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[Preprint]. 2024 Oct 16:2024.10.14.618190.
doi: 10.1101/2024.10.14.618190.

Chronic obesity does not alter cancer survival in Tp53 R270H/+ mice

Ilaria Panzeri  1   2 , Zachary Madaj  3 , Luca Fagnocchi  1 , Stefanos Apostle  1 , Megan Tompkins  4 , Galen Hostetter  5 , J Andrew Pospisilik  1   2
Affiliations

Chronic obesity does not alter cancer survival in Tp53 R270H/+ mice

Ilaria Panzeri et al. bioRxiv. .

Abstract

Obesity is a complex chronic disease characterized by excessive adiposity and associations with numerous co-morbidities, including cancer. Despite extensive research, we have limited understanding of the mechanisms coupling obesity to cancer risk, and, of the contexts in which obesity does or does not exacerbate disease. Here, we show that chronic high-fat diet (HFD)-induced obesity has no significant effect on the Tp53 R270H/+ mouse, a model of human Li-Fraumeni multi-cancer syndrome. Surprisingly, despite inducing rapid and highly penetrant obesity and long-term differences in metabolic and adiposity, greater than one year of HFD had no significant effect on survival or tumor burden. These findings were replicated in two separate cohorts and thus provide important negative data for the field. Given strong publication bias against negative data in the literature, this large cohort study represents a clear case where chronic diet-induced obesity does not accelerate or aggravate cancer outcomes. The data thus carry high impact for researchers, funders, and policymakers alike.

Keywords: Cancer; Li-Fraumeni; Tp53; Tp53R270H; high-fat diet; obesity.

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Conflict of interest statement

COMPETING INTERESTS STATEMENT The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. A cohort to study chronic effects of obesity on Tp53-dependent cancers.
A) Schematic of the experimental plan. Tp53+/R270H females were mated with the Trim28+/D9 FVB.J males. F1 genotypes were screened for health issues and mass development. Tissues were harvested at sickness report. Histopathology determined the presence of tumors. Body, fat, and lean mass were measured at multiple timepoints. Blood was collected at multiple timepoints for metabolomic analysis. Created with BioRender.com. B) Scatter plots and smoothed conditional means (95% confidence interval, “loess” method) for body (top) and fat (bottom) mass in Tp53+/R270H females and males (pooled data). N=195 animals (101 females and 94 males). C) Representative examples of hematoxylin and eosin-stained adipose tissue from chow- (top) and high-fat (bottom) diet-fed Tp53+/R270H male animal at 70 weeks of age. N=1 animal. D) Heatmap of differentially abundant circulating metabolites between chow- and high-fat diet-fed animals (females and males) at 8–16-40 weeks of age. N=44 animals (21 under high-fat vs 23 under chow diet) across 3 timepoints.
Figure 2.
Figure 2.. HFD does not alter survival, burden, or spectrum in Tp53R270H/+ mice.
A) Kaplan-Meier survival probability by diet for Tp53+/R270H animals. Log-rank test, p=0.84. N=155 animals (95 high-fat diet vs 60 chow diet, pooled female and male data). B) Cumulative distribution of tumor burden (number of tumors per animal) in Tp53+/R270H animals fed with chow- or high-fat diet. N=97 animals (61 high-fat diet vs 36 chow diet, pooled female and male data). C) Prevalence of each tumor type over the total number of tumors in chow- or high-fat diet-fed Tp53+/R270H animals. N=168 tumors (108 tumors in high-fat diet- vs 60 in chow diet-fed animals, pooled female and male data). D) Percentage of Tp53+/R270H animals with primary tumors targeting the different organs. N=92 animals (61 high-fat diet vs 36 chow diet, pooled female and male data).
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