Dataset Information

Obesogenic high-fat diet and MYC cooperate to promote lactate accumulation and tumor microenvironment remodeling in prostate cancer (Murine serum assays)

ABSTRACT:

Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic high-fat diet was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In prostate cancer patients, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like tumor-associated macrophages. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the tumor microenvironment and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer.

Murine serum assays are reported in the current study MTBLS3316.

Murine prostate assays are reported in MTBLS3317.

INSTRUMENT(S): Q Exactive

SUBMITTER: giorgia zadra

PROVIDER: MTBLS3316 | MetaboLights | 2024-04-10

REPOSITORIES: MetaboLights

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Dataset's files

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			Action	DRS
	MTBLS3316	Other
	FILES	Other
	a_MTBLS3316_METHOD1_POS_1_metabolite_profiling_mass_spectrometry.txt	Txt
	a_MTBLS3316_METHOD2_POS_2_metabolite_profiling_mass_spectrometry.txt	Txt
	a_MTBLS3316_METHOD3_NEG_1_metabolite_profiling_mass_spectrometry.txt	Txt

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Publications

Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.

Boufaied Nadia N Chetta Paolo P Hallal Tarek T Cacciatore Stefano S Lalli Daniela D Luthold Carole C Homsy Kevin K Imada Eddie L EL Syamala Sudeepa S Photopoulos Cornelia C Di Matteo Anna A de Polo Anna A Storaci Alessandra Maria AM Huang Ying Y Giunchi Francesca F Sheridan Patricia A PA Michelotti Gregory G Nguyen Quang-De QD Zhao Xin X Liu Yang Y Davicioni Elai E Spratt Daniel E DE Sabbioneda Simone S Maga Giovanni G Mucci Lorelei A LA Ghigna Claudia C Marchionni Luigi L Butler Lisa M LM Ellis Leigh L Bordeleau François F Loda Massimo M Vaira Valentina V Labbé David P DP Zadra Giorgia G

Cancer research 20240601 11

PMID: 38831751

Similar Datasets

Project description:Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic high-fat diet was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In prostate cancer patients, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like tumor-associated macrophages. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the tumor microenvironment and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. Murine prostate assays are reported in the current study MTBLS3317.Murine serum assays are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS3316' rel='noopener noreferrer' target='_blank'>MTBLS3316</a>.

Project description:PURPOSE: Previous mouse studies using corn oil (Ï?-6) as the dietary fat source suggest that decreasing dietary fat content can slow prostate cancer (PCa) growth. However, other studies, in which the diet was composed around saturated fat, showed no difference in outcomes between high-fat and low-fat diets. The relative effects of other fats, such as fish oil and olive oil, also remain unexplored. To our knowledge, no trial has yet compared the effect of various fats on prostate cancer progression. Therefore, we sought to systematically study the effect of fish oil, olive oil, corn oil, and saturated fat on prostate cancer progression. METHODS: A total of 96 male SCID mice were injected with LAPC-4 human PCa cells. Two weeks following injection, mice were singly-housed and randomized to either a fish oil, olive oil, corn oil, or saturated fat based diet. Animals were euthanized when tumors reached 1,000 mm3. Serum was collected at sacrifice and assayed for PSA, insulin, IGF-1, IGFBP-3, and PGE-2 levels. Tumors were also assayed for PGE-2, and COX-2 levels, and gene array analysis was performed. RESULTS: Mice weights and tumor volumes were equivalent across groups at randomization. Overall, fish-oil consumption was associated with improved survival, relative to all other dietary groups (Log-rank, all p<0.05). We did not detect any significant difference in serum PSA, insulin, IGF-1, IGFBP-3, and PGE-2 levels. Glucose at the time of sacrifice was statistically different between groups, with the fish-oil fed mice having the highest levels of serum glucose (Kruskal-Wallis, p=0.03). CONCLUSIONS: In this prostate cancer xenograft model, we found that consuming a diet in which fish-oil was the only fat source slowed tumor growth in improved survival, compared to mice consuming diets composed of olive oil, corn oil, or saturated fat sources. These results suggest that type of dietary fat consumed may be as important as amount of dietary fat consumed in the setting of prostate cancer. DESIGN: A total of 96 male SCID mice were injected with LAPC-4 human prostate cancer cells. After 2 weeks of tumor growth, the mice were randomized to one of four diets: corn oil, fish oil, olive oil, and saturated fat source diets. Animals were euthanized when tumor volumes exceeded 1000 mm^3. Sera and tissues from the median 6 surviving animals from each of the four dietary groups were analyzed.

Project description:PURPOSE: Previous mouse studies using corn oil (ω-6) as the dietary fat source suggest that decreasing dietary fat content can slow prostate cancer (PCa) growth. However, other studies, in which the diet was composed around saturated fat, showed no difference in outcomes between high-fat and low-fat diets. The relative effects of other fats, such as fish oil and olive oil, also remain unexplored. To our knowledge, no trial has yet compared the effect of various fats on prostate cancer progression. Therefore, we sought to systematically study the effect of fish oil, olive oil, corn oil, and saturated fat on prostate cancer progression. METHODS: A total of 96 male SCID mice were injected with LAPC-4 human PCa cells. Two weeks following injection, mice were singly-housed and randomized to either a fish oil, olive oil, corn oil, or saturated fat based diet. Animals were euthanized when tumors reached 1,000 mm3. Serum was collected at sacrifice and assayed for PSA, insulin, IGF-1, IGFBP-3, and PGE-2 levels. Tumors were also assayed for PGE-2, and COX-2 levels, and gene array analysis was performed. RESULTS: Mice weights and tumor volumes were equivalent across groups at randomization. Overall, fish-oil consumption was associated with improved survival, relative to all other dietary groups (Log-rank, all p<0.05). We did not detect any significant difference in serum PSA, insulin, IGF-1, IGFBP-3, and PGE-2 levels. Glucose at the time of sacrifice was statistically different between groups, with the fish-oil fed mice having the highest levels of serum glucose (Kruskal-Wallis, p=0.03). CONCLUSIONS: In this prostate cancer xenograft model, we found that consuming a diet in which fish-oil was the only fat source slowed tumor growth in improved survival, compared to mice consuming diets composed of olive oil, corn oil, or saturated fat sources. These results suggest that type of dietary fat consumed may be as important as amount of dietary fat consumed in the setting of prostate cancer.