Biology subjects

Hursting, S. D.

Publications and source records attributed to Hursting, S. D..

3 recordsLinked to original sources

bioRxiv2024

Tirzepatide attenuates mammary tumor progression in diet-induced obese mice

Obesity, an established risk and progression factor for at least 13 cancer types, is highly prevalent globally, and effective strategies to mitigate the burden of obesity-related cancer are urgently needed. We investigated whether tirzepatide, a widely used incretin-mimetic drug that induces substantial weight loss, offers anticancer benefits. Across 3 tumor models, we demonstrate that chronic tirzepatide treatment reverses diet-induced increases in body weight and fat mass, systemic metabolic perturbations, and tumor growth. We also showed that the anticancer activity of tirzepatide does not involve direct effects on the neoplastic cells used, which lack incretin receptor expression. The anticancer actions of tirzepatide require the reversal of both the metabolic dysregulation and hyporesponsiveness of CD8+ tumor infiltrating lymphocytes evident in obesity. Our findings establish tirzepatide as a promising compound for intercepting obesity-related cancers.

cancer biology↗

bioRxiv2023

Calorie Restriction Outperforms Bariatric Surgery in a Murine Model of Obesity and Triple-Negative Breast Cancer

Obesity promotes triple-negative breast cancer (TNBC), and effective interventions are urgently needed to break the obesity-TNBC link. Epidemiologic studies indicate that bariatric surgery reduces TNBC risk, while evidence is limited or conflicted for weight loss via low-fat diet (LFD) or calorie restriction (CR). Using a murine model of obesity- driven TNBC, we compared the antitumor effects of vertical sleeve gastrectomy (VSG) with LFD, chronic CR, and intermittent CR. Each intervention generated weight and fat loss and suppressed tumor growth relative to obese mice (greatest suppression with CR). VSG and CR regimens exerted both similar and unique effects, as assessed using multi-omic approaches, in reversing obesity-associated transcriptional, epigenetic, secretome, and microbiota changes and restoring antitumor immunity. Thus, in a murine model of TNBC, bariatric surgery and CR each reverse obesity-driven tumor growth via shared and distinct antitumor mechanisms, and CR is superior to VSG in reversing obesitys procancer effects.

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↗