supported 38 or indeed driven 39 by full conditional inactivation of Dicer , suggesting that it can act as a conventional tumor suppressor in certain contexts. This may be the case in human pineoblastoma, for which germline DICER1 mutation combined with loss-of-heterozygosity was detected 40 .…”

Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity

“…Genetic fate mapping reveals aP2-Cre expression in white and brown adipocytes, dorsal root ganglia, macrophages, and endothelial cells 20 , 22 , 40 . Compound mutant mice using aP2-Cre to drive recombination resulting in biallelic Dicer1 deletion or the combination of oncogenic Kras G12D activation and Cdkn2a deletion result in angiosarcoma from the transformation of endothelial cells 20 , 41 . However, activation of constitutively active, oncogenic SMO M2 , and hedgehog pathway signaling by aP2-Cre results in cell reprogramming and transformation of endothelial progenitor cells driving FN-RMS tumorigenesis 20 .…”

“…Images quantified with Nikon Elements Basic Research (v4.1.3) or FIJI’s (ImageJ, NIH) total nuclei cell counter. Specimens for transmission electron micrographs prepared and imaged as described in 41 . Briefly, tumor tissue was fixed in 2.5% glutaraldehyde, 2% paraformaldehyde, in 0.1 M sodium cacodylate buffer (pH 7.4) and post-fixed in 2% osmium tetroxide in 0.1 M cacodylate buffer with 0.15% potassium ferrocyanide.…”

Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice

“…The established role of DICER1 in mediating developmental and pathological angiogenesis and neovascularization is largely context-and tissue type-dependent. For example, whereas DICER1 ablation prevents developmental and postnatal angiogenesis in multiple diverse settings (23,(66)(67)(68)(69), DICER1 deficiency can promote neovascularization in stroke (70), angiosarcoma (71), and renal cell carcinoma (72,73). Furthermore, exogenous delivery of DICER1 suppresses tumor angiogenesis (72) and hypoxia-induced angiogenic responses in human endothelial cells (74).…”