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 co-culture of melanomas with fibroblasts from aged individuals. 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 #
3R01CA174746-03S1
Application #
9251074
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Ogunbiyi, Peter
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2016-08-01
Budget End
2017-04-30
Support Year
3
Fiscal Year
2016
Total Cost
$46,404
Indirect Cost
$21,981
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Ndoye, Abibatou; Budina-Kolomets, Anna; Kugel 3rd, Curtis H et al. (2017) ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma. Cancer Res 77:5873-5885
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
Behera, Reeti; Kaur, Amanpreet; Webster, Marie R et al. (2017) Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho. Clin Cancer Res 23:3181-3190
Webster, Marie R; Kugel 3rd, Curtis H; Weeraratna, Ashani T (2017) When metastasis 'Spns' out of control: Coverage of 'Genome-wide in vivo screen identifies novel host regulators of metastatic colonization'. Pigment Cell Melanoma Res 30:384-385
Homet Moreno, Blanca; Zaretsky, Jesse M; Garcia-Diaz, Angel et al. (2016) Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells. Cancer Immunol Res 4:845-857

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