Escape from NK cell tumor surveillance by NGFR-induced lipid remodeling in melanoma

Metastatic disease is a major cause of death for patients with melanoma. Melanoma cells can become metastatic not only due to cell-intrinsic plasticity but also due to cancer-induced protumorigenic remodeling of the immune microenvironment. Here, we report that innate immune surveillance by natural killer (NK) cells is bypassed by human melanoma cells expressing the stem cell marker NGFR. Using in vitro and in vivo cytotoxic assays, we show that NGFR protects melanoma cells from NK cell–mediated killing and, furthermore, boosts metastasis formation in a mouse model with adoptively transferred human NK cells. Mechanistically, NGFR leads to down-regulation of NK cell activating ligands and simultaneous up-regulation of the fatty acid stearoyl–coenzyme A desaturase (SCD) in melanoma cells. Notably, pharmacological and small interfering RNA–mediated inhibition of SCD reverted NGFR-induced NK cell evasion in vitro and in vivo. Hence, NGFR orchestrates immune control antagonizing pathways to protect melanoma cells from NK cell clearance, which ultimately favors metastatic disease

Characterization of the structure and control of the blood-nerve barrier identifies avenues for therapeutic delivery

The blood barriers of the nervous system protect neural environments but can hinder therapeutic accessibility. The blood-brain barrier (BBB) is well characterized, consisting of endothelial cells with specialized tight junctions and low levels of transcytosis, properties conferred by contacting pericytes and astrocytes. In contrast, the blood-nerve barrier (BNB) of the peripheral nervous system is poorly defined. Here, we characterize the structure of the mammalian BNB, identify the processes that confer barrier function, and demonstrate how the barrier can be opened in response to injury. The homeostatic BNB is leakier than the BBB, which we show is due to higher levels of transcytosis. However, the barrier is reinforced by macrophages that specifically engulf leaked materials, identifying a role for resident macrophages as an important component of the BNB. Finally, we demonstrate the exploitation of these processes to effectively deliver RNA-targeting therapeutics to peripheral nerves, indicating new treatment approaches for nervous system pathologies

The regulation of peripheral nerve homeostasis, regeneration and tumourigenesis

Peripheral nerves are regenerative, with Schwann cells (SCs), the main glial cells of the peripheral nervous system, orchestrating multiple aspects of the multicellular regenerative process. A regenerating nerve resembles tumours that form in this tissue in patients with Neurofibromatosis Type 1 (NF1) and in a mouse model we have developed, we have identified a key role for the injured microenvironment in stimulating tumour formation derived from adult Nf1-/- myelinating Schwann cells (mSCs). Here, we have investigated the homeostatic turnover of peripheral nerve and how this changes following injury in order to understand how the injured microenvironment could contribute to tumour formation. We find that mSCs do not turnover in adulthood. Following injury however, all mSCs proliferate and dedifferentiate to progenitor-like SCs, which contribute to the nerve regeneration process without the requirement for a distinct SC stem cell population. Moreover, lineage analysis, demonstrated that mSC derived cells retain the SC lineage but can switch from a mSC to a non-myelinating SC fate during nerve regeneration. In contrast, during tumourigenesis, Nf1-/- mSCs lose this lineage restriction. To identify the microenvironmental pro- and anti- tumourigenic signals involved in the early stages of tumourigenesis, we have characterised the early stages of tumour formation in our mouse model to identify the point of divergence between tissue regeneration and tumour formation. We subsequently performed a molecular analysis at this time-point that identified several potential pro- tumourigenic signals at the injury site. This work provides a further illustration of the distinct mechanisms that tissues use to maintain and repair themselves. Moreover, it provides insight into links between tissue repair and tumourigenesis and how studying these processes may provide new approaches for the treatment of this disease

Neural crest cells hijack pluripotent stem cell factors to realize their developmental potential

Neural crest cells arise in the neurectoderm of vertebrate embryos, but their developmental potential goes way beyond neurectodermal derivatives. In this issue of Developmental Cell, Hovland et al. reveal that neural crest cells re-employ embryonic stem cell factors in combination with specific transcription factors to enable their broad potential

Schwann cell precursors: a hub of neural crest development

Schwann cell precursors (SCPs) are transient glial progenitors that are important for the formation of late neural crest derivatives, yet their heterogeneity and developmental potential remain incompletely understood. In this issue, Kastriti, Faure, von Ahsen et al (2022) use comprehensive single-cell RNA sequencing analyses to identify a transient "hub" state common to SCPs and neural crest cells (NCCs), revealing a striking similarity of SCPs to late migrating NCCs. These results raise important questions about the potential role of such a state in adult tissue regeneration and tumourigenesis

Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4

Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::Nras$^{Q61K}$; Cdkn2a$^{−/−}$ melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism

The regulation of the homeostasis and regeneration of peripheral nerve is distinct from the CNS and independent of a stem cell population

Peripheral nerves are highly regenerative, in contrast to the poor regenerative capabilities of the central nervous system (CNS). Here, we show that adult peripheral nerve is a more quiescent tissue than the CNS, yet all cell types within a peripheral nerve proliferate efficiently following injury. Moreover, whereas oligodendrocytes are produced throughout life from a precursor pool, we find that the corresponding cell of the peripheral nervous system, the myelinating Schwann cell (mSC), does not turn over in the adult. However, following injury, all mSCs can dedifferentiate to the proliferating progenitor-like Schwann cells (SCs) that orchestrate the regenerative response. Lineage analysis shows that these newly migratory, progenitor-like cells redifferentiate to form new tissue at the injury site and maintain their lineage, but can switch to become a nonmyelinating SC. In contrast, increased plasticity is observed during tumourigenesis. These findings show that peripheral nerves have a distinct mechanism for maintaining homeostasis and can regenerate without the need for an additional stem cell population.</p

Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4

Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::Nras(Q61K); Cdkn2a(-/-) melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism. Melanoma cells can switch between proliferative and invasive phenotypes. Here the authors show that the embryonic stem cell factor Sall4 is a negative regulator of melanoma phenotype switching where its loss leads to the acquisition of an invasive phenotype, due to derepression of invasiveness genes.Funding Agencies|Functional Genomics Center Zurich (FGCZ) [p2155, p2419]; University of Zurich (University Priority Research Program (URPP) Translational Cancer Research); Swiss National Science FoundationSwiss National Science Foundation (SNSF)European Commission [31003A_169859, 310030_192075]; Swiss Cancer Research foundation [KFS-4570-08-2018]; Knut and Alice Wallenberg FoundationKnut &amp; Alice Wallenberg Foundation; CancerfondenSwedish Cancer Society [CAN 2018/542]; Candoc Forschungskredit [FK-19-026]</p