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 ß-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.
Subject(s)
Aging/metabolism , Drug Resistance, Neoplasm , Melanoma/drug therapy , Melanoma/pathology , Membrane Proteins/metabolism , Neoplasm Metastasis , Tumor Microenvironment , Adult , Animals , Cell Line, Tumor , Culture Media, Conditioned/pharmacology , DNA Damage , DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism , Disease Progression , Fibroblasts/metabolism , Humans , Indoles/pharmacology , Indoles/therapeutic use , Male , Melanoma/blood supply , Melanoma/genetics , Mice , Microphthalmia-Associated Transcription Factor/metabolism , Middle Aged , Molecular Targeted Therapy , Neovascularization, Pathologic , Oxidative Stress , Phenotype , Reactive Oxygen Species/metabolism , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Vemurafenib , Wnt Signaling Pathway , Wnt1 Protein/antagonists & inhibitors , beta Catenin/metabolismABSTRACT
ABSTRACT: Sarcomatoid dedifferentiated melanoma (SDDM) represents a diagnostic challenge as this cutaneous spindle cell melanoma lacks expression of classic melanocytic markers including S100, SOX10, Melan-A, HMB45, and MITF. The expression of the emerging melanoma marker preferentially expressed antigen in melanoma (PRAME) in SDDM is largely unknown. In this article, a case of SDDM arising in association with a nodular melanoma is highlighted. A 65-year-old man presented with a several week history of an ulcerated lesion on the right medial knee. A shave biopsy of the lesion revealed a biphasic neoplasm, which consisted of a centrally located poorly differentiated spindle cell component and an adjacent nodular component consisting of atypical melanocytes arranged in nests and fascicles. While the nodular component stained for S100, SOX10, and Melan-A, the spindle cell component failed to stain for these conventional melanocytic markers, only staining diffusely for CD10 and faintly for CD68. Both components stained for PRAME diffusely albeit less intensely within the spindle cell component. Next-generation DNA sequencing assay of the microdissected biphasic components revealed a shared mutation of NRAS. The results of the PRAME immunohistochemical stain and next-generation DNA sequencing assay facilitated in establishing the diagnosis of SDDM in association with nodular melanoma.
Subject(s)
Melanoma/diagnosis , Neoplasms, Complex and Mixed/diagnosis , Sarcoma/diagnosis , Skin Neoplasms/diagnosis , Aged , Combined Modality Therapy , Diagnosis, Differential , High-Throughput Nucleotide Sequencing , Humans , Knee , Male , Melanoma/pathology , Melanoma/therapy , Neoplasms, Complex and Mixed/pathology , Neoplasms, Complex and Mixed/therapy , Sarcoma/pathology , Sarcoma/therapy , Skin Neoplasms/pathology , Skin Neoplasms/therapyABSTRACT
UNLABELLED: An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the noncanonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Furthermore, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In patients with melanoma treated with the BRAF inhibitor vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance. SIGNIFICANCE: These data show for the fi rst time that a single signaling pathway, the Wnt signaling pathway, can effectively guide the phenotypic plasticity of tumor cells, when primed to do so by a hypoxic microenvironment. Importantly, this increased Wnt5A signaling can give rise to a subpopulation of highly invasive cells that are intrinsically less sensitive to novel therapies for melanoma, and targeting the Wnt5A/ROR2 axis could improve the efficacy and duration of response for patients with melanoma on vemurafenib.