Normalizing body weight with a dietary strategy mitigates obesity-accelerated pancreatic carcinogenesis in mice
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PROVIDER: PRJNA1246221 | ENA |
REPOSITORIES: ENA
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Project description:Although obesity is a modifiable risk factor for pancreatic cancer, the role of dietary changes that lead to weight loss in pancreatic carcinogenesis remains unknown. Thus, we determined the effects of weight normalization via dietary switch on pancreatic carcinogenesis and the associated mechanisms. Five-week-old male and female LSL-KrasG12D/+; p48Cre/+ (KC) mice (8-12/diet group/sex) were fed a high-fat, diet-induced obesity diet (DIO; 60 kCal% energy from fat) or a low-fat, control diet (CD; 11 kCal% energy from fat) for 21 weeks. A subset of mice was fed the DIO for 8 weeks, then switched to a CD for 13 additional weeks (DIO→CD). Cancer incidence was evaluated by histology. Lipidomics and RNAseq followed by bioinformatic analysis were conducted to identify possible mechanisms. The gut microbiome was characterized using 16s rRNA amplicon sequencing. After 21 weeks, DIO-fed mice had significantly higher body weight, fat mass, and pancreatic acinar-to-ductal metaplasia compared to the other 2 groups. While none of the 21 mice fed a CD developed cancer, 2 out of 21 DIO-fed mice did. Switching from a DIO to a CD normalized body weight and composition, reduced acinar-to-ductal metaplasia and prevented cancer incidence with no mice developing cancer. Mechanistically, the DIO affected the expression of genes regulating cellular metabolism, immune function, and cell-signaling, while CD and DIO→CD had similar global gene expression. Moreover, DIO increased epoxy metabolites of linoleic acid, which were mitigated by the dietary switch. Finally, compared to a CD, DIO altered the gut microbiome and switching from a DIO to a CD restored the gut microbiome profile to one close to the mice fed a CD. Body weight normalization mitigates obesity-accelerated pancreatic carcinogenesis, in part, by affecting inflammatory and cell signaling pathways, reducing epoxy metabolites, and modulating the gut microbiome.
2025-08-30 | GSE293790 | GEO
Project description:Regulatory T cells (Treg) are common in the tumor microenvironment in both human pancreatic cancer and in genetically engineered mouse models of the disease. Previous studies in orthotopic syngeneic models of pancreatic cancer -recapitulated in our own data- indicated that Treg depletion results CD8+ T cell-mediated tumor regression. In human patients and in mouse models, regulatory T cells accumulate during the onset of Pancreatic Intraepithelial Neoplasia (PanIN), the earliest steps of carcinogenesis. We thus generated a genetic model to investigate the role of regulatory T cells during the onset of pancreatic carcinogenesis. Unexpectedly, depletion of Tregs during early stages of carcinogenesis led to accelerated tumor progression.
2019-03-23 | GSE128707 | GEO
Project description:Regulatory T cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis.
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Project description:Regulatory T Cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis
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Project description:In human patients and in mouse models, immunosuppressive regulatory T cells(Tregs)accumulate in Pancreatic Intraepithelial Neoplasia (PanIN), the precursor lesions to pancreatic cancer. Tregs are considered a potential therapeutic target with the goal to reverse immunosuppression in a number of malignancies, including pancreatic cancer. Here, using a genetically engineered mouse that allows at will depletion of Tregs during pancreatic carcinogenesis, we determined that Treg depletion failed to relieve immunosuppression. Contradicting the current paradigm, depletion of Tregs led to accelerated tumorprogression. We demonstratedthat Treg depletion resultsin changes in the fibroblast population, exemplified by loss of Smooth Muscle Actinexpression and an increase the myeloid recruiting chemokines Ccl3, Ccl6, and Ccl8. Treg depletion further resulted ina compensatoryinflux of suppressive myeloid cells, thereby preventing an anti-tumor immune response. Mechanistically, we show that themyeloid recruitment was driven through the CCR1 axis, with the receptor expressed on tumor associated myeloid cells and several ligands up-regulated in epithelial cells and fibroblasts upon Treg depletion. Finally,blockade of CCR1 signalingcombined with Treg-depletionsuccessfully inhibitedtumorigenesis, uncovering the immune-suppressive myeloid CCR1 axis as a potential therapeutic targetin pancreatic cancer.
2020-01-13 | GSE140628 | GEO
Project description:Most individuals do not maintain weight loss, and weight regain increases cardio-metabolic risk beyond that of obesity. Adipose inflammation directly contributes to insulin resistance; however, immune-related changes that occur with weight loss and weight regain are not well understood. Single cell RNA-sequencing was completed with CITE-sequencing and biological replicates to profile changes in murine immune subpopulations following obesity, weight loss, and weight cycling. Weight loss normalized glucose tolerance, however, type 2 immune cells did not repopulate adipose following weight loss. Many inflammatory populations persisted with weight loss and increased further following weight regain. Obesity drove T cell exhaustion and broad increases in antigen presentation, lipid handing, and inflammation that persisted with weight loss and weight cycling. This work provides critical groundwork for understanding the immunological causes of weight cycling-accelerated metabolic disease.
