Bladder cancer remains one of the most lethal malignancies in the United States, with an estimated 84,530 new cases and 17,870 deaths projected in 2026 alone. Against this sobering backdrop, a team of international researchers has identified a previously underappreciated molecular player that helps drive the aggressiveness of this disease, offering fresh hope for both targeted therapies and biomarker development. In a study published in the Journal of Experimental & Clinical Cancer Research, scientists led by Andrea Morrione of Temple University’s Sbarro Institute for Cancer Research and Molecular Medicine report that FAM120A, a scaffold protein long suspected of participating in oncogenic signaling, functions as a critical effector in the progranulin/EphA2 axis, a signaling circuit previously shown by the same group to govern bladder tumor cell motility, invasion, and tumor formation in living organisms.

The discovery began, as many modern cancer biology investigations do, with proteomics. Rather than examining proteins one at a time, the researchers mapped the EphA2 interactome, the full constellation of proteins that physically associate with the EphA2 receptor, under conditions of progranulin stimulation. EphA2, or erythropoietin-producing hepatocellular carcinoma receptor A2, is a receptor tyrosine kinase that has long been implicated in cancer progression, but its behavior is unusual among kinase receptors: while it participates in normal developmental signaling, it is frequently overexpressed in aggressive tumors where its oncogenic function is driven less by classical kinase activity and more by its ability to recruit and organize signaling complexes. Progranulin, a secreted growth factor better known for its role in neurodegeneration, notably frontotemporal dementia, wound healing, and immune regulation, binds EphA2 and triggers downstream cascades. By comparing the composition of EphA2’s protein partners in the presence and absence of progranulin, the team uncovered a set of progranulin-dependent interactors, among them FAM120A, also known as Family with Sequence Similarity 120 Member A.

FAM120A is what biologists call a scaffold protein, a molecule that does not necessarily catalyze chemical reactions itself but instead serves as a physical platform upon which other signaling proteins assemble. This architectural role makes scaffold proteins powerful amplifiers and organizers of cellular communication, and disruptions in their function are increasingly recognized as contributors to malignancy. Using tissue microarrays and immunohistochemistry, the investigators demonstrated that FAM120A protein levels are elevated in bladder cancer tissues compared with normal tissue, suggesting that the protein is not merely a passive passenger but an active participant in the disease process.

To establish causality rather than mere correlation, the researchers turned to a battery of functional assays. They depleted FAM120A in bladder cancer cell lines using lentiviral shRNA approaches, a technique that uses viral vectors to deliver short hairpin RNA molecules capable of silencing a specific gene. The consequences were striking. Cells lacking FAM120A lost much of their clonogenic capacity, the ability to form colonies from single founder cells, a hallmark of cancer cell self-renewal. Wound healing assays, in which a scratch is made across a confluent cell monolayer and the rate of gap closure measured, showed dramatically impaired migratory capacity. Invasion through Matrigel, a synthetic basement membrane that mimics the extracellular matrix tumors must degrade to metastasize, was similarly crippled. Even three-dimensional spheroid formation, an in vitro model that captures aspects of tumor architecture more faithfully than flat cell culture, was compromised without FAM120A.

The team then extended these findings to anchorage-independent growth, assessed by soft agar assays, a classical test of malignant transformation in which cells must proliferate while suspended in semi-solid medium, something normal cells cannot do. FAM120A-depleted cells failed this test, and, critically, the loss of FAM120A also suppressed tumor formation in vivo using xenograft models, in which human cancer cells are implanted into immunocompromised mice. These animal experiments, performed under protocols approved by the Institutional Review Board of Thomas Jefferson University, provide the strongest evidence yet that FAM120A is not simply associated with aggressive bladder cancer but is functionally required for it.

Mechanistically, the study dissected how FAM120A exerts its oncogenic influence. Progranulin stimulation of bladder cancer cells is known to activate two major signaling highways: the AKT pathway, central to cell survival and growth, and the ERK1/2 pathway, a canonical mitogen-activated protein kinase cascade driving proliferation. Using western immunoblots, the researchers showed that FAM120A depletion blunted progranulin-evoked activation of both AKT and ERK1/2, placing the scaffold protein upstream of these critical signaling events. Co-immunoprecipitation experiments and proximity ligation assays, a technique that detects proteins located within roughly 40 nanometers of each other in intact cells, confirmed that the physical interaction between EphA2 and FAM120A is enhanced upon progranulin stimulation. Immunofluorescence microscopy further revealed colocalization of the two proteins within cells, painting a picture of a dynamically assembled signaling complex that assembles when progranulin arrives and drives the aggressive behavior of bladder cancer cells.

