Biology subjects

Teegarden, D.

Publications and source records attributed to Teegarden, D..

3 recordsLinked to original sources

bioRxiv2026

Obesity and Tumor Development Reprogram the Proteome and Metabolic Effects of Adipose- and Tumor-Derived Extracellular Vesicles

Obesity alters systemic metabolism and immune function, yet how obesity and tumor progression regulate extracellular vesicle (EV) composition and function within the tumor microenvironment remains unclear. Using a preclinical model of diet-induced obesity (DIO) and triple-negative breast cancer (TNBC), we investigated how obesity and tumor stage shape the proteomic composition of EVs from visceral adipose tissue (VAT-EVs) and mammary tumors (tumor-EVs), and how these EVs regulate immune and tumor cell metabolism. Orthotopically transplanted metM-Wntlung tumors were classified as early ([~]0.5 cm3) or late ([~]1.0 cm3), and EV proteomes were analyzed by mass spectrometry. At early stages, tumor-EVs from DIO mice, compared with control lean mice, were depleted in immune-related proteins, whereas VAT-EVs were enriched in mitochondrial and fatty acid oxidation proteins. In contrast, at later stages, tumor-EVs from DIO mice were enriched in lipid metabolism and oxidative stress-associated proteins, while VAT-EVs exhibited loss of mitochondrial proteins consistent with metabolic dysfunction. Functionally, tumor-EVs and VAT-EVs differentially regulated CD8 T cell mitochondrial activity and cytokine production and induced distinct, stage-dependent metabolic reprogramming in non-aggressive epithelial-like (E-Wnt) versus mesenchymal-like (M-Wnt) tumor cells. These findings suggest that obesity and tumor progression dynamically reshapes EV cargo, enabling EV-mediated metabolic reprogramming that may contribute to immune suppression and TNBC progression.

cancer biology↗

bioRxiv2022

Hypoxia-mediated suppression of pyruvate carboxylase drives tumor microenvironment immunosuppression

Metabolic reprogramming and immune evasion are established hallmarks of the tumor microenvironment (TME). Growing evidence supports tumor metabolic dysregulation as an important mediator of tumor immune evasion. High TME levels of lactate potently suppress antitumor immunity. Pyruvate carboxylase (PC), the enzyme responsible for the anaplerotic conversion of pyruvate to oxaloacetate, is essential for lung metastasis in breast cancer. Moreover, PC may be dispensable in some cells within the TME, and loss of PC expression is associated with immunosuppression. Here we test whether PC suppression alters tumor metabolism and immunosuppression. Using multiple animal models of breast cancer, we identify a dimorphic role for PC expression in mammary cancer cells. Specifically, PC supports metastatic colonization of the lungs, while suppression of PC promotes primary tumor growth and suppresses histological and transcriptomic markers of antitumor immunity. We demonstrate that PC is potently suppressed by hypoxia, and that PC is frequently suppressed in solid tumors, particularly those with higher levels of hypoxia. Using metabolomics, high-resolution respirometry, and extracellular flux analysis, we show that PC-suppressed cells produce more lactate and undergo less oxidative phosphorylation than controls. Finally, we identify lactate metabolism as a targetable dependency of PC-suppressed cells, which is sufficient to restore T cell populations to the TME of PC-suppressed tumors. Taken together, these data demonstrate that elevated lactate following PC suppression by hypoxia may be a key mechanism through which primary tumors limit antitumor immunity. Thus, these data highlight that PC-directed tumor metabolism is a nexus of tumor progression and antitumor immunity.

cancer biology↗

bioRxiv2018

Pyruvate carboxylase supports the pulmonary tropism of metastatic breast cancer

Background: Overcoming systemic dormancy and initiating secondary tumor grow under unique microenvironmental conditions is a major rate-limiting step in metastatic progression. Disseminated tumor cells encounter major changes in nutrient supplies and oxidative stresses compared to the primary tumor and must demonstrate significant metabolic plasticity to adapt to specific metastatic sites. Recent studies suggest that differential utilization of pyruvate sits as a critical node in determining the organotropism of metastatic breast cancer. Pyruvate carboxylase (PC) is key enzyme that converts pyruvate into oxaloacetate for utilization in gluconeogenesis and replenishment of the TCA cycle.\n\nMethods: Patient survival was analyzed with respect to gene copy number alterations and differential mRNA expression levels of PC. Expression of PC was analyzed in the MCF-10A, D2-HAN and the 4T1 breast cancer progression series under in vitro and in vivo growth conditions. PC expression was depleted via shRNAs and the impact on in vitro cell growth, mammary fat pad tumor growth, and pulmonary and non-pulmonary metastasis was assessed by bioluminescent imaging. Changes in glycolytic capacity, oxygen consumption and response to oxidative stress were quantified upon PC depletion.\n\nResults: Genomic copy number increases in PC were observed in 16-30% of metastatic breast cancer patients. High expression of PC mRNA was associated with decreased patient survival in the MCTI and METABRIC patient datasets. Enhanced expression of PC was not recapitulated in breast cancer progression models when analyzed under glucose-rich in vitro culture conditions. In contrast, PC expression was dramatically enhanced upon glucose deprivation and in vivo in pulmonary metastases. Depletion of PC led to a dramatic decrease in 4T1 pulmonary metastasis but did not affect orthotopic primary tumor growth. Tail vein inoculations confirmed the role of PC in facilitating pulmonary, but not extra-pulmonary tumor initiation. PC-depleted cells demonstrated a decrease in glycolytic capacity and oxygen consumption rates and an enhanced sensitivity to oxidative stress.\n\nConclusions: Our studies indicate that PC is specifically required for the growth of breast cancer that has disseminated to the lungs. Overall, these findings point to the potential of targeting PC for the treatment of pulmonary metastatic breast cancer.

cancer biology↗