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SFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.

ABSTRACT: 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 ?-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.

SUBMITTER: Kaur A

PROVIDER: S-EPMC4833579 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.

Kaur Amanpreet A Webster Marie R MR Marchbank Katie K Behera Reeti R Ndoye Abibatou A Kugel Curtis H CH Dang Vanessa M VM Appleton Jessica J O'Connell Michael P MP Cheng Phil P Valiga Alexander A AA Morissette Rachel R McDonnell Nazli B NB Ferrucci Luigi L Kossenkov Andrew V AV Meeth Katrina K Tang Hsin-Yao HY Yin Xiangfan X Wood William H WH Lehrmann Elin E Becker Kevin G KG Flaherty Keith T KT Frederick Dennie T DT Wargo Jennifer A JA Cooper Zachary A ZA Tetzlaff Michael T MT Hudgens Courtney C Aird Katherine M KM Zhang Rugang R Xu Xiaowei X Liu Qin Q Bartlett Edmund E Karakousis Giorgos G Eroglu Zeynep Z Lo Roger S RS Chan Matthew M Menzies Alexander M AM Long Georgina V GV Johnson Douglas B DB Sosman Jeffrey J Schilling Bastian B Schadendorf Dirk D Speicher David W DW Bosenberg Marcus M Ribas Antoni A Weeraratna Ashani T AT

Nature 20160404 7598

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 t ...[more]

PMID: 27042933

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Project description:BackgroundConsidering melanoma is the deadliest malignancy among dermatoma and presently lacks effective therapies, there is an urgent need to investigate the potential mechanisms underlying melanoma metastasis and determine prospective therapeutic targets for precise treatment of melanoma.MethodHub genes in melanoma metastasis were identified by analyzing RNA-seq data (mRNA, miRNA, and lncRNA) obtained from TCGA database. Then the identified hub genes were validated in human tissues with qRT-PCR, followed by survival analysis. Competing endogenous RNAs of the hub genes were defined to clarify potential molecular mechanism of melanoma progression. Then central gene-related signaling pathways were analyzed, followed by immune cell abundance analysis in tumor microenvironment with CYTERSORTx.ResultA tetrad of IL2RA, IL2RG, IFNG, and IL7R genes were determined as hub genes and verified by qRT-PCR, which were significantly associated with unfavorable prognosis in melanoma. LINC02446, LINC01857, and LINC02384 may act as competing endogenous lncRNAs of IL2RA and IL7R through absorbing their shared miR.891a.5p and miR.203b.3p. JAK-STAT signaling pathway identified as the most relevant pathway in melanoma metastasis, as well as a wealthy of genes including TNFRSF 13B, TNFRSF17, TNFRSF9, TNFRSF8, TNFRSF13C, TNFRSF11B, LAG3, NRP1, ENTPD1, NT5E, CCL21, and CCR7, may induce tumor autoimmune suppression through enhancing regulatory T-cell abundance and performance in the tumor microenvironment. And regulatory T-cell proportion was indeed critically elevated in metastatic melanoma relative to primary melanoma, as well as in highly expressed IL2RA, IL2RG, IL7R, and IFNG group than their respective counterparts.ConclusionElevated IL2RA, IL2RG, IL7R, and IFNG expression may play a central role in promoting melanoma metastasis through up regulation of intratumoral regulatory T-cell proportion mainly by activation of JAK-STAT signaling pathway. LINC02446, LINC01857, and LINC02384 may stimulate melanoma progression by reducing tumor-protecting miR.891a.5p and miR.203b.3p. A number of identified molecules including TNFRSF13B, LAG3, NRP1, ENTPD1, NT5E, CCL21, and CCR7 can serve as future therapeutic targets in melanoma treatment.

Dataset Information

SFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.

Publications

sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.

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