Seminario - Biotecnologie e Bioscienze - Giovedì 12 giugno 2025, ore 16:30, edificio BIOS-U3, aula U3-04
Andrea Morrione, Temple University, USA
Abstract
Progranulin is a pleiotropic growth factor with important physiological roles in embryogenesis and maintenance of adult tissue homeostasis. While-progranulin deficiency is associated with a broad range of pathological conditions affecting the brain, such as frontotemporal dementia and neuronal ceroid lipofuscinosis, progranulin upregulation characterizes many tumors, including brain tumors, multiple myeloma, leiomyosarcoma, mesothelioma and epithelial cancers such as ovarian, liver, breast, bladder, adrenal, prostate and kidney carcinomas. The increase of progranulin levels in tumors might have diagnostic and prognostic significance. In cancer, progranulin has a pro-tumorigenic role by promoting cancer cell proliferation, migration, invasiveness, anchorage-independent growth and resistance to chemotherapy. In addition, progranulin regulates the tumor microenvironment, affects the function of cancer-associated fibroblasts, and modulates tumor immune surveillance. However, the molecular mechanisms of progranulin oncogenic function are not fully elucidated.
We previously demonstrated that, in bladder cancer, progranulin action relies on the activation of its functional signaling receptor EphA2. Notably, more recent data suggest that progranulin can also modulate a functional crosstalk between multiple receptor-tyrosine kinases, demonstrating a more complex and context-dependent role of progranulin in cancer. Here, we will present data on the identification of novel progranulin/EphA2 downstream effectors, including FAM120A, and their relevance in bladder cancer. We will also discuss the role that ubiquitination and trafficking play in modulating EphA2 action. Lastly, we will present data on progranulin action in malignant mesothelioma, where progranulin regulates cell migration, invasion, adhesion, and in vivo tumor formation by modulating a complex signaling network involving multiple receptor tyrosine kinase (RTK)s. Progranulin biological activity relies on EGFR and RYK, a co-receptor of the Wnt signaling pathway, which are both required for progranulin-induced downstream signaling.
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