Vitek, M. P. | bioRxiv Science

bioRxiv2026

Anti-Polyamine Therapy Restrains Kidney Cyst Growth in an Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common monogenic kidney disease worldwide. Tolvaptan is currently the only approved intervention to slow kidney cyst growth, but its indication is limited to rapidly progressing ADPKD and use compromises quality of life. Hence, new therapeutic options are of high clinical importance. Metabolic dysregulation is a hallmark of kidney cyst growth, including reprogramming of arginine metabolism and polyamine production. Sustained increases in polyamine synthesis drive pathological epithelial cell proliferation, tissue remodeling, and activation of M2-like macrophages, all known drivers of PKD. Difluoromethylornithine (DFMO) is an FDA approved irreversible inhibitor of ornithine decarboxylase (ODC1), the rate limiting enzyme in the arginine-polyamine pathway. Here, we treated C57Bl6/J p.R3277C (Pkd1RC/RC) mice for five months with DFMO-supplemented drinking water to test if DFMO treatment can slow kidney cyst growth in an orthologous model of ADPKD that mimics the disease pathophysiology seen in patients. At study end, Pkd1RC/RC mice treated with DFMO presented with significantly reduced percent kidney weight normalized to body weight as well as kidney cystic index and cyst number compared to control. Kidney RNA-seq analyses revealed correction of many genes and pathways perturbed in PKD post DFMO treatment, as well as overall heathier kidney cellular architecture as inferred by RNAseq-base cell type deconvolution. Our data highlight significant potential to repurpose DFMO for the treatment of patients with ADPKD and investigate the role of polyamines in modulating epithelial as well as myeloid cell fate in the setting of PKD.

pharmacology and toxicology↗

bioRxiv2023

Spatial analysis of NOS2 and COX2 interaction with T-effector cells reveals immunosuppressive landscapes associated with poor outcome in ER- breast cancer patients

Multiple immunosuppressive mechanisms exist in the tumor microenvironment that drive poor outcomes and decrease treatment efficacy. The co-expression of NOS2 and COX2 is a strong predictor of poor prognosis in ER- breast cancer and other malignancies. Together, they generate pro-oncogenic signals that drive metastasis, drug resistance, cancer stemness, and immune suppression. Using an ER- breast cancer patient cohort, we found that the spatial expression patterns of NOS2 and COX2 with CD3+CD8+PD1- T effector (Teff) cells formed a tumor immune landscape that correlated with poor outcome. NOS2 was primarily associated with the tumor-immune interface, whereas COX2 was associated with immune desert regions of the tumor lacking Teff cells. A higher ratio of NOS2 or COX2 to Teff was highly correlated with poor outcomes. Spatial analysis revealed that regional clustering of NOS2 and COX2 was associated with stromal-restricted Teff, while only COX2 was predominant in immune deserts. Examination of other immunosuppressive elements, such as PDL1/PD1, Treg, B7H4, and IDO1, revealed that PDL1/PD1, Treg, and IDO1 were primarily associated with restricted Teff, whereas B7H4 and COX2 were found in tumor immune deserts. Regardless of the survival outcome, other leukocytes, such as CD4 T cells and macrophages, were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to a massive cell infiltration, thus validating the hypothesis that COX2 is an essential component of the Teff exclusion process and, thus, tumor evasion. Our study indicates that NOS2/COX2 expression plays a central role in tumor immunosuppression. Our findings indicate that new strategies combining clinically available NOS2/COX2 inhibitors with various forms of immune therapy may open a new avenue for the treatment of aggressive ER- breast cancers.

cancer biology↗