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Abstract:Dysregulation of signaling networks controlling self-renewal and migration of developmental cell lineages is closely linked to the proliferative and invasive properties of tumors. Identification of such signaling pathways and their critical regulators is vital for successful design of effective targeted therapies against neoplastic tissue growth. The neurotrophin receptor (CD271/NGFR/p75NTR) is a key regulator of the melanocytic cell lineage through its ability to mediate cell growth, survival, and differentia… Show more
“…2c, d ). Taken together, these results indicate that NGFR is essential for proliferation, survival, and colony formation of MIC cells we isolated here, which is in agreement with previous studies 16 , 17 . Fig.…”
Section: Resultssupporting
confidence: 94%
“…Its high level was associated with melanoma progress in a clinical case study 23 , although another study suggested that its protein is unstable and thus might not be an ideal biomarker for human melanoma clinically 24 . Most recently, a clinical gene profiling study suggested that NGFR might play a divergent role in melanocyte and melanoma development through two different signaling pathways 17 . These studies highlight the importance of NGFR in MICs' renewal, proliferation, and derived tumorigenesis.…”
Section: Introductionmentioning
confidence: 99%
“…We showed that NGFR, in a negative feedback manner, suppresses p53 functions by directly inhibiting its transcriptional activity and assisting MDM2 in p53 degradation, consequently promoting the growth of human lung cancer cell-derived xenograft tumors 14 . Interestingly, NGFR has been shown to play a role in MIC renewal and proliferation 15 , 16 , as well as melanoma tumorigenesis and metastasis 15 , 17 .…”
Section: Introductionmentioning
confidence: 99%
“…For its physiological functions, it often partners with other receptors, such as TrkA, and is involved in a multitude of processes during neurogenesis, such as neural cell death, neuronal differentiation, neurite growth, and synaptic plasticity 18 . However, its level is also considerably high in several primary and metastatic human cancers 16 , 17 , 19 , including melanoma 16 , 17 . Earlier studies identified NGFR as a potential biomarker for MICs, as it was highly expressed in MICs and was important for MIC-derived tumor growth 15 , 20 .…”
Nerve growth factor receptor (NGFR, CD271, or p75NTR) is highly expressed in melanoma-initiating cells (MICs) and is critical for their proliferation and tumorigenesis, and yet the underlying mechanism(s) remain incompletely understood. We previously showed that NGFR inhibits p53 activity in a negative feedback manner in various cancer cells. Here we report that this feedback inhibition of p53 by NGFR plays an essential role in maintaining the sphere formation (stem-like phenotype) and proliferation of MICs, and in promoting MIC-derived melanoma growth in vivo. Knockdown of NGFR markedly reduced the size and number of spheroid formation of melanoma cells, which can be rescued by ectopically expressed NGFR. This reduction was also reversed by depleting p53. Consistently, knockdown of NGFR led to the suppression of MIC-derived xenograft tumor growth by inducing the p53 pathway. These results demonstrate that the NGFR-p53 feedback loop is essential for maintaining MIC stem-like phenotype and MIC-derived tumorigenesis, and further validates NGFR as a potential target for developing a molecule-based therapy against melanoma.
