Conditional inactivation of Smarcb1 in P0 permissive mouse cells generates rhabdoid tumors in the peripheral nervous system and in the brain

Jeremie Vitte 1, Fabrice Chareyre1, Anat Stemmer-Rachamimov2, Alexander Judkins3, Marco Giovannini1
1Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, USA, 2Molecular Neuro-Oncology and Pathology Department, Massachusetts General Hospital and Harvard Medical School, Boston, USA, 3Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, USA

Inactivation of the SMARCB1/Snf5/Ini1 tumor-suppressor gene was originally described as a hallmark of malignant rhabdoid tumors (MRT), an aggressive tumor of early childhood. Recently, SMARCB1 germline mutations have been found in patients with familial or sporadic schwannomatosis, which is characterized by the onset of multiple schwannomas, benign tumors occurring during adolescence and adulthood. The mechanisms by which SMARCB1 germline mutations predispose to schwannomatosis versus MRT are still unknown. Schwannomas are benign neoplasms of the peripheral nerve sheath and are believed to have their origin in embryonic neural crest cells. We used conditional mutagenesis to investigate the role of Smarcb1 biallelic inactivation in mouse neural crest and Schwann cell lineage. In this model, Cre recombinase expression was under the control of the protein zero (P0) gene promoter. P0Cre;Smarcb1flox/flox mice showed reduced viability and at 5 months of age most of the mice presented tumors arising from different cranial nerves (olfactory, trigeminal, vestibulocochlear) or developing in the brain. Brain tumors were mostly found very close to or in contact with the meninges of the rostral part of the cortex leading to the hypothesis that these tumors would arise from the cranial neural crest cell-derived meninges. Analysis of the tumors demonstrated typical histological features of rhabdoid tumors with a histologic spectrum from a primitive neuroectodermal pattern to a more differentiated mesenchymal pattern with extensive spindle shape cell differentiation. Typical rhabdoid cells were found isolated or in nest in most of the tumors. Molecular analysis of the tumors showed derepression of cyclin D1 as found in mouse and human MRT. Altogether, our data not only establish a new model of Smarcb1-related tumorigenesis, but also provide important insight into the cell of origin of MRT.