Biology subjects

Mazzilli, S.

Publications and source records attributed to Mazzilli, S..

3 recordsLinked to original sources

bioRxiv2025

An atlas of gene programs in non-small cell lung cancer delineates novel patterns of lineage vacillation, plasticity, and aggressiveness

Combinations of molecular programs can be altered in cancer cells and contribute to tumor initiation and aggressiveness. We developed a novel framework called a Gene Program Association Study (GPAS) to create an atlas of gene co-expression modules in cancer cells from 127 primary non-small-cell-lung cancers (NSCLCs) and determine their association with clinical and histopathological features. Lung adenocarcinoma (LUAD) displayed "lineage vacillation" defined by extensive heterogeneity of modules from different alveolar cell types. Modules associated with late-stage LUAD were found in cells from early-stage tumors suggesting that aggressive phenotypes can be observed before clinical progression. Basal- and squamous-like intermediate cells were observed in the transition to invasive mucinous LUAD. In lung squamous cell carcinoma, a novel subtype was identified with lower levels of canonical squamous modules and higher levels of fibrinogen. Overall, this atlas elucidated the combinations of molecular programs in cancer cells that contribute to heterogeneity and aggressiveness in NSCLC. Statement of SignificanceWe performed a Gene Program Association Study (GPAS) to create an atlas of gene modules in cancer cells from NSCLCs. This atlas revealed extensive lineage vacillation, combinations of modules that defined late-stage disease, novel routes of lineage plasticity, and novel subtypes in lung adenocarcinoma or lung squamous cell carcinoma.

bioinformatics↗

bioRxiv2023

Aberrant macrophage activation and failed regeneration of pulmonary epithelium promote tuberculosis progression uniquely in lung tissue

Pulmonary tuberculosis (PTB) represents 85% of the disease burden caused by Mycobacterium tuberculosis (Mtb) and promotes aerosol transmission infecting about a quarter of people globally. Most Mtb infections are effectively limited within primary granulomatous lesions. Containment failures lead to hematogenous spread and the formation of post-primary destructive PTB lesions. Factors that favor Mtb survival and replication in the lungs after hematogenous spread despite systemic immunity represent appealing targets for host-directed TB therapies, but are currently unknown. We developed a novel mouse model that mimics progression of chronic post-primary PTB in humans: wherein PTB lesions form after hematogenous spread from a remote primary lesion in immunocompetent but TB-susceptible B6.Sst1S mice. The B6.Sst1S mice developed PTB lesions featuring granulomatous pneumonia, bronchogenic expansion and broncho-occlusion closely resembling post-primary PTB in humans. Using spatial transcriptomic and fluorescent multiplexed immunochemistry, we demonstrated the expansion of myeloid cell populations with the appearance of alternatively activated macrophages, dissolution of initial lymphoid follicles, and accumulation of de-differentiated lung epithelial cells in the advanced PTB lesions. To determine whether lung parenchymal cells or lung oxygenation were necessary for the pulmonary TB progression, we implanted lung and spleen fragments subcutaneously to serve as potential targets for hematogenous spread. The lung (but not spleen) implants displayed characteristic organized granulomas with necrosis and Mtb replication demonstrating that deleterious interactions of aberrantly activated macrophages with the inflammation-injured lung resident cells, and possibly hypoxia, not oxygenation, are critical determinants of PTB progression in immunocompetent hosts. Necrotic TB lesions also developed in subcutaneous implants of human lung tissue in mice with human immune system after respiratory infection. These animal models may serve to further dissect the lung-specific mechanisms of host susceptibility to virulent Mtb and for testing therapeutic interventions targeting these mechanisms.

immunology↗

bioRxiv2022

SnFFPE-Seq: towards scalable single nucleus RNA-Seq of formalin-fixed paraffin-embedded (FFPE) tissue

Profiling cellular heterogeneity in formalin-fixed paraffin-embedded (FFPE) tissues is key to characterizing clinical specimens for biomarkers, therapeutic targets, and drug responses. Here, we optimize methods for isolating intact nuclei and single nucleus RNA-Seq from FFPE tissues in the mouse brain, and demonstrate a pilot application to a human clinical specimen of lung adenocarcinoma. Our method opens the way to broad applications of snRNA-Seq to archival tissues, including clinical samples.

genomics↗