Microenvironmental influences in melanoma progression

Lee, John Tayu; Herlyn, Meenhard

doi:10.1002/jcb.21204

Cited by 80 publications

(76 citation statements)

References 45 publications

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“…We were interested to follow up on our results in metastatic melanoma, because it is known that both HIF and hypoxia increase the aggressive nature of the disease (17,18). A panel of AKAP family members in K457 melanoma cells was examined for hypoxic induction, with AKAP12 mRNA induced by hypoxia ( Fig.…”

Section: Akap12 Is Elevated In Human Metastaticmentioning

confidence: 99%

Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells

Finger

Castellini

Rankin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Scaffold proteins are critical hubs within cells that have the ability to modulate upstream signaling molecules and their downstream effectors to fine-tune biological responses. Although they can serve as focal points for association of signaling molecules and downstream pathways that regulate tumorigenesis, little is known about how the tumor microenvironment affects the expression and activity of scaffold proteins. This study demonstrates that hypoxia, a common element of solid tumors harboring low oxygen levels, regulates expression of a specific variant of the scaffold protein AKAP12 (Akinase anchor protein 12), AKAP12v2, in metastatic melanoma. In turn, through a kinome-wide phosphoproteomic and MS study, we demonstrate that this scaffolding protein regulates a shift in protein kinase A (PKA)-mediated phosphorylation events under hypoxia, causing alterations in tumor cell invasion and migration in vitro, as well as metastasis in an in vivo orthotopic model of melanoma. Mechanistically, the shift in AKAP12-dependent PKAmediated phosphorylations under hypoxia is due to changes in AKAP12 localization vs. structural differences between its two variants. Importantly, our work defines a mechanism through which a scaffold protein can be regulated by the tumor microenvironment and further explains how a tumor cell can coordinate many critical signaling pathways that are essential for tumor growth through one individual scaffolding protein.AKAP12 | melanoma | metastasis S caffold proteins, also known as anchoring proteins, are of crucial importance within cells because they allow dynamic association of signaling molecules, often present in low abundance, by concentrating them at discrete subcellular localizations, forming intricate signal transduction complexes. However, the mechanisms by which scaffold proteins are regulated within the tumor microenvironment and how altering their expression can result in a switch between kinase targets and promote tumor progression remain unknown. Importantly, scaffold proteins have recently been identified as new therapeutic targets, highlighting the necessity of understanding the biology behind these potential targets (1). In this paper, we focus on the scaffold protein AKAP12, which is a member of the larger "A Kinase Anchoring Protein" family that regulates signal transduction from the cell surface to the cytoskeleton. Previous studies have reported that AKAP12 binds to protein kinase A (PKA), protein kinase C (PKC), Src, and the actin cytoskeleton, all involved in tumorigenesis (2). However, the role of the tumor microenvironment in regulating the scaffolding protein AKAP12 and the outputs of these downstream signaling cascades has not been fully investigated.Hypoxia, or tumor cell oxygen deficiency, is a component of the tumor microenvironment and is strongly linked to metastasis and the poor clinical outcome of patients, through the activation of specific transcriptional, translational, and signaling programs (3-8). Induction of the hypoxia-inducible transcription factor (H...

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Section: Akap12 Is Elevated In Human Metastaticmentioning

confidence: 99%

Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells

Finger

Castellini

Rankin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…[87][88][89] At a molecular level, EMT involves changes in cell adhesion and cytoskeletal proteins. Environmental influences, such as the fibroblast-secreted growth factor TGF-b, 131,132 encourage downregulation of the cell adhesion protein, E-cadherin, and upregulation of N-cadherin. 133 Cytoskeletal proteins are also rearranged during EMT; 134 for example, in certain epithelial cancers a characteristic increase in vimentin expression and loss of cytokeratins is observed.…”

Section: How Primitive Melanoma Cells May Encourage 'Vasculogenic Mimmentioning

confidence: 99%

Melanoma stem cells: not rare, but well done

Girouard

Murphy

2011

Laboratory Investigation

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Since the identification of self-renewing cells in the hematopoietic system, stem cells have transformed the study of medicine. Cancer biologists have identified stem-like cells in multiple malignancies, including those of solid organs. This has led to the development of a stem cell theory of cancer, which purports that a subpopulation of self-renewing tumor cells is responsible for tumorigenesis. This contrasts with the stochastic model of tumor development, which advances that all tumor cells are capable of tumor formation. Within the field of melanoma, the identity and existence of cancer stem cells has been the subject of recent debate. Much of the controversy may be traced to differences in interpretations and definitions related to the cancer stem cell theory, and the use of dissimilar methodologies to study melanoma cells. Accumulating evidence suggests that cancer stem cells may exist in melanoma, although their frequency may vary and they may be capable of phenotypic plasticity. Importantly, these primitive melanoma cells are not only capable of self-renewal and differentiation plasticity, but also may confer virulence via immune evasion and multidrug resistance, and potentially via vasculogenic mimicry and transition to migratory and metastasizing derivatives. Therapeutic targeting of melanoma stem cells and the pathways that endow them with virulence hold promise for the design of more effective strategies for amelioration and eradication of this most lethal form of skin cancer.

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“…Perhaps as perplexing as the frequency and phenotypic identity of MM stem cells and plasticity of MM cells 33 is the complex role for the microenvironment of both primary and metastatic lesions as important contributors to the biology and drug responses involving MM. 61 As MM cells do not reside in a vacuum, the surrounding cells and microenvironment contain a confederacy of cell types that are being dissected in primary and metastatic lesions as an active area of research. Indeed, discussions governing the relative role for the seed and soil in cancer biology dates back a generation, 62 with studies of MM having an early and central role to better understand this complex set of interactions.…”

Section: Pathophysiology: Sharing Of Signal Transduction Pathways mentioning

confidence: 99%