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1.
Clin Cancer Res ; 26(21): 5709-5719, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33097493

RESUMO

PURPOSE: Angiogenesis is thought to be critical for tumor metastasis. However, inhibiting angiogenesis using antibodies such as bevacizumab (Avastin), has had little impact on melanoma patient survival. We have demonstrated that both angiogenesis and metastasis are increased in older individuals, and therefore sought to investigate whether there was an age-related difference in response to bevacizumab, and if so, what the underlying mechanism could be. EXPERIMENTAL DESIGN: We analyzed data from the AVAST-M trial of 1,343 patients with melanoma treated with bevacizumab to determine whether there is an age-dependent response to bevacizumab. We also examined the age-dependent expression of VEGF and its cognate receptors in patients with melanoma, while using syngeneic melanoma animal models to target VEGF in young versus old mice. We also examined the age-related proangiogenic factor secreted frizzled-related protein 2 (sFRP2) and whether it could modulate response to anti-VEGF therapy. RESULTS: We show that older patients respond poorly to bevacizumab, whereas younger patients show improvement in both disease-free survival and overall survival. We find that targeting VEGF does not ablate angiogenesis in an aged mouse model, while sFRP2 promotes angiogenesis in vitro and in young mice. Targeting sFRP2 in aged mice successfully ablates angiogenesis, while the effects of targeting VEGF in young mice can be overcome by increasing sFRP2. CONCLUSIONS: VEGF is decreased during aging, thereby reducing response to bevacizumab. Despite the decrease in VEGF, angiogenesis is increased because of an increase in sFRP2 in the aged tumor microenvironment. These results stress the importance of considering age as a factor for designing targeted therapies.

2.
Cancer Discov ; 10(9): 1282-1295, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32499221

RESUMO

Older patients with melanoma (>50 years old) have poorer prognoses and response rates to targeted therapy compared with young patients (<50 years old), which can be driven, in part, by the aged microenvironment. Here, we show that aged dermal fibroblasts increase the secretion of neutral lipids, especially ceramides. When melanoma cells are exposed to the aged fibroblast lipid secretome, or cocultured with aged fibroblasts, they increase the uptake of lipids via the fatty acid transporter FATP2, which is upregulated in melanoma cells in the aged microenvironment and known to play roles in lipid synthesis and accumulation. We show that blocking FATP2 in melanoma cells in an aged microenvironment inhibits their accumulation of lipids and disrupts their mitochondrial metabolism. Inhibiting FATP2 overcomes age-related resistance to BRAF/MEK inhibition in animal models, ablates tumor relapse, and significantly extends survival time in older animals. SIGNIFICANCE: These data show that melanoma cells take up lipids from aged fibroblasts, via FATP2, and use them to resist targeted therapy. The response to targeted therapy is altered in aged individuals because of the influences of the aged microenvironment, and these data suggest FATP2 as a target to overcome resistance.See related commentary by Montal and White, p. 1255.This article is highlighted in the In This Issue feature, p. 1241.

4.
Mol Cell ; 77(3): 633-644.e5, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31836388

RESUMO

Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.


Assuntos
Melanoma/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Wnt-5a/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , MAP Quinase Quinase Quinases/metabolismo , Melanoma/genética , Melanoma/patologia , Terapia de Alvo Molecular , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/fisiologia
5.
Cancer Discov ; 9(1): 82-95, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30279172

RESUMO

Older patients with melanoma have lower rates of sentinel lymph node (LN) metastases yet paradoxically have inferior survival. Patient age correlated with an inability to retain Technetium radiotracer during sentinel LN biopsy in more than 1,000 patients, and high Technetium counts correlated to better survival. We hypothesized that loss of integrity in the lymphatic vasculature due to extracellular matrix (ECM) degradation might play a role. We have implicated HAPLN1 in age-dependent ECM degradation in the dermis. Here, we queried whether HAPLN1 could be altered in the lymphatic ECM. Lymphatic HAPLN1 expression was prognostic of long-term patient survival. Adding recombinant HAPLN1 to aged fibroblast ECMs in vitro reduced endothelial permeability via modulation of VE-cadherin junctions, whereas endothelial permeability was increased following HAPLN1 knockdown in young fibroblasts. In vivo, reconstitution of HAPLN1 in aged mice increased the number of LN metastases, but reduced visceral metastases. These data suggest that age-related changes in ECM can contribute to impaired lymphatics. SIGNIFICANCE: Our studies reveal that changes in the stroma during aging may influence the way tumor cells traffic through the lymphatic vasculature. Aging may dictate the route of metastatic dissemination of tumor cells, and understanding these changes may help to reveal targetable moieties in the aging tumor microenvironment.See related commentary by Marie and Merlino, p. 19.This article is highlighted in the In This Issue feature, p. 1.


