Biology subjects

Peura, J.

Publications and source records attributed to Peura, J..

4 recordsLinked to original sources

bioRxiv2025

American mink as an animal model to study SARS-CoV-2 and vaccine response

Selecting a suitable animal model is crucial in understanding infectious diseases and developing vaccines. Here, we developed a receptor-binding domain -based SARS-CoV-2 vaccine with mouse Fc an immunopotentiator in a mink model. Four different variations of the vaccine were tested in groups of 30-31 American mink and followed for IgG and neutralizing antibodies (nAb) up to 27 weeks. Subcutaneous version induced a strong IgG and nAb response within two weeks and was still detectable at 27 weeks. Intranasal version also caused a detectable, although weaker, immune response. A simultaneously given subcutaneous vaccine against virus enteritis, botulism and hemorrhagic pneumonia potentially caused a lower SARS-CoV-2 antibody response, highlighting the need for further studies on co-effects of vaccines. In virus challenge with Alpha variant (B.1.1.7), vaccinated mink had a stronger antibody response than unvaccinated mink. Despite not preventing the infection, vaccinated mink had milder clinical signs and less virus in saliva. Another challenge of unvaccinated mink with Omicron variant showed similar results to alpha (BA.1) variant. Virus RNA was detected in the brain of unvaccinated mink but not vaccinated mink by in situ hybridization, indicating a suitability of mink to study neurological effects of SARS-CoV-2 and potentially long COVID as well. Author summaryFinding a good animal model is very important in studying infectious diseases and their treatment. The recent SARS-CoV2 pandemic highlighted this dilemma. We have developed an animal model based on mink due to their close match to humans in the symptomology of this disease. Such model will enable the study of relative susceptibility, transmission, tissue tropism, complex pathogenesis and long COVID, as well as prophylaxis and vaccines. This model will also help reduce the use of primates in this research. We have further developed a new vaccine for SARS-CoV2 based on the receptor binding domain of the S-protein with an inbuilt immune-enhancer. This vaccine underwent extensive testing in mink to determine response, long term protection, and safety. The vaccine was found to provide excellent titers of neutralizing antibodies with wide range in target variants. It also reduced the severity and duration of visible symptoms in the animals significantly. We propose this vaccine candidate for further study and future commercialization.

microbiology↗

bioRxiv2025

Pancreatic cancer cachexia is mediated by PTHrP-driven disruption of adipose de novo lipogenesis

Pancreatic cancer patients have the highest rates and most severe forms of cancer cachexia, yet cachexia etiologies remain largely elusive, leading to a lack of effective intervening therapies. Parathyroid hormone-related protein (PTHrP) has been clinically implicated as a putative regulator of cachexia, with serum PTHrP levels correlating with increased weight loss in PDAC patients. Here we show that cachectic PDAC patients have high expression of tumor PTHrP and use a genetically engineered mouse model to functionally demonstrate that loss of PTHrP blocks cachectic wasting, dramatically extending overall survival. The re-expression of PTHrP in lowly cachectic models is sufficient to induce wasting and reduce survival in mice, which is reversed by the conditional deletion of the PTHrP receptor, Pth1r, in adipocytes. Mechanistically, tumor-derived PTHrP suppresses de novo lipogenesis in adipocytes, leading to a molecular rewiring of adipose depots to promote wasting in the cachectic state. Finally, the pharmacological disruption of the PTHrP-PTH1R signaling axis abrogates wasting, highlighting that a targeted disruption of tumor-adipose crosstalk is an effective means to limit cachexia. STATEMENT OF SIGNIFICANCEPancreatic ductal adenocarcinoma (PDAC) is the prototypical cancer type associated with cancer cachexia, a debilitating wasting syndrome marked by adipose tissue loss and muscle atrophy. Herein, we establish that PTHrP is a tumor-derived factor that facilitates cachexia by downregulating de novo lipogenesis in adipocytes and that blocking PTHrP is an effective means to limit wasting in preclinical mouse models.

cancer biology↗

bioRxiv2024

Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity

Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGF{beta}. Snail re-expression and TGF{beta} treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.

cancer biology↗

bioRxiv2023

Nanoparticle delivery of innate immune agonists combines with senescence-inducing agents to mediate T cell control of pancreatic cancer

Pancreatic ductal adenocarcinoma has quickly risen to become the 3rd leading cause of cancer-related death. This is in part due to its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here we investigated an innovative immunotherapy approach combining local delivery of STING and TLR4 innate immune agonists via lipid-based nanoparticles (NPs) co-encapsulation with senescence-inducing RAS-targeted therapies that can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other pro-inflammatory signaling, increased antigen presentation by tumor cells and antigen presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and Type I interferon-dependent tumor regressions and long-term survival in preclinical PDAC models. STING and TLR4-mediated Type I interferon signaling were also associated with enhanced NK and CD8+ T cell immunity in human PDAC. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can synergize to orchestrate a coordinated innate and adaptive immune assault to overcome immune suppression and activate durable anti-tumor T cell responses against PDAC. SUMMARYCombining senescence-inducing MEK and CDK4/6 inhibitors with nanoparticle delivery of STING and TLR4 agonists leads to interferon-driven and cytotoxic T cell-mediated PDAC control.

cancer biology↗