Abstract 2962: Investigation of the relationship between obesity, weight cycling, and tumor progression in a murine myeloma model

Abstract

Abstract Background: The purpose of this study was to investigate physiologic effects of body weight regulation patterns and myeloma progression in vivo. Obesity and obesogenic behaviors are positively associated with both monoclonal gammopathy of unknown significance and multiple myeloma (MM). As the only known modifiable risk factor, this association has emerged as an optimal target for MM prevention, but little is known about the mechanistic relationship of weight patterns with MM progression. In two large prospective cohorts, we have reported an association of episodes of weight cycling (WC), e.g., intentional weight loss followed by unintentional weight gain, with increased MM risk compared to weight-stable individuals (Marinac et al. JNCI Cancer Spectrum, 2019). Experimental Procedures: We used two murine MM models (C57BL/6J Vk*Myc and SCID-Beige MM.1Sluc+ xenograft); male mice were fed a control diet (CD; 10% kcal from fat), high fat diet (HFD; 60% kcal from fat), or a diet cycling regimen (DC; 4 weeks on CD then 4 weeks on HFD) for 16 weeks and thereafter injected them intravenously with tumor cells (1x106 Vk*Myc or 2x106 MM.1S). Body composition was assessed via PIXIMUS-DEXA (SCID-Beige) or NMR (C57BL/6J). Tumor burden was assessed via CD138+ FACS (Vk*Myc) or in vivo bioluminescent imaging (IVIS; MM.1S). Results: The C57BL/6J mice (n=20) on HFD consistently gained weight and sustained the gains throughout the study duration; mice on the DC regimen exhibited dramatic weight cycling responses to diet switching. We observed significant differences in body fat (%) between HFD and CD mice, as assessed by NMR (p<= 0.0001), while body fat fluctuated with diet in the DC mice. At the time of tumor cell injection, HFD mice had higher body weights versus CD (p<0.000001) and DC (p<0.000001) mice; however, weights of DC mice were comparable to CD despite weight fluctuation throughout the study. Three weeks after MM inoculation, we detected elevated tumor burden in DC mice vs. CD mice (n-10, p=0.0061) and a trend toward elevated tumor burden in HFD mice (p=0.145). C57BL/6J mice on the DC regimen also had greater Vk*Myc tumor burden (p=0.0413) within the bone marrow (BM), specifically. In the SCID-Beige MM.1Sluc+ model (n=10), we observed similar trends for weight gain and cycling, and greater early tumor burden in both the HFD (p<0.0001) and DC (p=0.0214) groups compared to CD. Tumor burden was also elevated (p=0.0004) in the heaviest mice (vs. the lightest), regardless of diet, later in the SCID-Beige study. Conclusions: Combined, these results suggest that HFD and WC may contribute to MM risk via changes in the BM microenvironment that affect MM cell homing, engraftment and early expansion. This study lays the groundwork for the future characterization of the relationship between weight patterns, the BM, and MM pathogenesis, which may affect MM prevention and treatment strategies. Citation Format: Heather Fairfield, Catherine Marinac, Mariah Farrell, Brenda Birmann, Michaela Ruth Reagan. Investigation of the relationship between obesity, weight cycling, and tumor progression in a murine myeloma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2962.