0 avis
Glial-to-mesenchymal transition drives malignant progression of plexiform neurofibromas in a mouse model of NF1
Archive ouverte
Edité par CCSD -
International audience. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with no effective therapy to date. In the context of NF1, MPNSTs arise from plexiform neurofibromas (pNFs), which are benign nerve sheath tumors. Better characterization of the mechanisms driving pNF-to-MPNST transformation is crucial to develop effective treatment strategies for preventing disease progression.Our lab developed a mouse model in which Nf1 is conditionally invalidated in boundary cap cells1 and that recapitulates several symptoms of NF1, including the development of pNF and their spontaneous progression into MPNSTs. To further characterize the progression of pNF into MPNST, we generated a biobank of tumors and particularly focused on tumor cells.By whole exome sequencing, we showed that the loss of copies of Cdkn2a is the earliest genetic event in MPNST and is accompanied by few other variants. Successive tumor cells transplantation leads to an increased number of variants, including pathogenic p53 variant, indicating that most of our primary tumors were low grade (LG) MPNSTs.Using single-cell RNA sequencing data, we identified that malignant transformation is characterized by the loss of canonical Schwann cell lineage markers and activation of mesenchymal gene expression programs, a process that we named glial-to-mesenchymal transition (GMT), and which has been described in NF1 patients. Immuno-histochemistry staining highlighted that the GMT is concordant with disruption of cellular adhesion, increased tumor cells proliferation, and acquisition of migratory and invasive properties. In some LG MPNSTs, GMT precedes the genetic burden, suggesting that it might be driven by epigenetic events, highlighting a possible reversibility of the process. Differential expression analyses during GMT provided a list of known and novel candidate target genes that might guide development of therapeutic solutions, including Sox9, that we propose as a biomarker of GMT. To functionally validate the role of Sox9 in MPNST progression, we blocked Sox9 in tumor cell culture from primary MPNST using shRNA. We showed that Sox9 blockage impedes tumor growth for several days in allografted immunocompromised mice, thus suggesting Sox9 as an actionable target. Using it as a read-out for a screening of 3,000 FDA approved drugs showed that top 12 drugs directly target RAS pathway. Our mouse model spontaneously develops MPNST from pNF, that faithfully recapitulates their human counterparts, including GMT and loss of Cdkn2a. We decoded and targeted early steps of malignant progression. Using Sox9 as a biomarker of malignant transformation, we identified RAS pathway as a therapeutic target in LG MPNST. Since GMT can occur in absence of genetic burden, we aim to characterize the epigenetic events driving early GMT.
Consulter en ligne
Suggestions
Du même auteur
