Biology subjects

Pierantoni, A.

Publications and source records attributed to Pierantoni, A..

3 recordsLinked to original sources

bioRxiv2026

A novel Gorilla-derived oncolytic Adenovirus with natural selective replication in cancer cells

Oncolytic virotherapy exploits viruses to selectively infect and destroy cancer cells while sparing normal tissues and represents a promising strategy in oncology. Human adenovirus type 5 (HAd5), although widely used, shows limited clinical efficacy due to high levels of preexisting immunity and suboptimal tumor selectivity. In this study, we evaluated novel gorilla-derived adenoviruses (GRAd) as alternative oncolytic vectors. Two distinct GRAd groups, GRAdBs and GRAdCs, were characterized for replication and cytopathic activity. GRAd25 (GRAdB group) exhibited robust replication in both tumor and normal cells, whereas GRAd32 (GRAdC group) demonstrated selective replication in tumor cells. To broaden tumor tropism while preserving selectivity, we generated a chimeric GRAd32 vector, GRAd32Fk25, by replacing its native fiber knob with that of GRAd25, potentially shifting receptor usage from CAR to CD46, which is more abundantly expressed in tumor cells. The vector was further armed with a therapeutic antibody by inserting the coding sequence for the single-chain Fc form (scFv-Fc) of EV20, a humanized anti-HER3 antibody, under endogenous viral regulatory control. In vitro analyses showed that GRAd32Fk25 maintained tumor-restricted replication and produced functional EV20 capable of binding HER3 and inhibiting downstream PI3K/Akt signaling. These results indicate that engineered GRAd vectors, exemplified by GRAd32Fk25 armed with EV20, provide a selective and versatile platform for oncolytic virotherapy with potential advantages over HAd5-based approaches.

cancer biology↗

bioRxiv2024

Comparative effects of proton and photon irradiation on the molecular and cellular profiles of triple-negative breast cancer: the crucial impact of VEGFC on tumor microenvironment remodeling

Metastatic triple-negative breast cancers (TNBC) are among the most aggressive types of breast cancer and are often treated with adjuvant radiotherapy and chemotherapy. Despite initial efficacy, relapses are common, leading to poor prognosis. Understanding the response of tumor microenvironment to radiotherapy is crucial, particularly comparing photon (X) and proton (P) radiotherapy due to proton radiations reduced side effects. MethodsWe investigated the effects of single and multiple X and P irradiations on various cell types within the tumor microenvironment, including vascular and lymphatic endothelial cells, fibroblasts, and TNBC tumor cells. VEGFC, a key factor in lymphatic vessel formation and metastasis, was a primary focus. We used protein arrays to evaluate the effects of irradiation and examined the impact of VEGFC inactivation on the sensitivity to X and P radiation. Additionally, we tested tumor-forming capabilities of irradiated cells and assessed the impact of genetic or therapeutic VEGFC inhibition on TNBC growth. Transcriptomic and proteomic analyses further characterized the differences between X and P tumors, providing deeper insights into their distinct molecular profiles. ResultsBoth X and P irradiations caused a transient increase in VEGFC levels, along with other pro-angiogenic, pro-lymphangiogenic, and pro-fibrotic factors, such as angiopoietin 2, artemin, endostatin, IGFBP2, serpinE1, PDGFA, and DPPIV. Endothelial cells exposed to multiple rounds of radiation showed enhanced proliferation but lost the ability to form pseudo vessels, indicating an endothelial-mesenchymal transition. Tumor cells lacking VEGFC were more sensitive to radiation, and anti-VEGFC antibodies significantly suppressed TNBC cells proliferation, both naive and multi-irradiated. Tumor xenografts formed by multi-irradiated cells grew larger in nude mice, particularly following proton irradiation, while X-irradiated tumors exhibited a more pro-lymphangiogenic phenotype compared to P-irradiated tumors. ConclusionsOur findings show that while P multi-irradiated TNBC cells form larger tumors, X multi-irradiated tumors are more aggressive, with elevated expression of genes linked to angiogenesis, lymphangiogenesis, and endothelial-mesenchymal transition. Targeting VEGFC during photon or proton radiotherapy could reduce metastasis and improve TNBC prognosis.

cancer biology↗

bioRxiv2024

p16High immune cell - controlled disease tolerance as a broad defense and healthspan extending strategy

The ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens. Accumulating evidence, however, indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we report that p16High immune cells play a key role in establishing disease tolerance. We found that the FDA-approved BNT162b2 mRNA COVID-19 vaccine is a potent and rapid inducer of p16High immune subsets both in mice and humans. In turn, p16High immune cells were indispensable for counteracting different lethal conditions, including LPS-induced sepsis, acute SARS-CoV-2 infection and ionizing irradiation. Mechanistically, we propose that activation of TLR7 or a low physiological activity of STING is sufficient to induce p16High immune subset that, in turn, establishes a low adenosine environment and disease tolerance. Furthermore, containing these signals within a beneficial range by deleting MDA5 that appeared sufficient to maintain a low activity of STING, induces p16High immune cells and delays organ deterioration upon aging with improved healthspan. Our data highlight the beneficial role of p16High immune subsets in establishing a low adenosine environment and disease tolerance.

cell biology↗