Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.

Axon-dependent expression of YAP/TAZ mediates Schwann cell remyelination but not proliferation after nerve injury

“…YAP (Yes-associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif), are paralogous transcription coactivators, chiefly known as potent stimulators of cellular proliferation in diverse developing (von Gise et al, 2012; Zhang et al, 2012; Xin et al, 2013; Cotton et al, 2017) and neoplastic (Yu et al, 2015; Zanconato et al, 2016; Moon et al, 2018) tissues. Consistent with this role, we and others have recently shown that YAP/TAZ promote vigorous proliferation of immature Schwann cells (SC) in developing peripheral nerves (Poitelon et al, 2016; Deng et al, 2017; Grove et al, 2017), and that overexpression of YAP/TAZ promotes tumorigenic proliferation of mature SCs in adult peripheral nerves (Mindos et al, 2017; Wu et al, 2018). Unexpectedly, several groups demonstrated that YAP or YAP/TAZ promote differentiation of developing SCs by upregulating myelin-associated genes, thereby mediating developmental myelination (Fernando et al, 2016; Lopez-Anido et al, 2016; Poitelon et al, 2016; Deng et al, 2017; Grove et al, 2017).…”

“…YAP/TAZ are located in the nuclei of developing SCs, where they promote proliferation and differentiation (Poitelon et al, 2016; Deng et al, 2017; Grove et al, 2017). They are also nuclear and transcriptionally active in adult SCs that maintain the myelin sheath (Grove et al, 2017) and that proliferate abnormally (Wu et al, 2018). It was therefore particularly intriguing to find that YAP/TAZ become undetectable in denervated SCs, and that they reappear as axons regenerate.…”

“…This result is consistent with the notion that the mechanism for SC proliferation during development differs from that for proliferation after injury (Atanasoski et al, 2001; Atanasoski et al, 2008). However, abnormally high levels of YAP elicit excessive SC proliferation in Merlin mutants after nerve injury (Mindos et al, 2017), and YAP/TAZ overexpression induced by LATS1/2 inactivation elicits tumorigenic SC proliferation in adult nerves (Wu et al, 2018). These observations, together with our present results, indicate that YAP/TAZ are not normally involved in injury-elicited SC proliferation, but that, if overexpressed, YAP/TAZ can stimulate mature or denervated SCs to proliferate.…”

“…Third, YAP/TAZ in adult SCs function primarily to maintain myelination, which may explain why they are removed completely from denervated SCs. Tumorigenic proliferation of adult SCs associated with abnormally increased YAP/TAZ levels (Wu et al, 2018) suggests the importance of maintaining proper levels of YAP/TAZ, but it does not explain why denervated SCs must lose YAP/TAZ completely. We attribute the requirement for complete loss to the pivotal role of YAP/TAZ in myelin maintenance by adult SCs (Grove et al, 2017).…”

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

“…Indeed, clinical case studies of patients with concurrent NF1-induced tumors and Charcot-Marie Tooth disease have been reported in the literature suggesting a possible overlap in underlying biology [40][41][42] . While the role of EGR2 in Schwann cell differentiation is still under active investigation [43] , EGR2-driven pathways have been found to be significantly downregulated in Lats1/2 deficient Schwann cell based MPNST models [44] . Furthermore, EGR2 expression in immune cells has been shown to be important for activation of M1/M2 macrophages [45] as well as regulation of CD4+ T cells [46] .…”