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Breast cancer survivors treated with tamoxifen and aromatase inhibitors report weight gain and have an elevated risk of type 2 diabetes, especially if they have obesity. These patient experiences are inconsistent with, preclinical studies using high doses of tamoxifen which reported acute weight loss. We investigated the impact of breast cancer endocrine therapies in a preclinical model of obesity and in a small group of breast adipose tissue samples from women taking tamoxifen to understand the clinical findings. Mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in mesenchymal stem cells from adipose tissue, endocrine therapy was associated with adipose accumulation and more preadipocytes compared with estrogen-treated control mice but resulted in fewer adipocyte progenitors only in the context of HFHS. Analysis of subcutaneous adipose stromal cells revealed diet- and treatment-dependent effects of endocrine therapies on various cell types and genes, illustrating the complexity of adipose tissue estrogen receptor signaling. Breast cancer therapies supported adipocyte hypertrophy and associated with hepatic steatosis, hyperinsulinemia, and glucose intolerance, particularly in obese females. Current tamoxifen use associated with larger breast adipocyte diameter only in women with obesity. Our translational studies suggest that endocrine therapies may disrupt adipocyte progenitors and support adipocyte hypertrophy, potentially leading to ectopic lipid deposition that may be linked to a greater type 2 diabetes risk. Monitoring glucose tolerance and potential interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

Background & Aims Pharmacologic agents targeting bile acid signaling show promise for treating nonalcoholic steatohepatitis (NASH). However, clinical findings suggest that new treatment strategies with enhanced therapeutic efficacy and minimized undesired effects are needed. This preclinical study investigates whether combining an apical sodium-bile acid transporter (ASBT) inhibitor GSK233072 (GSK672) and fibroblast growth factor-15 (FGF15) signaling activation improves anti-NASH efficacy. Methods Mice with high fat, cholesterol, and fructose (HFCFr) diet-induced NASH and stage 2 fibrosis are used as a NASH model. GSK672 or AAV8-TBG-FGF15 interventions are administered alone or in combination to HFCFr diet-fed mice. Results The combined treatment significantly enhances therapeutic efficacy against steatosis, inflammation, ballooning, and fibrosis than either single treatment. Mechanistically, the synergistic actions of GSK672 and FGF15 on inhibiting gut bile acid reuptake and hepatic bile acid synthesis achieve greater magnitude of bile acid pool reduction that not only decreases bile acid burden in NASH livers but also limits intestinal lipid absorption, which, together with FGF15 signaling activation, produces weight loss, reduction of adipose inflammation, and attenuated hepatocellular organelle stress. Furthermore, the combined treatment attenuates increased fecal bile acid excretion and repressed bile acid synthesis, which underlie diarrhea and hypercholesterolemia associated with ASBT inhibition and FGF19 analogue, respectively, in clinical settings. Conclusions Concomitant ASBT inhibition and FGF15 signaling activation produce metabolic changes that partially mimic the bariatric surgery condition whereby lipid malabsorption and increased FGF15/19 signaling synergistically mediate weight loss and metabolic improvement. Further clinical studies may be warranted to investigate whether combining ASBT inhibitor and FGF19 analogue enhances anti-NASH efficacy and reduced treatment-associated adverse events in humans., Graphical abstract

Glioblastoma multiforme (GBM) cells migrating in physically confined environments are affected by mechanical stress that potentially lead to transcriptomic changes. To simulate those stresses, microfluidic channels were made with micro-patterned polydimethylsiloxane (PDMS) replicating the physical microenvironment of white matter tracts by confining the cells in linear channels similar to the space between axons. We employed a combination of microarray transcriptomic profiling and single cell-sequencing analyses to investigate cells undergoing linear confined space migration (LCSM). GBM cells spontaneously migrate through confined spaces along 5x5 mm (height/width) microfluidic channels, 0.5 to 5 mm in length. Our previous studies demonstrated that cells migrating in LCSM are more resistant to treatment with temozolomide than the same cells growing in standard monolayer culture (SMC). Cells in confined migration evaluated by microarray-based transcriptomic profiling demonstrated that linear confined migration induces increased expression in pathways involving angiogenesis, cell adhesion, cell motility, DNA damage repair, extracellular matrix structure, HIF1α, and others. Single cell transcriptomic analysis could identify GBM cells in different migratory states (LCSM vs. SMC), and similar pathways were seen upregulated with additional changes in cholesterol biosynthesis pathways and cell cycle regulation pathways. Trajectory Inference aligned single cells according to changes in migration status and demonstrated transcript changes during LCSM were progressive but generally reversible on return to SMC. Pathway analyses showed alterations in the cholesterol biosynthesis pathway and cell cycle regulation in cell clusters of confined migrating cells. Molecular studies confirmed that cholesterol biosynthesis pathway regulatory genes (SQLE, MVD, and HMGCR) are upregulated during LCSM. Expression analysis demonstrated increased G1 phase delay in confined migrating cells (LCSM) confirmed by FUCCI expression analysis. We propose that migration in linear confined spaces like white matter structures produces significant transcriptome changes that produce chemoresistance as a new mechanism for treatment resistance of Glioblastoma.