Biology subjects

Bracci, P.

Publications and source records attributed to Bracci, P..

3 recordsLinked to original sources

bioRxiv2025

Spatial Single-Cell Atlas Reveals KSHV-Driven Broad Cellular Reprogramming, Progenitor Expansion, Immune and Vascular Remodeling in Kaposi's Sarcoma

Kaposis sarcoma (KS) is a highly inflammatory, angiogenic tumor driven by Kaposis sarcoma-associated herpesvirus (KSHV), yet the origins of tumor cells and mechanisms of progression remain unclear. Here, we present the first spatial single-cell atlas of KS, profiling 256 samples across patch, plaque, and nodular lesions and normal controls. We identify CD34 progenitor lymphatic endothelial cells (LECs) as the primary targets of KSHV, whose clonal expansion drives tumor growth. KSHV infection induces widespread cellular reprogramming across the tumor microenvironment, including LECs, vascular endothelial cells, fibroblasts, and macrophages, generating hybrid phenotypes that support angiogenesis, inflammation, and immune modulation. KSHV macrophages are enriched in tumor-proximal niches, further promoting a proangiogenic, immunosuppressive environment. Spatial analysis reveals evolving tumor-associated niches, with a core-to-periphery gradient correlating with infection, immune modulation, and cellular remodeling. We identify disease progression predictive signatures, offering mechanistic insights into KS pathogenesis and potential new therapeutic strategies by reprogramming the tumor microenvironment. Highlights CD34+ progenitor lymphatic endothelial cells are the primary KSHV target cells, with their clonal expansion driving Kaposis sarcoma growth. KSHV infection reprograms broad cell types into hybrid identities, and drives tumor-specific niche and vascular remodeling, endothelial plasticity, and immune modulation. KSHV-reprogrammed macrophages drive inflammation, angiogenesis, and immune modulation. Spatially resolved molecular and cellular signatures predict Kaposis sarcoma progression, offering novel therapeutic strategies targeting the tumor microenvironment.

cancer biology↗

bioRxiv2020

Pseudomonas aeruginosa Stimulates Inflammation and Enhances KSHV-Induced Cell Proliferation and Cellular Transformation through Both LPS and Flagellin

Inflammation triggered by innate immunity promotes carcinogenesis in cancer. Kaposis sarcoma (KS), a hyperproliferative and inflammatory tumor caused by Kaposis sarcoma-associated herpesvirus (KSHV) infection, is the most common cancer in AIDS patients. KSHV infection sensitizes cells to pathogen-associated molecular patterns (PAMPs). We examined the role of Pseudomonas aeruginosa (PA), an opportunistic bacterium that can affect AIDS patients, in inflammation and cell proliferation of KSHV-transformed cells. PA stimulation increased cell proliferation and efficiency of colony formation in softagar of KSHV-transformed rat primary mesenchymal precursor (KMM) cells but had no significant effect on the untransformed (MM) cells. PA stimulation also increased cell proliferation of KSHV-infected human B-cells, Bjab, but not the uninfected cells. Mechanistically, PA stimulation resulted in increased inflammatory cytokines and activation of p38, ERK1/2, and JNK mitogen-activated protein kinase (MAPK) pathways in KMM cells while having no obvious effect on MM cells. PA induction of inflammation and MAPKs were observed with and without inhibition of Toll-like receptor 4 (TLR4) pathway while a flagellin-deleted mutant of PA required a functional TLR4 pathway to induce inflammation and MAPKs. Furthermore, treatment with both LPS or flagellin alone was sufficient to induce inflammatory cytokines, activate MAPKs, and increase cell proliferation and efficiency of colony formation in softagar of KMM cells. These results demonstrate that both LPS and flagellin are PAMPs that contribute to PA induction of inflammation in KSHV-transformed cells. Because AIDS-KS patients are susceptible to PA infection, our work highlights the preventive and therapeutic potential of targeting PA infection in these patients. ImportanceKaposis sarcoma (KS), caused by infection of Kaposis sarcoma-associated herpesvirus (KSHV), is one of the most common cancers in AIDS patients. KS is a highly inflammatory tumor but how KSHV infection induces inflammation remains unclear. We have previously shown that KSHV infection upregulates Toll-like receptor 4 (TLR4), sensitizing cells to lipopolysaccharide (LPS) and Escherichia coli. In the current study, we examined the role of Pseudomonas aeruginosa (PA), an opportunistic bacterium that can affect AIDS patients, in inflammation and cell proliferation of KSHV-transformed cells. PA stimulation increased cell proliferation, inflammatory cytokines, and activation of growth and survival pathways in KSHV-transformed cells through two pathogen-associated molecular patterns LPS and flagellin. Because AIDS-KS patients are susceptible to PA infection, our work highlights the preventive and therapeutic potential of targeting PA infection in these patients.

cancer biology↗

bioRxiv2020

Bayesian copy number detection and association in large-scale studies

Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging. We developed an approach called CNPBayes to identify latent batch effects, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. We demonstrate this approach in a Pancreatic Cancer Case Control study of 7,598 participants where the major sources of technical variation were not captured by study site and varied across the genome. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Supressor Candidate 3 (TUSC3). This study provides a robust Bayesian inferential framework for estimating copy number and evaluating the role of copy number in heritable diseases.

genetics↗