“…2c, d ). Taken together, these results indicate that NGFR is essential for proliferation, survival, and colony formation of MIC cells we isolated here, which is in agreement with previous studies 16 , 17 . Fig.…”
Section: Resultssupporting
confidence: 94%
“…Its high level was associated with melanoma progress in a clinical case study 23 , although another study suggested that its protein is unstable and thus might not be an ideal biomarker for human melanoma clinically 24 . Most recently, a clinical gene profiling study suggested that NGFR might play a divergent role in melanocyte and melanoma development through two different signaling pathways 17 . These studies highlight the importance of NGFR in MICs' renewal, proliferation, and derived tumorigenesis.…”
Section: Introductionmentioning
confidence: 99%
“…We showed that NGFR, in a negative feedback manner, suppresses p53 functions by directly inhibiting its transcriptional activity and assisting MDM2 in p53 degradation, consequently promoting the growth of human lung cancer cell-derived xenograft tumors 14 . Interestingly, NGFR has been shown to play a role in MIC renewal and proliferation 15 , 16 , as well as melanoma tumorigenesis and metastasis 15 , 17 .…”
Section: Introductionmentioning
confidence: 99%
“…For its physiological functions, it often partners with other receptors, such as TrkA, and is involved in a multitude of processes during neurogenesis, such as neural cell death, neuronal differentiation, neurite growth, and synaptic plasticity 18 . However, its level is also considerably high in several primary and metastatic human cancers 16 , 17 , 19 , including melanoma 16 , 17 . Earlier studies identified NGFR as a potential biomarker for MICs, as it was highly expressed in MICs and was important for MIC-derived tumor growth 15 , 20 .…”
Nerve growth factor receptor (NGFR, CD271, or p75NTR) is highly expressed in melanoma-initiating cells (MICs) and is critical for their proliferation and tumorigenesis, and yet the underlying mechanism(s) remain incompletely understood. We previously showed that NGFR inhibits p53 activity in a negative feedback manner in various cancer cells. Here we report that this feedback inhibition of p53 by NGFR plays an essential role in maintaining the sphere formation (stem-like phenotype) and proliferation of MICs, and in promoting MIC-derived melanoma growth in vivo. Knockdown of NGFR markedly reduced the size and number of spheroid formation of melanoma cells, which can be rescued by ectopically expressed NGFR. This reduction was also reversed by depleting p53. Consistently, knockdown of NGFR led to the suppression of MIC-derived xenograft tumor growth by inducing the p53 pathway. These results demonstrate that the NGFR-p53 feedback loop is essential for maintaining MIC stem-like phenotype and MIC-derived tumorigenesis, and further validates NGFR as a potential target for developing a molecule-based therapy against melanoma.
“…S1A). This high ENPP2 expression is unrelated to gene amplification or activation of oncogenic pathways (https://www.cbioportal.org) but rather reflects high ATX expression observed in normal melanocytes (Filipp et al, 2019) and results not shown). Remarkably, however, ENPP2 expression in cancer cells correlates rather poorly with that in the corresponding tumors (Suppl.…”
To improve immunotherapy efficacy, a better understanding of the factors that regulate Tcell migration into tumors is essential. Here we uncover a role for autotaxin (ATX) in this process. ATX (encoded by ENPP2) produces lysophosphatidic acid (LPA) that activates G protein-coupled receptors (LPAR1-6) to regulate multiple (patho)physiological processes, including tumor progression via LPAR1 and lymphocyte homing via LPAR2.Unexpectedly, we find that melanoma cell-secreted ATX is a major chemorepellent for tumor-infiltrating lymphocytes ex vivo through Gα12/13-coupled LPAR6, with ATX functioning as an LPA-producing chaperone. Using an anti-cancer vaccination model, we provide proof-of-concept that secreted ATX opposes tumor infiltration of CD8+ T cells.Additionally, ENPP2 expression in melanoma tumors correlates with reduced CD8+ T-cell infiltration as inferred from single-cell transcriptomics. Hence, by counteracting T-cell infiltration while activating tumor cells via different LPA receptors, the ATX/LPA complex exerts dual actions in the tumor immune microenvironment, which may provide new therapeutic approaches.
Melanoma is the deadliest of all skin cancers due to its high metastatic potential. In recent years, advances in targeted therapy and immunotherapy have contributed to a remarkable progress in the treatment of metastatic disease. However, intrinsic or acquired resistance to such therapies remains a major obstacle in melanoma treatment. Melanoma disease progression, beginning from tumor initiation and growth to acquisition of invasive phenotypes and metastatic spread and acquisition of treatment resistance, has been associated with cellular dedifferentiation and the hijacking of gene regulatory networks reminiscent of the neural crest (NC)-the developmental structure which gives rise to melanocytes and hence melanoma. This review summarizes the experimental evidence for the involvement of NC stem cell (NCSC)-like cell states during melanoma progression and addresses novel approaches to combat the emergence of stemness characteristics that have shown to be linked with aggressive disease outcome and drug resistance.
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