ABSTRACT
Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/ß-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment.
Subject(s)
Carcinogenesis/metabolism , Cell Proliferation , ELAV-Like Protein 1/metabolism , Neoplasm Proteins/metabolism , Nerve Sheath Neoplasms/metabolism , Signal Transduction , Animals , Carcinogenesis/genetics , Carcinogenesis/pathology , Cell Line, Tumor , ELAV-Like Protein 1/genetics , Humans , Mice , Neoplasm Metastasis , Neoplasm Proteins/genetics , Nerve Sheath Neoplasms/genetics , Nerve Sheath Neoplasms/pathologyABSTRACT
Most of the studies on cutaneous wound healing are focused on epidermal closure. This is obviously important, as the epidermis constitutes the main barrier that separates the inner organism from the environment. However, dermal remodeling is key to achieve long-lasting healing of the area that was originally wounded. In this chapter, we summarize what is known on the stromal components that strongly influence the outcome of healing and postulate that dedifferentiation of stably differentiated cells plays a major role in the initial response to wounding, as well as in long-term wound remodeling. Specifically, we explore the available evidence implicating skin pericytes, endothelial cells, Schwann cells, and macrophages as major players in a complex symphony of cellular plasticity and signaling events whose balance will promote healing (by tissue regeneration or repair) or fibrosis.
Subject(s)
Pericytes , Wound Healing , Cell Differentiation , Schwann Cells , SkinABSTRACT
The embryonic origin of lineage precursors of the trunk dermis is somewhat controversial. Precursor cells traced by Myf5 and Twist2 (Dermo1) promoter activation (i.e., cells of presumed dermomyotomal lineage) have been reported to generate Schwann cells. On the other hand, abundant data demonstrate that dermal Schwann cells derive from the neural crest. This is relevant because dermal precursors give rise to neural lineages, and multilineage differentiation potential qualifies them as adult stem cells. However, it is currently unclear whether neural lineages arise from dedifferentiated Schwann cells instead of mesodermally derived dermal precursor cells. To clarify these discrepancies, we traced SOX2+ adult dermal precursor cells by two independent Myf5 lineage tracing strains. We demonstrate that dermal Schwann cells do not belong to the Myf5+ cell lineage, indicating that previous tracing data reflected aberrant cre recombinase expression and that bona fide Myf5+ dermal precursors cannot transdifferentiate to neural lineages in physiological conditions.
Subject(s)
Cell Lineage , Dermis/cytology , Mouse Embryonic Stem Cells/cytology , Myogenic Regulatory Factor 5/metabolism , Schwann Cells/cytology , Animals , Cells, Cultured , Dermis/embryology , Mice , Mouse Embryonic Stem Cells/metabolism , Myogenic Regulatory Factor 5/genetics , SOXB1 Transcription Factors/genetics , SOXB1 Transcription Factors/metabolism , Schwann Cells/metabolismABSTRACT
Dermal neurofibromas are characteristic of neurofibromatosis type one (NF1), and their developmental origin still unsolved. Although NF1 loss is required for neurofibroma initiation, some features of these benign tumors resemble a skin injury state and cutaneous trauma or other insults might support tumor development. Since adult terminal Schwann cells ensheathing nerve endings are able to dedifferentiate into a progenitor-like state in response to nerve crushing, we hypothesized that dedifferentiation of NF1-/- Schwann cells could be at the origin of human dermal neurofibromas. In support of this, here we show that CDH19 (a marker specific of Schwann cell precursors) and Schwann cell dedifferentiation marker SOX2 are significantly upregulated in NF1 tumors. We posit that onset of nerve regeneration might have a role in dermal neurofibroma initiation via dedifferentiation of NF1-/- Schwann cells.
Subject(s)
Cell Dedifferentiation , Neurofibroma/etiology , Schwann Cells/physiology , Skin Neoplasms/etiology , HumansABSTRACT
Resident neural precursor cells (NPCs) have been reported for a number of adult tissues. Understanding their physiological function or, alternatively, their activation after tissue damage or in vitro manipulation remains an unsolved issue. Here, we investigated the source of human dermal NPCs in adult tissue. By following an unbiased, comprehensive approach employing cell-surface marker screening, cell separation, transcriptomic characterization, and in vivo fate analyses, we found that p75NTR(+) precursors of human foreskin can be ascribed to the Schwann (CD56(+)) and perivascular (CD56(-)) cell lineages. Moreover, neural differentiation potential was restricted to the p75NTR(+)CD56(+) Schwann cells and mediated by SOX2 expression levels. Double-positive NPCs were similarly obtained from human cardiospheres, indicating that this phenomenon might be widespread.
Subject(s)
Cell Lineage , Dermis/cytology , Neural Stem Cells/cytology , Schwann Cells/cytology , Adolescent , Adult , Aged , Animals , CD56 Antigen/genetics , CD56 Antigen/metabolism , Cell Differentiation/genetics , Cells, Cultured , Child , Child, Preschool , Dermis/metabolism , Foreskin/cytology , Gene Expression Profiling , Humans , Infant , Male , Mice , Microscopy, Confocal , Middle Aged , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neural Stem Cells/metabolism , Neurons/cytology , Neurons/metabolism , Receptors, Nerve Growth Factor/genetics , Receptors, Nerve Growth Factor/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Schwann Cells/metabolism , Young AdultABSTRACT
We report a new supramolecular dynamic hydrogel, based on a new concept of reversible aurophilic cross-linkers, mimicking the rheological behaviour of healthy synovial fluid under physiological conditions with good cell viability.
Subject(s)
Gold/chemistry , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Synovial Fluid/chemistry , Cell Line , Cell Survival , Cross-Linking Reagents/chemistry , Humans , Hydrogel, Polyethylene Glycol Dimethacrylate/pharmacology , Hydrogen-Ion Concentration , Polyethylene Glycols/chemistry , RheologyABSTRACT
The most characteristic feature of neurofibromatosis type 1 (NF1) is the development of neurofibromas. It has been suggested that these tumors are caused by somatic inactivation of the wild-type NF1 allele, but the cell that originally suffers this mutation remains controversial. Several lines of evidence support the clonal origin of these tumors, and it has been recently suggested that skin-derived precursor cells (SKPs) could be the cell of origin of dermal neurofibromas. Nullizygous (NF1(-/-)) SKPs do give rise to neurofibromas when transplanted to heterozygous mice. Moreover, a nullizygous population of cells that is S100ß negative is present in human neurofibromas, and NF1(+/-) multipotent progenitor cells are seemingly recruited to the tumor. This evidence supports the neurofibroma stem cell hypothesis and a putative involvement of SKPs in the aetiopathogenesis of the disease, suggesting that SKPs could become a valuable tool for the in vitro study of NF1.
