Loss of autophagy affects melanoma development in a manner dependent on PTEN status.
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ABSTRACT:
SUBMITTER: Rosenfeldt MT
PROVIDER: S-EPMC8027884 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors.
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Project description:The development of targeted inhibitors, vemurafenib and dabrafenib, has led to improved clinical outcome for melanoma patients with BRAFV600E mutations. Although the initial response to these inhibitors can be dramatic, sometimes causing complete tumor regression, the majority of melanomas eventually become resistant. Mitogen-activated protein kinase kinase (MEK) mutations are found in primary melanomas and frequently reported in BRAF melanomas that develop resistance to targeted therapy; however, melanoma is a molecularly heterogeneous cancer, and which mutations are drivers and which are passengers remains to be determined. In this study, we demonstrate that in BRAFV600E melanoma cell lines, activating MEK mutations drive resistance and contribute to suboptimal growth of melanoma cells following the withdrawal of BRAF inhibition. In this manner, the cells are drug-addicted, suggesting that melanoma cells evolve a 'just right' level of mitogen-activated protein kinase signaling and the additive effects of MEK and BRAF mutations are counterproductive. We also used a novel mouse model of melanoma to demonstrate that several of these MEK mutants promote the development, growth and maintenance of melanoma in vivo in the context of Cdkn2a and Pten loss. By utilizing a genetic approach to control mutant MEK expression in vivo, we were able to induce tumor regression and significantly increase survival; however, after a long latency, all tumors subsequently became resistant. These data suggest that resistance to BRAF or MEK inhibitors is probably inevitable, and novel therapeutic approaches are needed to target dormant tumors.
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Project description:BackgroundPTEN is a tumor suppressor that is often mutated and nonfunctional in many types of cancer. The high heterogeneity of PTEN function between tumor types makes new Pten knockout models necessary to assess its impact on cancer progression and/or treatment outcomes.MethodsWe aimed to show the effect of CRISPR/Cas9-mediated Pten knockout on murine melanoma (B16 F10) and kidney cancer (Renca) cells. We evaluated the effect of PTEN deregulation on tumor progression in vivo and in vitro, as well as on the effectiveness of drug treatment in vitro. In addition, we studied the molecular changes induced by Pten knockout.ResultsIn both models, Pten mutation did not cause significant changes in cell proliferation in vitro or in vivo. Cells with Pten knockout differed in sensitivity to cisplatin treatment: in B16 F10 cells, the lack of PTEN induced sensitivity and, in Renca cells, resistance to drug treatment. Accumulation of pAKT was observed in both cell lines, but only Renca cells showed upregulation of the p53 level after Pten knockout. PTEN deregulation also varied in the way that it altered PAI-1 secretion in the tested models, showing a decrease in PAI-1 in B16 F10 Pten/KO and an increase in Renca Pten/KO cells. In kidney cancer cells, Pten knockout caused changes in epithelial to mesenchymal transition marker expression, with downregulation of E-cadherin and upregulation of Snail, Mmp9, and Acta2 (α-SMA).ConclusionsThe results confirmed heterogenous cell responses to PTEN loss, which may lead to a better understanding of the role of PTEN in particular types of tumors and points to PTEN as a therapeutic target for personalized medicine.
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Project description:Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. To build a model of human melanoma, we generated mice with conditional melanocyte-specific expression of BRaf(V600E). Upon induction of BRaf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRaf(V600E) combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide a system to study melanoma's cardinal feature of metastasis and for preclinical evaluation of agents designed to prevent or treat metastatic disease.
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