2022-03-04 | GSE182233 | GEO
Project description:Disruption of skin homeostasis by environmental insults activates pathologic circuitries leading to inflammation and carcinogenesis. Galectin-7 (Gal-7), a lectin preferentially expressed in keratinocytes, has been implicated in wound healing and defective skin repair. Here we report using genetically-engineered mouse models and human samples, essential roles for Gal-7 during skin carcinogenesis via coordinated intracellular and extracellular mechanisms. Heightened Gal-7 expression delineated malignant lesions in non-melanoma skin cancer (NMSC) patients and shaped the course of skin carcinogenesis in mice. Intracellularly, increased Gal-7 conferred genomic instability to skin lesions and favored transcription of inflammation-related genes reprogramming the immune landscape toward a myeloid immunoregulatory profile. Extracellularly, Gal-7 accelerated skin carcinogenesis through glycan-dependent induction of monocytic myeloid-derived suppressor cells with enhanced immune regulatory activity. Our findings identify a lectin-driven molecular circuitry that promotes skin carcinogenesis by coupling genomic instability, transcriptional regulation and myeloid immunosuppressive programs, suggesting a potential therapeutic target for the treatment of NMSC.
2023-01-13 | GSE165285 | GEO
Project description:OBJECTIVE: To characterize the hormonal milieu and adipose gene expression in response to catch-up growth (CUG), a growth pattern associated with obesity and diabetes risk, in a mouse model of low birth weight (LBW). RESEARCH DESIGN AND METHODS: ICR mice were food restricted by 50% from gestational days 12.5-18.5, reducing offspring birth weight by 25%. During the suckling period, dams were either fed ad libitum, permitting CUG in offspring, or food restricted, preventing CUG. Offspring were killed at age 3 weeks, and gonadal fat was removed for RNA extraction, array analysis, RT-PCR, and evaluation of cell size and number. Serum insulin, thyroxine (T4), corticosterone, and adipokines were measured. RESULTS: At age 3 weeks, LBW mice with CUG (designated U-C) had body weight comparable with controls (designated C-C); weight was reduced by 49% in LBW mice without CUG (designated U-U). Adiposity was altered by postnatal nutrition, with gonadal fat increased by 50% in U-C and decreased by 58% in U-U mice (P < 0.05 vs. C-C mice). Adipose expression of the lipogenic genes Fasn, AccI, Lpin1, and Srebf1 was significantly increased in U-C compared with both C-C and U-U mice (P < 0.05). Mitochondrial DNA copy number was reduced by >50% in U-C versus U-U mice (P = 0.014). Although cell numbers did not differ, mean adipocyte diameter was increased in U-C and reduced in U-U mice (P < 0.01). CONCLUSIONS: CUG results in increased adipose tissue lipogenic gene expression and adipocyte diameter but not increased cellularity, suggesting that catch-up fat is primarily associated with lipogenesis rather than adipogenesis in this murine model. Epididymal fat samples were obtained at age 3 weeks from 5 control mice (CC), 5 mice exposed to in utero undernutrition (UC), and 4 mice exposed to undernutrition in utero and during suckling (UU).
2010-03-04 | E-GEOD-16083 | biostudies-arrayexpress
Project description:OBJECTIVE: To characterize the hormonal milieu and adipose gene expression in response to catch-up growth (CUG), a growth pattern associated with obesity and diabetes risk, in a mouse model of low birth weight (LBW). RESEARCH DESIGN AND METHODS: ICR mice were food restricted by 50% from gestational days 12.5-18.5, reducing offspring birth weight by 25%. During the suckling period, dams were either fed ad libitum, permitting CUG in offspring, or food restricted, preventing CUG. Offspring were killed at age 3 weeks, and gonadal fat was removed for RNA extraction, array analysis, RT-PCR, and evaluation of cell size and number. Serum insulin, thyroxine (T4), corticosterone, and adipokines were measured. RESULTS: At age 3 weeks, LBW mice with CUG (designated U-C) had body weight comparable with controls (designated C-C); weight was reduced by 49% in LBW mice without CUG (designated U-U). Adiposity was altered by postnatal nutrition, with gonadal fat increased by 50% in U-C and decreased by 58% in U-U mice (P < 0.05 vs. C-C mice). Adipose expression of the lipogenic genes Fasn, AccI, Lpin1, and Srebf1 was significantly increased in U-C compared with both C-C and U-U mice (P < 0.05). Mitochondrial DNA copy number was reduced by >50% in U-C versus U-U mice (P = 0.014). Although cell numbers did not differ, mean adipocyte diameter was increased in U-C and reduced in U-U mice (P < 0.01). CONCLUSIONS: CUG results in increased adipose tissue lipogenic gene expression and adipocyte diameter but not increased cellularity, suggesting that catch-up fat is primarily associated with lipogenesis rather than adipogenesis in this murine model.
2009-05-14 | GSE16083 | GEO
Project description:Exercise late in life mitigates skeletal muscle epigenetic aging, providing evidence that physical activity is a "fountain of youth".
2021-12-31 | GSE175410 | GEO