Assuntos
Envelhecimento , Proteínas da Matriz Extracelular/metabolismo , Melanoma/metabolismo , Proteoglicanas/metabolismo , Pele/metabolismo , Adulto , Animais , Células Cultivadas , Humanos , Sistema Imunitário , Metástase Linfática , Melanoma/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pele/fisiopatologia , Microambiente Tumoral
6.
Cancer Discov ; 9(1): 64-81, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30279173

RESUMO

Physical changes in skin are among the most visible signs of aging. We found that young dermal fibroblasts secrete high levels of extracellular matrix (ECM) constituents, including proteoglycans, glycoproteins, and cartilage-linking proteins. The most abundantly secreted was HAPLN1, a hyaluronic and proteoglycan link protein. HAPLN1 was lost in aged fibroblasts, resulting in a more aligned ECM that promoted metastasis of melanoma cells. Reconstituting HAPLN1 inhibited metastasis in an aged microenvironment, in 3-D skin reconstruction models, and in vivo. Intriguingly, aged fibroblast-derived matrices had the opposite effect on the migration of T cells, inhibiting their motility. HAPLN1 treatment of aged fibroblasts restored motility of mononuclear immune cells, while impeding that of polymorphonuclear immune cells, which in turn affected regulatory T-cell recruitment. These data suggest that although age-related physical changes in the ECM can promote tumor cell motility, they may adversely affect the motility of some immune cells, resulting in an overall change in the immune microenvironment. Understanding the physical changes in aging skin may provide avenues for more effective therapy for older patients with melanoma. SIGNIFICANCE: These data shed light on the mechanochemical interactions that occur between aged skin, tumor, and immune cell populations, which may affect tumor metastasis and immune cell infiltration, with implications for the efficacy of current therapies for melanoma.See related commentary by Marie and Merlino, p. 19.This article is highlighted in the In This Issue feature, p. 1.


Assuntos
Envelhecimento , Colágeno/metabolismo , Melanoma/metabolismo , Pele/metabolismo , Animais , Células Cultivadas , Proteínas da Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Humanos , Sistema Imunitário , Melanoma/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Proteoglicanas/metabolismo , Pele/fisiopatologia , Microambiente Tumoral
7.
Clin Cancer Res ; 24(21): 5347-5356, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29898988

RESUMO

Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1.Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies.Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8+:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice.Conclusions: While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response. Clin Cancer Res; 24(21); 5347-56. ©2018 AACR See related commentary by Pawelec, p. 5193.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Imunomodulação/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Fatores Etários , Animais , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Transgênicos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Res ; 77(21): 5873-5885, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28887323

RESUMO

Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of ß-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low ß-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5Ahigh cells decreased Wnt5A and increased ß-catenin. To define the physiologic relevance of this loop, melanoma cells with different Wnt status were treated in vitro and in vivo with the potent lysosomotropic compound Lys05. Wnt5Ahigh cells were less sensitive to Lys05 and could be reverted by inducing ß-catenin activity. Our results suggest the efficacy of autophagy inhibitors might be improved by taking the Wnt signature of melanoma cells into account. Cancer Res; 77(21); 5873-85. ©2017 AACR.


Assuntos
Proteína 5 Relacionada à Autofagia/genética , Autofagia/genética , Melanoma/genética , Via de Sinalização Wnt/genética , Aminoquinolinas/farmacologia , Animais , Autofagia/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia/metabolismo , Western Blotting , Linhagem Celular Tumoral , Retroalimentação Fisiológica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Poliaminas/farmacologia , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
10.
Clin Cancer Res ; 23(12): 3181-3190, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28232477

