Genetic context of oncogenic drivers dictates vascular sarcoma development in aP2‐Cre mice

Abstract

Angiosarcomas are aggressive vascular sarcomas that arise from endothelial cells and have an extremely poor prognosis. Because of the rarity of angiosarcomas, knowledge of molecular drivers and optimized treatment strategies is lacking, highlighting the need for in vivo models to study the disease. Previously, we generated genetically engineered mouse models of angiosarcoma driven by aP2‐Cre‐mediated biallelic loss of Dicer1 or conditional activation of KrasG12D with Cdkn2a loss that histologically and genetically resemble human tumors. In the present study, we found that DICER1 functions as a potent tumor suppressor and its deletion, in combination with either KRASG12D expression or Cdkn2a loss, is associated with angiosarcoma development. Independent of the genetic driver, the mTOR pathway was activated in all murine angiosarcoma models. Direct activation of the mTOR pathway by conditional deletion of Tsc1 with aP2‐Cre resulted in tumors that resemble intermediate grade human kaposiform hemangioendotheliomas, indicating that mTOR activation was not sufficient to drive the malignant angiosarcoma phenotype. Genetic dissection of the spectrum of vascular tumors identified genes specifically regulated in the aggressive murine angiosarcomas that are also enriched in human angiosarcoma. The genetic dissection driving the transition across the malignant spectrum of endothelial sarcomas provides an opportunity to identify key determinants of the malignant phenotype, novel therapies for angiosarcoma, and novel in vivo models to further explore angiosarcoma pathogenesis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

MicroRNAs and angiosarcoma: are there promising reports?

“…Studies demonstrated that biallelic Dicer1 deletion can lead to aggressive and metastatic angiosarcoma, even in the absence of additional oncogenic mutations (90). Studies in mice have demonstrated that biallelic loss of Dicer1 predisposes endothelial cells to angiosarcoma formation, highlighting the critical role of DICER1 in maintaining proper miRNA biogenesis (90,91). This finding strengthens the link between miRNA alterations and angiosarcoma development (82).…”

Target gene regulatory network of miR-497 in angiosarcoma

“…3D and Supplementary Table S3). To determine the miR-497 target genes potentially involved in AS, GO was performed on the 72 overlapping genes downregulated in the miR-497 transfected cells and upregulated in aP2-Cre;Dicer1 cKO (AD cKO ) 30 murine AS tumors (Fig. 4D).…”

“…Resources to study AS are limited, therefore developing models to study the disease is crucial for making novel discoveries. We have previously developed mouse models to recapitulate AS, including models driven by oncogenic KRAS and conditional Dicer1 deletion in endothelial cells 29,30,43 . Because Dicer1 is essential for microRNA (miRNA) biogenesis, this suggests that loss of mature miRNAs is responsible for this tumor development, however, other non-canonical Dicer1 could be attributed as well.…”

“…Furthermore, DICER1 mutations have been reported in patient AS samples, suggesting that global miRNA perturbations may be an important component of AS pathogenesis 28 . In addition, we previously demonstrated biallelic loss of Dicer1 in endothelial cells drives AS tumor formation in mice 29,30 . Given the essential role DICER1 serves in miRNA biogenesis, these findings suggest that miRNAs loss plays a critical role in the development of AS, therefore warranting more investigation into their role in disease progression.…”

“…Cells were obtained from the following sources: HMEC-1 (CRL-3243, American Type Culture Collection [ATCC], Manassas, VA, USA), MS1 (ATCC, CRL-2279), SVR (ATCC, CRL-2280), EOMA (M. Roussel, St. Jude Children's Research Hospital), ADC106 (derived from our lab as previously described 30 ), HEK-293T (M. Kazemian, Purdue University), MDA-MB-231 (M. Wendt, Purdue University), AS5 (E. Dickerson, University of Minnesota 54,55 ). HMEC-1 cells were maintained in MCDB131 (15100CV Corning, NY, USA) supplemented with 10 ng/ml EGF (23626, R&D Systems, Minneapolis, MN, USA), 1 μg/ml hydrocortisone (0219456901, MP Biomedicals, Irvine, CA, USA), 1× Glutamax (35050, Gibco/Thermo Fisher Scientific, Waltham, MA, USA), and 10% FBS (SH3091003, Hyclone, Logan, UT, USA).…”