DNp73-induced degradation of tyrosinase links depigmentation with EMT-driven melanoma progression

Fürst, Katharina; Steder, Marc; Logotheti, Stella; Angerilli, Alessandro; Spitschak, Alf; Marquardt, Stephan; Schumacher, Toni; Engelmann, David; Herchenröder, Ottmar; Rupp, Ralph A.W.; Pützer, Brigitte M.

doi:10.1016/j.canlet.2018.11.009

Cited by 25 publications

(32 citation statements)

References 54 publications

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“…Similarly, p73∆Ex2/3 expression in less invasive melanoma cells enhances stemness and self-renewal capacity through an interplay with MIR885 [35], an miRNA with brain/cerebellum-restricted expression (data mined from miRiad database [47]), that targets IGFR [35]. Again in an IGFR-dependent manner, p73∆Ex2/3 drives EMT phenotypic conversion and initiation of metastasis [33], along with tyrosinase degradation, depigmentation and loss of melanocyte identity [48]. In the presence of p73∆Ex2/3 and persistently high TAp73α levels, melanoma cells lose their original cell-type characteristics and simultaneously activate stemness [35], EMT [33] and nervous system-related genes (this study).…”

Section: Discussionmentioning

confidence: 99%

Neural Networks Recapitulation by Cancer Cells Promotes Disease Progression: A Novel Role of p73 Isoforms in Cancer-Neuronal Crosstalk

Logotheti

Marquardt

Richter

et al. 2020

Cancers

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Mechanisms governing tumor progression differ from those of initiation. One enigmatic prometastatic process is the recapitulation of pathways of neural plasticity in aggressive stages. Cancer and neuronal cells develop reciprocal interactions via mutual production and secretion of neuronal growth factors, neurothrophins and/or axon guidance molecules in the tumor microenvironment. Understanding cancer types where this process is active, as well as the drivers, markers and underlying mechanisms, has great significance for blocking tumor progression and improving patient survival. By applying computational and systemic approaches, in combination with experimental validations, we provide compelling evidence that genes involved in neuronal development, differentiation and function are reactivated in tumors and predict poor patient outcomes across various cancers. Across cancers, they co-opt genes essential for the development of distinct anatomical parts of the nervous system, with a frequent preference for cerebral cortex and neural crest-derived enteric nerves. Additionally, we show that p73, a transcription factor with a dual role in neuronal development and cancer, simultaneously induces neurodifferentiation and stemness markers during melanoma progression. Our data yield the basis for elucidating driving forces of the nerve–tumor cell crosstalk and highlight p73 as a promising regulator of cancer neurobiology.

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Section: Discussionmentioning

confidence: 99%

Neural Networks Recapitulation by Cancer Cells Promotes Disease Progression: A Novel Role of p73 Isoforms in Cancer-Neuronal Crosstalk

Logotheti

Marquardt

Richter

et al. 2020

Cancers

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“…Additionally, Slug plays an important role in tumor metastasis and recurrence. It has been reported that Slug is essential in the metastatic process of melanoma cells ( Furst et al, 2019 ). Increased levels of Slug were associated with cancer recurrence ( Schinke et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

PPA1 Promotes Breast Cancer Proliferation and Metastasis Through PI3K/AKT/GSK3β Signaling Pathway

Guo

Liang

et al. 2021

Front. Cell Dev. Biol.

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Breast cancer is the most common malignancy among women. Inorganic pyrophosphatase 1 (PPA1) is a multifunctional protein involved in the development of several tumors. However, the role of PPA1 in breast cancer progression remains unclear. In this study, we found that PPA1 was highly expressed in breast cancer compared to its levels in normal breast tissue and that it was correlated with breast cancer clinicopathological characteristics, as well as poor survival in breast cancer patients. Silencing PPA1 restrained breast cancer proliferation and metastasis by regulating Slug-mediated epithelial-mesenchymal transition (EMT). Opposite results were observed following PPA1 overexpression. In addition, investigation of the underlying mechanism demonstrated that PPA1 ablation led to decrease phosphatidylinositol 3 kinase (PI3K) phosphorylation levels and attenuate phosphorylated AKT and glycogen synthase kinase-3 β (GSK3β), while ectopic PPA1 expression had the opposite effects. Moreover, PI3K inhibitors suppress the signaling pathways mediating the effects of PPA1 on breast cancer, resulting in tumor growth and metastasis suppression in vitro and in vivo. In summary, our results verify that PPA1 can act as an activator of PI3K/AKT/GSK3β/Slug-mediated breast cancer progression and that it is a potential therapeutic target for the inhibition of tumor progression.

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“…Thus, vitiligo patients show a lower melanoma risk because the antibodies against melanocytes confer natural cancer protection [20]. Vice versa, some melanoma patients develop a similar antibody-based condition, called melanoma-associated hypopigmentation or vitiligo-like depigmentation, which is usually considered as a predictor of better outcomes [21], although there are also reports demonstrating that hypopigmentation can be associated with disease progression [22,23,24]. Given that malignant melanoma co-evolves with immune cell phenotypes [25], this dynamic interaction between autoimmunity-based hypopigmentation and skin cancer could, in the long run, become a double-edged sword.…”

Section: Associations Among Melanoma Inflammation and Autoimmune mentioning

confidence: 99%

“…Such MDA-negative cells possess enhanced invasive capabilities. In this way, anti-MDA responses provoked by the melanoma tumor, can, in turn, promote clonal expansion of low-MDA-expressing cell variants with activated prometastatic programs that can migrate to distant sites, giving rise to secondary tumors [24].…”

Section: Associations Among Melanoma Inflammation and Autoimmune mentioning

confidence: 99%

STAT3 and STAT5 Targeting for Simultaneous Management of Melanoma and Autoimmune Diseases

Logotheti

Pützer

2019

Cancers

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Melanoma is a skin cancer which can become metastatic, drug-refractory, and lethal if managed late or inappropriately. An increasing number of melanoma patients exhibits autoimmune diseases, either as pre-existing conditions or as sequelae of immune-based anti-melanoma therapies, which complicate patient management and raise the need for more personalized treatments. STAT3 and/or STAT5 cascades are commonly activated during melanoma progression and mediate the metastatic effects of key oncogenic factors. Deactivation of these cascades enhances antitumor-immune responses, is efficient against metastatic melanoma in the preclinical setting and emerges as a promising targeting strategy, especially for patients resistant to immunotherapies. In the light of the recent realization that cancer and autoimmune diseases share common mechanisms of immune dysregulation, we suggest that the systemic delivery of STAT3 or STAT5 inhibitors could simultaneously target both, melanoma and associated autoimmune diseases, thereby decreasing the overall disease burden and improving quality of life of this patient subpopulation. Herein, we review the recent advances of STAT3 and STAT5 targeting in melanoma, explore which autoimmune diseases are causatively linked to STAT3 and/or STAT5 signaling, and propose that these patients may particularly benefit from treatment with STAT3/STAT5 inhibitors.

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DNp73-induced degradation of tyrosinase links depigmentation with EMT-driven melanoma progression

Cited by 25 publications

References 54 publications

Neural Networks Recapitulation by Cancer Cells Promotes Disease Progression: A Novel Role of p73 Isoforms in Cancer-Neuronal Crosstalk

Neural Networks Recapitulation by Cancer Cells Promotes Disease Progression: A Novel Role of p73 Isoforms in Cancer-Neuronal Crosstalk

PPA1 Promotes Breast Cancer Proliferation and Metastasis Through PI3K/AKT/GSK3β Signaling Pathway

STAT3 and STAT5 Targeting for Simultaneous Management of Melanoma and Autoimmune Diseases

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