RESUMO

Purpose: Aging is a poor prognostic factor for melanoma. We have shown that melanoma cells in an aged microenvironment are more resistant to targeted therapy than identical cells in a young microenvironment. This is dependent on age-related secreted factors. Klotho is an age-related protein whose serum levels decrease dramatically by age 40. Most studies on klotho in cancer have focused on the expression of klotho in the tumor cell. We have shown that exogenous klotho inhibits internalization and signaling of Wnt5A, which drives melanoma metastasis and resistance to targeted therapy. We investigate here whether increasing klotho in the aged microenvironment could be an effective strategy for the treatment of melanoma.Experimental Design: PPARγ increases klotho levels and is increased by glitazones. Using rosiglitazone, we queried the effects of rosiglitazone on Klotho/Wnt5A cross-talk, in vitro and in vivo, and the implications of that for targeted therapy in young versus aged animals.Results: We show that rosiglitazone increases klotho and decreases Wnt5A in tumor cells, reducing the burden of both BRAF inhibitor-sensitive and BRAF inhibitor-resistant tumors in aged, but not young mice. However, when used in combination with PLX4720, tumor burden was reduced in both young and aged mice, even in resistant tumors.Conclusions: Using glitazones as adjuvant therapy for melanoma may provide a new treatment strategy for older melanoma patients who have developed resistance to vemurafenib. As klotho has been shown to play a role in other cancers too, our results may have wide relevance for multiple tumor types. Clin Cancer Res; 23(12); 3181-90. ©2017 AACR.


Assuntos
Glucuronidase/genética , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Tiazolidinedionas/administração & dosagem , Proteína Wnt-5a/genética , Adulto , Fatores Etários , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glucuronidase/antagonistas & inibidores , Humanos , Indóis/administração & dosagem , Melanoma/genética , Melanoma/patologia , Camundongos , Pessoa de Meia-Idade , Mutação , PPAR gama/antagonistas & inibidores , PPAR gama/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Rosiglitazona , Sulfonamidas/administração & dosagem , Tiazolidinedionas/efeitos adversos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Proc Natl Acad Sci U S A ; 114(9): E1617-E1626, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-28196892

RESUMO

Cancer cell invasion from primary tumors is mediated by a complex interplay between cellular adhesions, actomyosin-driven contractility, and the physical characteristics of the extracellular matrix (ECM). Here, we incorporate a mechanochemical free-energy-based approach to elucidate how the two-way feedback loop between cell contractility (induced by the activity of chemomechanical interactions such as Ca2+ and Rho signaling pathways) and matrix fiber realignment and strain stiffening enables the cells to polarize and develop contractile forces to break free from the tumor spheroids and invade into the ECM. Interestingly, through this computational model, we are able to identify a critical stiffness that is required by the matrix to break intercellular adhesions and initiate cell invasion. Also, by considering the kinetics of the cell movement, our model predicts a biphasic invasiveness with respect to the stiffness of the matrix. These predictions are validated by analyzing the invasion of melanoma cells in collagen matrices of varying concentration. Our model also predicts a positive correlation between the elongated morphology of the invading cells and the alignment of fibers in the matrix, suggesting that cell polarization is directly proportional to the stiffness and alignment of the matrix. In contrast, cells in nonfibrous matrices are found to be rounded and not polarized, underscoring the key role played by the nonlinear mechanics of fibrous matrices. Importantly, our model shows that mechanical principles mediated by the contractility of the cells and the nonlinearity of the ECM behavior play a crucial role in determining the phenotype of the cell invasion.


Assuntos
Matriz Extracelular/patologia , Melanoma/patologia , Invasividade Neoplásica/patologia , Actomiosina/metabolismo , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Colágeno/metabolismo , Simulação por Computador , Elasticidade/fisiologia , Matriz Extracelular/metabolismo , Retroalimentação , Humanos , Melanoma/metabolismo , Dinâmica não Linear
12.
Br J Cancer ; 115(11): 1273-1279, 2016 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-27764844

RESUMO

Although the clinical landscape of melanoma is improving rapidly, metastatic melanoma remains a deadly disease. Age remains one of the greatest risk factors for melanoma, and patients older than 55 have a much poorer prognosis than younger individuals, even when the data are controlled for grade and stage. The reasons for this disparity have not been fully uncovered, but there is some recent evidence that Wnt signalling may have a role. Wnt signalling is known to have roles both in cancer progression as well as in organismal ageing. In melanoma, the interplay of Wnt signalling pathways is complex, with different members of the Wnt family guiding different aspects of invasion and proliferation. Here, we will briefly review the current literature addressing the roles of different Wnt pathways in melanoma pathogenesis, provide an overview of Wnt signalling during ageing, and discuss the intersection between melanoma and ageing in terms of Wnt signalling.


