GNAQ^Q209L expression initiated in multipotent neural crest cells drives aggressive melanoma of the central nervous system

Abstract

Primary leptomeningeal melanocytic neoplasms represent a spectrum of rare tumors originating from melanocytes of the leptomeninges, which are the inner two membranes that protect the central nervous system. Like other non‐epithelial melanocytic lesions, they bear frequent oncogenic mutations in the heterotrimeric G protein alpha subunits, GNAQ or GNA11. In this study, we used Plp1‐creERT to force the expression of oncogenic GNAQQ209L in the multipotent neural crest cells of the ventro‐medial developmental pathway, beginning prior to melanocyte cell differentiation. We found that this produces leptomeningeal melanocytic neoplasms, including cranial melanocytomas, spinal melanocytomas, and spinal melanomas, in addition to blue nevus‐like lesions in the dermis. GNAQQ209L drove different phenotypes depending upon when during embryogenesis (E9.5, E10.5, or E11.5) it was induced by tamoxifen and which Cre driver (Plp1‐creERT, Tyr‐creERT2, or Mitf‐cre) was used. Given these differences, we propose that melanocytes go through temporary phases where they become sensitive to the oncogenic effects of GNAQQ209L. R26‐fs‐GNAQQ209L; Plp1‐creERT mice will be useful for defining biomarkers for potentially aggressive leptomeningeal melanocytomas and for developing new therapeutics for advanced disease.

Endothelin signaling promotes melanoma tumorigenesis driven by constitutively active GNAQ

“…One of the Mitf-cre/+; Rosa26-fs-GNAQ Q209L /+; +/+ mice developed a large, raised leptomeningeal melanoma on the spine that necessitated its euthanasia at 34 weeks (described in Figure S9). A GNAQ Q209L model that consistently drives this tumor type is described in Urtatiz et al (2019). The other Mitf-cre/+; Rosa26-fs-GNAQ Q209L /+; +/+ mouse had no raised lesions that we could observe upon visual inspection, but it had begun to lose weight (9% at its last weighing) and was found dead at 40 weeks of age.…”

“…However, all lesions were restricted to the dermis, uveal tract, or meninges. We documented benign dermal hyperpigmentation (the Dsk alleles) (Van Raamsdonk et al., 2004), nevi/melanocytomas that were composed of abnormal melanocytes, yet remained diffuse and flat (Huang, Urtatiz, & Van Raamsdonk, 2015; Urtatiz, Cook, Huang, Yeh, & Van Raamsdonk, 2019), and malignant melanomas that rose vertically were composed of a dense concentration of hyper‐pigmented cells and grew in size (Huang et al., 2015; Urtatiz et al., 2019). These latter lesions caused a decline in mouse health, ulcerated if in the dermis, spread into surrounding tissues, and sometimes formed large metastases in the lungs.…”

Update on GNA Alterations in Cancer: Implications for Uveal Melanoma Treatment

“…Although a direct link between the activation of G proteins/GPCRs and tumor development has been proven, no therapeutic strategy targeting the function of G proteins is currently available in clinics [81]. Nevertheless, in light of the data discussed above, it appears quite obvious that the inhibition of oncogenic G proteins and their downstream targets should lead to the efficient killing of tumors that developed from driver GNA mutations [82].…”

“…inhibition of oncogenic G proteins and their downstream targets should lead to the efficient killing of tumors that developed from driver GNA mutations [82]. The so-called guanine nucleotide dissociation inhibitors (GDI) are molecules that are able to maintain G proteins in their GDP-bound inactive state (Figure 1).…”

Uveal melanoma cells use ameboid and mesenchymal mechanisms of cell motility crossing the endothelium

“…The eye is the second most common site of melanoma. UM and cutaneous melanoma are distinct diseases [1,2].…”