Su, Y. R. | Search bioRxiv

bioRxiv2024

Proteogenomic Characterization of Primary Oral Squamous Cell Carcinomas Unveils the Extracellular Matrix Remodeling and Immunosuppressive Microenvironment Linked with Lymph Node Metastasis

Oral squamous cell carcinoma (OSCC) is an increasingly prevalent malignancy worldwide. This study aims to understand molecular alterations associated with lymph node metastasis of OSCC in order to improve treatment strategies. We analyzed a cohort of 46 patients with primary OSCC, including 10 with lymph node metastasis and 36 without. Using a comprehensive multi-omics approach--encompassing genomic, transcriptomic, proteomic, epigenetic, single-cell, and spatial analyses--we integrated data to delineate the molecular landscape of OSCC in the context of lymph node metastasis. Our genomic analysis identified significant mutations in key genes within the MAPK, TGF-{beta}, and WNT signaling pathways, which are essential for tumor development. The proteogenomic analysis highlighted pathways critical for lymph node dissemination and factors contributing to an immunosuppressive tumor microenvironment. Elevated levels of POSTN were found to reorganize the extracellular matrix (ECM), interact with TGF-{beta}, disrupt cell cycle regulation, and suppress the immune response by reducing VCAM1 activity. Integrated analyses of single-cell and spatial transcriptome data revealed that cancer-associated fibroblasts (CAFs) secrete TGF-{beta}1/2, promoting cancer cell metastasis through epithelial-mesenchymal transition (EMT). Our integrated multi-omics analysis provides a detailed understanding of molecular mechanisms driving lymph node metastasis of OSCC. These insights could lead to more precise diagnostics and targeted treatments.

cancer biology↗

bioRxiv2023

Myeloid Cell-Derived IL1β Contributes to Pulmonary Vascular Remodeling in Heart Failure with Preserved Ejection Fraction

BackgroundPulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are not well understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH in HFpEF, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF. MethodsEight week old male and female C57/BL6J mice were given either L-NAME and high fat diet (HFD) or control water/diet for 2,5, and 12 weeks. Bulk RNA sequencing and single cell RNA sequencing was performed to identify early and cell-specific pathways that might regulate pulmonary vascular remodeling in PH-HFpEF. Finally, clodronate liposome and IL1{beta} antibody treatments were utilized to deplete macrophages or IL1{beta}, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF. ResultsMice given L-NAME/HFD developed PH, small vessel muscularization, and right heart dysfunction after 2 weeks of treatment. Inflammation-related gene ontologies were over-represented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68+ cells in both murine and human PH-HFpEF lungs. Cytokine profiling of mouse lung and plasma showed an increase in IL1{beta}, which was confirmed in plasma from patients with HFpEF. Single cell sequencing of mouse lungs also showed an increase in M1-like, pro-inflammatory populations of Ccr2+ monocytes and macrophages, and transcript expression of IL1{beta} was primarily restricted to myeloid-type cells. Finally, clodronate liposome treatment prevented the development of PH in L-NAME/HFD treated mice, and IL1{beta} antibody treatment also attenuated PH in L-NAME/HFD treated mice. ConclusionsOur study demonstrated that a well-accepted model of HFpEF recapitulates features of pulmonary vascular remodeling commonly seen in patients with HFpEF, and we identified myeloid cell derived IL1{beta} as an important contributor to PH in HFpEF.

cell biology↗