Assuntos
Envelhecimento , Melanoma/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Humanos , Melanoma/patologia , Prognóstico , Microambiente Tumoral
14.
Nature ; 532(7598): 250-4, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-27042933

RESUMO

Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in ß-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.


Assuntos
Envelhecimento/metabolismo , Resistencia a Medicamentos Antineoplásicos , Melanoma/tratamento farmacológico , Melanoma/patologia , Proteínas de Membrana/metabolismo , Metástase Neoplásica , Microambiente Tumoral , Adulto , Animais , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Dano ao DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Progressão da Doença , Fibroblastos/metabolismo , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Masculino , Melanoma/irrigação sanguínea , Melanoma/genética , Camundongos , Fator de Transcrição Associado à Microftalmia/metabolismo , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neovascularização Patológica , Estresse Oxidativo , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Vemurafenib , Via de Sinalização Wnt , Proteína Wnt1/antagonistas & inibidores , beta Catenina/metabolismo
15.
Cancer Res ; 76(9): 2720-30, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-26984758

RESUMO

The stress-inducible chaperone protein HSP70 (HSPA1) is implicated in melanoma development, and HSP70 inhibitors exert tumor-specific cytotoxic activity in cancer. In this study, we documented that a significant proportion of melanoma tumors express high levels of HSP70, particularly at advanced stages, and that phospho-FAK (PTK2) and BRAF are HSP70 client proteins. Treatment of melanoma cells with HSP70 inhibitors decreased levels of phospho-FAK along with impaired migration, invasion, and metastasis in vitro and in vivo Moreover, the HSP70 inhibitor PET-16 reduced levels of mutant BRAF, synergized with the BRAF inhibitor PLX4032 in vitro, and enhanced the durability of response to BRAF inhibition in vivo Collectively, these findings provide strong support for HSP70 inhibition as a therapeutic strategy in melanoma, especially as an adjuvant approach for overcoming the resistance to BRAF inhibitors frequently observed in melanoma patients. Cancer Res; 76(9); 2720-30. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Quinase 1 de Adesão Focal/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Indóis/farmacologia , Melanoma/patologia , Sulfonamidas/farmacologia , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imunofluorescência , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica/patologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Análise Serial de Tecidos , Vemurafenib
16.
Biochim Biophys Acta ; 1856(2): 244-51, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26546268

RESUMO

The outgrowth of metastatic and therapy-resistant subpopulations in cancer remains a critical barrier for the successful treatment of this disease. In melanoma, invasion and proliferation are uncoupled, such that highly proliferative melanoma cells are less likely to be invasive, and vice versa. The transition between each state is likely a dynamic rather than a static, permanent change. This is referred to as "phenotype switching". Wnt signaling pathways drive phenotypic changes and promote therapy resistance in melanoma, as well as play roles in the modulation of the immune microenvironment. Three Wnt signaling pathways play a role in melanoma progression, canonical (ß-catenin dependent), polar cell polarity (PCP), and the Wnt/Ca²âº pathway. Here we summarize phenotype plasticity and its role in therapy resistance and immune evasion. Targeting the Wnt signaling pathways may be an effective way to overcome tumor plasticity in melanoma.


Assuntos
Melanoma/metabolismo , Melanoma/patologia , Proteínas de Neoplasias/metabolismo , Microambiente Tumoral , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Animais , Diferenciação Celular , Plasticidade Celular , Proliferação de Células , Humanos , Modelos Biológicos , Invasividade Neoplásica , Fenótipo
17.
Proc Natl Acad Sci U S A ; 112(28): 8638-43, 2015 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-26124089

RESUMO

Molecular therapies are hallmarks of "personalized" medicine, but how tumors adapt to these agents is not well-understood. Here we show that small-molecule inhibitors of phosphatidylinositol 3-kinase (PI3K) currently in the clinic induce global transcriptional reprogramming in tumors, with activation of growth factor receptors, (re)phosphorylation of Akt and mammalian target of rapamycin (mTOR), and increased tumor cell motility and invasion. This response involves redistribution of energetically active mitochondria to the cortical cytoskeleton, where they support membrane dynamics, turnover of focal adhesion complexes, and random cell motility. Blocking oxidative phosphorylation prevents adaptive mitochondrial trafficking, impairs membrane dynamics, and suppresses tumor cell invasion. Therefore, "spatiotemporal" mitochondrial respiration adaptively induced by PI3K therapy fuels tumor cell invasion, and may provide an important antimetastatic target.


