Imaging Cell Surface Plectin in PDAC Patients - A First-In-Human Phase 0 Study ReportDimastromatteo, He, Adams
et alMol Imaging Biol (2025)
Abstract: Plectin is traditionally an intracellular cytoskeletal protein that maintains cell structure and stability. However, we and others have identified its surface-localized form in cancer (CSP), where it influences cell adhesion, migration, immune response, and tumor signaling. CSP-positive tumors (pancreatic, lung, ovarian, and breast cancers) contribute to over 3 million annual deaths, highlighting its clinical relevance. This phase 0 study aimed to evaluate PTP-01's ability to target CSP in pancreatic tumors, despite their dense desmoplastic stroma, and to estimate CSP density and tumor vascularity.Pancreatic cancer patients (n = 3) received an intravenous injection of 100 µg PTP-01 labeled with 370 MBq 111In one day before resection. Whole-body planar scintigraphy and SPECT imaging were performed at multiple time points. Resected tumors and adjacent tissues were collected 28 h post-injection. Blood and urine samples were obtained for pharmacokinetic analysis. Tissue biodistribution was assessed using whole-body SPECT scans.PTP-01 injection caused no reported adverse events. Uptake was primarily observed in the kidneys, liver, and bladder, with some tumor uptake. CSP density in tumors was estimated at 10⁶ molecules per cell. The elimination half-life (T₁/₂) ranged from 5 to 22 h across patients.PTP-01 imaging of pancreatic tumors revealed the ability of a targeted agent to bind to CSP. Further, CSP density in tumors was estimated to be on par with other surface molecules such as Her2 with effective targeted therapies. This study suggests that CSP is a highly expressed, accessible molecule for the development of targeted therapies such as antibodies or antibody-drug conjugates.© 2025. The Author(s).
Plectin-mediated cytoskeletal crosstalk as a target for inhibition of hepatocellular carcinoma growth and metastasisOutla, Oyman-Eyrilmez, Korelova
et alElife (2025) 13
Abstract: The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/Akt signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.© 2024, Outla et al.
A biomimetic dual-targeting nanomedicine for pancreatic cancer therapyZhou, Zhang, Cai
et alJ Mater Chem B (2025) 13 (11), 3716-3729
Abstract: The physiological characteristics of pancreatic cancer (PC) involve the interplay between tumor cells, cancer-associated fibroblasts (CAF) and the extracellular matrix (ECM). This intricate microenvironment contributes to the cancer's resistance to conventional chemoradiotherapy and its poor prognosis. Carbon monoxide (CO), a promising molecule in gas therapy, can effectively penetrate solid tumors and induce tumor cell apoptosis at high concentrations. However, precise dosing control remains a significant challenge in the administration of exogenous CO, and its inherent toxicity at elevated concentrations presents substantial barriers to clinical translation. In this study, we developed a novel biomimetic nanomedical drug delivery system capable of simultaneously targeting CAF and PC tumor cells, degrading the ECM, and inhibiting tumor growth. The strategy integrates iron carbonyl (FeCO), an anti-cancer agent, and losartan (Lo), a drug that degrades tumor matrix, into a biodegradable nanomaterial-mesoporous polydopamine (MPDA). The resulting nanoparticles are then coated with CAF cell membranes (CAFM) and functionalized with plectin-1 targeted peptide (PTP), a molecule that targets PC cells, to construct the (Lo + FeCO)@MPDA@CAFM-PTP nanomedicine. This system utilizes the homologous adhesion properties of CAF membranes to target CAFs, delivering Lo to degrade the ECM. Following ECM degradation, the nanomedicine penetrates further to bind to PC tumor cells via PTP. Then anti-cancer drug FeCO is released to react with the excessive reactive oxygen species (ROS) in PC tumor cells to produce high concentrations of CO, effectively inducing tumor cell apoptosis. The (Lo + FeCO)@MPDA@CAFM-PTP nanomedicine demonstrated significant cytotoxicity against Panc-1 cells in vitro and effectively inhibited PC tumor growth in vivo. This innovative approach holds great promise for advancing pancreatic cancer treatment.
Proteomic characterization of particle-protein coronas shows differences between osteoarthritic and contralateral knees in a rat modelShah, Partain, Aldrich
et alConnect Tissue Res (2025) 66 (1), 59-72
Abstract: When synthetic particles are injected into a biofluid, proteins nonspecifically adsorb onto the particle surface and form a protein corona. Protein coronas are known to alter how particles function in blood; however, little is known about protein corona formation in synovial fluid or how these coronas change with osteoarthritis (OA). In this study, protein coronas were characterized on particles incubated within OA-affected or healthy rat knees.First, to evaluate particle collection techniques, magnetic polystyrene particles were placed in bovine synovial fluid and separated using either magnetics or centrifugation. In a second experiment, 12 male and 12 female Lewis rats received a simulated medial meniscal injury. At 2, 5, or 8 weeks post-surgery, operated and contralateral limbs were injected with clean magnetic particles (n = 8 per timepoint). After a 4-h incubation, animals were euthanized and particles were magnetically recovered. In both experiments, protein coronas were characterized using an Orbitrap fusion mass spectrometer.In the first experiment, the particle separation method affected the identified proteins, likely due to centrifugation forces causing some large proteins to spin-down with the particles. In the OA model, 300-500 proteins were identified in the particle-protein coronas with 35, 59, and 13 proteins differing between the OA-affected and contralateral limbs at 2, 5, and 8 weeks, respectively. In particular, plectin, a serine (or cysteine) proteinase inhibitor, and cathepsin B were more prominent in the particle-protein coronas of OA-affected knees.Synthetic particles nonspecifically adsorb proteins in synovial fluid, and these binding events differ with OA severity.
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