Perhaps the most mechanistically illuminating findings concern the cytoskeleton. For a cancer cell to migrate and invade, it must continuously remodel its actin cytoskeleton, the meshwork of F-actin filaments that provides mechanical force and shape. The team observed that progranulin stimulation triggers F-actin rearrangements in bladder cancer cells, and that this rearrangement is inhibited when FAM120A is depleted. Tracing the pathway further, they identified the small GTPase RhoA, a master regulator of actin dynamics and cell contractility, as a key mediator. Progranulin-induced activation of RhoA was abolished upon FAM120A depletion, and the researchers concluded that FAM120A operates through ERK1/2 and RhoA-dependent pathways to orchestrate the cytoskeletal changes that enable motility and invasion. This work builds on insights from experts in Rho protein biology, with the authors acknowledging discussions with Dr. Kenneth L. Van Golen of the University of Delaware.

The translational implications of these findings are twofold. First, FAM120A emerges as a candidate drug target. Because scaffold proteins occupy a nodal position in signaling networks, disrupting the EphA2-FAM120A interaction or destabilizing FAM120A itself could, in principle, simultaneously cripple multiple oncogenic outputs, from AKT-mediated survival to RhoA-driven invasion. Second, and more immediately achievable, FAM120A holds promise as a biomarker. Its upregulation in bladder cancer tissues suggests it could aid diagnosis, and the authors argue its expression patterns may carry prognostic value, potentially helping clinicians identify patients whose tumors are most likely to progress.

There is also an intriguing therapeutic synergy buried in the data. The researchers found that depleting FAM120A sensitized bladder cancer cells to cisplatin, a cornerstone chemotherapy drug used in the treatment of muscle-invasive and metastatic bladder cancer. Cisplatin kills cells primarily by cross-linking DNA, but resistance is a persistent clinical problem. The observation that removing a scaffold protein from a growth factor signaling axis can restore chemosensitivity hints that combinations of standard chemotherapy with agents targeting the progranulin/EphA2/FAM120A circuitry could one day improve outcomes, though such strategies remain firmly in the preclinical realm.

The collaborative nature of the study reflects the complexity of the problem. The work united researchers from Temple University in Philadelphia, Thomas Jefferson University’s Sidney Kimmel Cancer Center, the University of Siena, the University of Milano-Bicocca, the University of Naples Federico II, the University of Catania, the Mayo Clinic Alix School of Medicine, and the S.H.R.O. Italia Foundation, with funding from the Sbarro Health Research Organization and National Institutes of Health grants supporting Thomas Jefferson University’s Translational Core Facility. Corresponding author Andrea Morrione and colleagues, including co-author Antonio Giordano, director of the Sbarro Institute, and veteran extracellular matrix researcher Renato V. Iozzo, brought complementary expertise in growth factor signaling, proteomics, tumor biology, and translational oncology to bear on the question.

Important caveats remain. The study relies heavily on cell lines and xenograft models, which, while informative, do not fully recapitulate the heterogeneity of human bladder tumors or the microenvironment in which they grow. Whether FAM120A expression levels correlate with patient outcomes in large clinical cohorts, whether the protein can be safely and effectively targeted pharmacologically, and how its function intersects with established bladder cancer drivers such as FGFR3 alterations and immune checkpoint pathways are questions that will require substantial further research. The fact that progranulin also participates in neurodegenerative disease adds another layer of complexity, as any therapeutic strategy modulating progranulin signaling must carefully consider effects beyond the tumor.

Nevertheless, the identification of FAM120A as an oncogenic effector in the progranulin/EphA2 axis represents a meaningful advance in understanding how bladder cancer cells acquire their invasive, treatment-resistant phenotype. By converting a proteomic observation into a mechanistic model validated across molecular, cellular, and animal levels, the study provides the scientific community with both a new lens on an established signaling pathway and a concrete starting point for the development of diagnostic markers and therapeutic interventions. For a disease that kills nearly 18,000 Americans each year, that is progress worth noting.

Subject of Research: The role of FAM120A as a scaffold protein and novel effector in the progranulin/EphA2 oncogenic signaling axis in bladder cancer

Subject of Research: Cancer

Article Title: Functional characterization of FAM120A as a novel effector in the progranulin/EphA2 oncogenic axis in bladder cancer

Article References: Satasiya, V., Martinelli, C., Pascal, G., Ducci, G., Ventura, E., Williams, S. J., Burk, S. R., Tchamou, M. N., Shani, S., Klain, M., Sacco, E., Vanoni, M., Belfiore, A., Iozzo, R. V., Giordano, A., & Morrione, A. (2026). Functional characterization of FAM120A as a novel effector in the progranulin/EphA2 oncogenic axis in bladder cancer. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03808-1

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03808-1

Keywords: FAM120A, EphA2, Progranulin, Bladder cancer, Migration, Invasion, Anchorage-independent growth, AKT, ERK1/2, RhoA, Cisplatin sensitivity, Oncogenic signaling

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Nathaniel Bowman. (September 6, 2026). FAM120A acts as a new effector in progranulin/EphA2-driven bladder cancer. Scienmag. https://scienmag.com/fam120a-acts-as-a-new-effector-in-progranulin-epha2-driven-bladder-cancer/

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