Assuntos
Inibidores Enzimáticos/farmacologia , Mitocôndrias/efeitos dos fármacos , Invasividade Neoplásica , Inibidores de Fosfoinositídeo-3 Quinase , Transporte Biológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Citoesqueleto/metabolismo , Metabolismo Energético , Humanos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
18.
J Invest Dermatol ; 135(6): 1521-1532, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25705850

RESUMO

Multipotent stem cells with neural crest-like properties have been identified in the dermis of human skin. These neural crest stem cell (NCSC)-like cells display self-renewal capacity and differentiate into neural crest derivatives, including epidermal pigment-producing melanocytes. NCSC-like cells share many properties with aggressive melanoma cells, such as high migratory capabilities and expression of the neural crest markers. However, little is known about which intrinsic or extrinsic signals determine the proliferation or differentiation of these neural crest-like stem cells. Here we show that, in NCSC-like cells, Notch signaling is highly activated, similar to melanoma cells. Inhibition of Notch signaling reduced the proliferation of NCSC-like cells, induced cell death, and downregulated noncanonical Wnt5a, suggesting that the Notch pathway contributes to the maintenance and motility of these stem cells. In three-dimensional skin reconstructs, canonical Wnt signaling promoted the differentiation of NCSC-like cells into melanocytes. This differentiation was triggered by the endogenous Notch inhibitor Numb, which is upregulated in the stem cells by Wnt7a derived from UV-irradiated keratinocytes. Together, these data reveal a cross talk between the two conserved developmental pathways in postnatal human skin, and highlight the role of the skin microenvironment in specifying the fate of stem cells.


Assuntos
Receptores Notch/metabolismo , Pele/metabolismo , Raios Ultravioleta , Proteínas Wnt/metabolismo , Diferenciação Celular , Linhagem da Célula , Sobrevivência Celular , Humanos , Queratinócitos/metabolismo , Lentivirus/genética , Melanócitos/citologia , Melanócitos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Pigmentação , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Fenômenos Fisiológicos da Pele , Células-Tronco/citologia , Proteína Wnt-5a , beta Catenina/metabolismo
19.
Pigment Cell Melanoma Res ; 28(2): 184-95, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25407936

RESUMO

We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAF(V600E) mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence-associated ß-galactosidase (SA-ß-gal), senescence-associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence such as SA-ß-gal and SAHF, these Wnt5A-high cells are able to colonize the lungs in in vivo tail vein colony-forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance.


Assuntos
Senescência Celular , Melanoma/metabolismo , Melanoma/patologia , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Estresse Fisiológico , Proteínas Wnt/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Células Clonais , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Humanos , Camundongos Nus , Invasividade Neoplásica , Fenótipo , Ensaio Tumoral de Célula-Tronco , Proteína Wnt-5a
20.
Mol Cancer Ther ; 13(2): 297-306, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24310621

RESUMO

Bisphosphonates are used clinically to treat disorders of calcium metabolism and malignant bone disease and are known to inhibit cancer cell growth, adhesion, and invasion. However, clinical use of these agents for the treatment of extraskeletal disease is limited because of low cell permeability. We recently described a bisphosphonamidate prodrug strategy for efficient intracellular release of bisphosphonates, including clodronate (CLO), in non-small cell lung cancer cells. To evaluate anticancer activity of this prodrug class across many cancer cell types, the bisphosphonamidate clodronate prodrug (CLO prodrug) was screened against the NCI-60 cell line panel, and was found to exhibit selectivity toward melanoma cell lines. Here, we confirm efficient cellular uptake and intracellular activation of this prodrug class in melanoma cells. We further demonstrate inhibition of melanoma cell proliferation, induction of apoptosis, and an antitumor effect of CLO prodrug in a xenograft model. These data suggest a novel therapeutic application for the CLO prodrug and potential to selectively target melanoma cells.


Assuntos
Antineoplásicos/farmacologia , Ácido Clodrônico/farmacologia , Pró-Fármacos/farmacologia , Amidas/química , Amidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Difosfonatos/química , Difosfonatos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Concentração Inibidora 50 , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos Nus , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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