Malignant melanoma is an aggressive disease for which there are limited therapeutic options. In particular, individuals over the age of 55 have a much poorer prognosis for melanomas of equal grade and stage, compared to younger individuals. To date, no one has addressed the reasons for this disparity in melanoma aggressiveness and metastasis in aging individuals. Our long-term objective is test the hypothesis that the aging microenvironment drives the local aggressiveness and systemic dissemination of melanoma cells. In previous work we identified a critical signaling pathway that modulates melanoma invasiveness, by the secreted factor Wnt5a. We have found that melanomas with high Wnt5A have a mesenchymal phenotype, an increased propensity to migrate and invade, and are significantly associated with poorer prognosis. In preliminary data for this application we show that co-culture of melanomas with fibroblasts from aged individuals, but not young individuals, induces them to express high Wnt5a levels, a mesenchymal phenotype, and increased invasiveness. Interestingly, we have also discovered that melanomas co-cultured with aged but not young fibroblasts show evidence for a senescent-like phenotype. Our preliminary data implicate the aging-regulated hormone Klotho in this switch to an invasive, senescent- like phenotype induced by aged fibroblasts. We find that aged fibroblasts consistently decrease their expression of Klotho, and that Klotho is a potent inhibitor of Wnt5A signaling and senescence. We hypothesize that the decreased expression of Klotho within the aged tumor micro-environment contributes to increased Wnt5A signaling and increased invasiveness in melanomas in the elderly. The proposed studies will lead to an improved understanding of the role of Klotho and the aging micro-environment in the increased aggressiveness and invasiveness seen in melanomas in patients over the age of 55. It is expected that elucidating the role of Klotho and Wnt5a in melanomas in aging will lead to improved therapy.

Public Health Relevance

The vast majority of cancers are diagnosed more frequently in older individuals, and the prognosis for these patients is significantly worse. As longevity increases in the U.S. population, understanding how aging can contribute to tumor progression becomes increasingly important. We are particularly interested in how changes that occur during aging can govern tumor metastasis, including changes in the secretory environment of the tumor. In this study we will examine the contributions of the aging microenvironment to tumor metastasis as well as the contributions of an age-related hormone klotho, and the developmental protein Wnt5A, to the modulation of tumor invasion in older patients. Understanding how aging affects tumor growth and progression may lead to new approaches to therapy, as well as to better assays for the monitoring of patients in long-term remission.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA174746-01A1
Application #
8695553
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Ahmadzadeh, Hossein; Webster, Marie R; Behera, Reeti et al. (2017) Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion. Proc Natl Acad Sci U S A 114:E1617-E1626
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Kaur, Amanpreet; Webster, Marie R; Weeraratna, Ashani T (2016) In the Wnt-er of life: Wnt signalling in melanoma and ageing. Br J Cancer 115:1273-1279
Kaur, Amanpreet; Webster, Marie R; Marchbank, Katie et al. (2016) sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532:250-4
Ndoye, Abibatou; Weeraratna, Ashani T (2016) Autophagy- An emerging target for melanoma therapy. F1000Res 5:
Weeraratna, Ashani T; Gorospe, Myriam (2016) UNRelenting Translation UNRestrains Melanoma Migration. Cancer Cell 30:655-657
Krepler, Clemens; Xiao, Min; Sproesser, Katrin et al. (2016) Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies. Clin Cancer Res 22:1592-602

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