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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 multiomics approaches, in reversing obesity-associated transcript, epigenetics, 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 obesity's procancer effects.

PurposeMalnutrition severely impacts tolerance to anticancer therapies, but any relationship with overall survival (OS) at the time of solid tumour diagnosis in outpatients in the USA remains unclear.MethodsThis retrospective study evaluated 3562 patients who completed the Malnutrition Screening Tool (MST) at diagnosis, identifying the relationship between MST risk, a validated tool evaluating anorexia and weight loss, and OS. MST score of ≥2 of 5 was classified as high malnutrition risk (H-MST). Kaplan-Meier techniques and Cox proportional hazards models were used to analyse OS in H-MST versus low malnutrition risk (L-MST).ResultsIn the unadjusted models, MST risk was individually associated with OS. Multivariable regression confirmed that MST risk remained independently prognostic for OS after controlling for key confounding variables, HR=1.51 (95% CI: 1.33 to 1.72). The H-MST group had shorter OS (50-month survival rates: 69% L-MST vs 60% H-MST).ConclusionMST risk at diagnosis is an independent prognostic factor for OS. H-MST risk is associated with shorter survival in a broad cohort of solid tumour oncology outpatients.

Obesity affects more than 40% of American adults and is a well-established risk factor for breast cancer (BC) incidence and progression. BC is the second leading cause of cancer deaths among American women with the basal-like (BL) subtype considered particularly deadly. While immune checkpoint inhibitors (ICI) are one potential treatment, and the intestinal microbiota causally contribute to ICI response for some cancers, it is not yet understood how microbial communities influence ICI response in obesity-driven BC. Hence, we utilized a murine model of diet-induced obesity (DIO) and BLBC to investigate cecal microbial populations and tumor outcomes, and to establish the presence of tumoral microbiota. We found that DIO and ICI treatment modulate gut and tumoral microbial communities, and Bacteroides and Muribaculaceae cecal genera correlate with mammary tumor burden. Taken together, these data highlight the potential for manipulation of microbial communities to eventually improve ICI response in obesity-driven BLBC.

Grain-based diets (GBDs) are widely used in rodent studies but their utility is limited due to batch-to-batch variability resulting from inconsistent ingredients. Purified diets (PDs) are composed of only known and refined ingredients and offer a solution to the constraints of GBDs. However, unlike GBDs, PDs commonly used as control diets typically contain little to no soluble fiber. We therefore sought to identify a combination of fibers in PDs that best recapitulates the gastrointestinal morphometry and intestinal microbial composition of mice fed GBDs. Adult male mice (n=30) were randomly assigned to one of six diets—two GBDs and four PDs with varying insoluble and soluble fiber composition—for 28 days. 16S rRNA gene sequencing was used to compare microbial profiles across different gastrointestinal (GI) niches and diets. Gut microbiotas and cecal weights were distinct between mice fed the two GBDs, indicating that GBDs are unreliable controls in diet-based studies. Unexpectedly, intestinal microbial richness decreased as the amount of soluble fiber in the PDs increased and the addition of multiple soluble fibers did not rescue this effect. Mice fed PDs with high soluble fiber content (≥ 75% of dietary fiber was soluble fiber) best recapitulated GI morphometry of mice fed GBDs, but intestinal microbial communities were distinct between PD- and GBD-fed mice. Although supplementing PDs with soluble fiber improved GI morphometry, further research to determine the optimal mixture of soluble and insoluble fibers is required to more closely mirror the intestinal microbial diversity observed in mice fed GBDs. Dietary fibers are essential for maintaining gut health. Insoluble fibers aid in fecal bulking and water retention while soluble fiber is a fermentative substrate for intestinal microbial communities. GBDs are commonly used in preclinical research but the variability in ingredients across batches impedes reproducibility. PDs, which are composed of highly refined ingredients, pose a potential solution but the most widely used low-fat control PDs contain no soluble fiber. This study intended to identify a PD with a combination of fibers that promotes murine gut health and microbial diversity. A PD with optimal fiber composition would aid in the standardization and reproducibility of studies investigating intestinal physiology and the gut microbiota.

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.

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 obesity’s procancer effects.