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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wistar Institute
United States
Zip Code
Kugel 3rd, Curtis H; Douglass, Stephen M; Webster, Marie R et al. (2018) Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations. Clin Cancer Res 24:5347-5356
Ecker, Brett L; Kaur, Amanpreet; Douglass, Stephen M et al. (2018) Age-Related Changes in HAPLN1 Increase Lymphatic Permeability and Affect Routes of Melanoma Metastasis. Cancer Discov :
Kaur, Amanpreet; Ecker, Brett L; Douglass, Stephen M et al. (2018) Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility. Cancer Discov :
Caino, M Cecilia; Seo, Jae Ho; Wang, Yuan et al. (2017) Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer. J Clin Invest 127:3755-3769
Kumar, Vinit; Donthireddy, Laxminarasimha; Marvel, Douglas et al. (2017) Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors. Cancer Cell 32:654-668.e5
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

Showing the most recent 10 out of 23 publications