Thrilled to share our study in @CR_AACR! #Obesogenic high-fat diet (HFD) and #MYC cooperate to promote lactate accumulation and TME remodeling in #prostatecancer. Co-first authors @BoufNadia and Paolo Chetta. Co-lead @ZadraGiorgia + 30 co-authors! https://t.co/6owwtKMqwn (1/17)

🚨 New Review in Gene! Therapy-Induced Senescence in Prostate Cancer ✔ Mechanisms & biomarkers ✔ Dual role of TIS: tumor-suppressive vs. tumor-promoting ✔ Senolytics & senomorphics as next-gen strategies ✔ Clinical trials & future directions 🔗 https://t.co/L1lzzn1SFm

We are hiring a 👩‍🔬 Research Assistant 👨‍🔬 to work on cutting-edge dietary interventions to potentiate DNA damaging therapies in prostate cancer. Come working with us at the @CUSM_MUHC @McGillDeptSurg @mcgillu! Please share: https://t.co/H2plgM6GUf @UrologySBUR @PCF_Science

It is an honour to be listed among this list of outstanding prostate cancer scientists! @mcgillu @RIMUHC1 @McGillDeptSurg @MUHCFoundation @CedarsCancer

It was a pleasure to meet and discuss research with like-minded scientists on a mission to make a difference for patients with urological diseases at the #URS2024 meeting hosted at @YaleMed! Thanks for the invitation and the great time!

Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer out on @CR_AACR https://t.co/EkVeyJNXYo Study explores how systemic metabolism, particularly through a high-fat diet (HFD) rich in saturated

Thanks to the Marathon of Hope Cancer Centres Network for this outstanding opportunity to help improve the efficacy of prostate cancer treatments through lifestyle interventions!

Drs. @DavidP_Labbe & @ZadraGiorgia's team, led by Drs. @BoufNadia & Paolo Chetta, showed that an obesogenic high fat diet 🍟 🍔 rich in saturated fats promotes the development of c-MYC–driven invasive #ProstateCancer through metabolic rewiring. @RIMUHC1 https://t.co/k9qkUyqbrL

Funds: @PCF_Science @CIHR_IRSC @FRQS1 @CUSM_MUHC @McGillDeptSurg @UrologySBUR @mcgillu @McGillMed @cancersociety @McGillGCI @SRC_CRS @MUHCFoundation @foundation_hgm @CedarsCancer

Thanks to co-authors for doing the work, reviewers and the editor @CR_AACR for helping improve our work and funders to have made this work possible! Co-authors on Twitter: @annadepolo84 @Carole_Luthold @Davicioni @DrSpratticus @drleighellis @BordeleauLab @MassimoLodaMD (17/17)

Altogether diet and tumor genetics conspire to promote prostate cancer metabolism and shape the tumor microenvironment, take a look at the topnotch commentary by @DanielFrigo on our work! https://t.co/1Ei0sFnBul (16/17)

Dietary interventions aimed at limiting MYC activity and reversing lactate accumulation represent potential means to overcome/delay resistance to standard of care treatments and improve response to immunotherapy, insofar largely ineffective in advanced prostate cancer. (15/17)

Our work supports the use of glycolysis-targeting agents for metabolically (e.g., LDHA, lactate, hyperpolarized 13C-pyruvate MRI, FDG-PET) and genetically codefined prostate cancer subtypes. (14/17)

Altogether, the oncogene MYC promotes a broad metabolic reprogramming. Obesogenic HFD not only enhances MYC-driven metabolic vulnerabilities but also induces aerobic glycolysis and lactate accumulation, boosting cancer hallmarks and prostate cancer progression. (13/17)

Critically, tumor acquisition of glycolytic features, characterized by high levels of LDHA is associated with worse prognosis in two independent cohorts (TCGA/PRAD and META855 datasets). (12/17)

Deconvolution models uncovered ⬆️ proportion of M2-like macrophages in ⬆️ glycolytic prostate cancer from patients with ⬆️ saturated fat intake. This strongly suggests that acquisition of glycolytic features contributes to shaping a TME supportive of cancer progression. (11/17)

Interrogation of the prospective HPFS/PHS cohorts that high saturated fat intake, but not BMI, is associated with an enrichment in a glycolysis transcriptional signature in clinical samples. (10/17)

Lactate also promotes tumor cell migration, leading to a greater fraction of motile cells and increased displacement over time. Critically, lactate also potentiates the traction force of cancer cells on the extracellular matrix, in line with a more invasive phenotype. (9/17)

Lactate also promotes vascular tubulogenesis. Inhibiting LDHA (enzyme that catalyzes the conversion of pyruvate to lactate) with FX11, or preventing lactate import with MCT-1/MCT-4 inhibitor syrosingopine, reduced tubulogenesis/organization of capillary-like tubules. (8/17)

Intra-tumoral lactate accumulation is associated with multiple cancer hallmarks, such as immune evasion, serving as fuel for lactate-avid Treg cells and as a stimulator of TAM M2 polarization. (7/17)

Accordingly, obesogenic HFD boost glucose uptake, as evidenced by 18F-FDG uptake in MyC-CaP allografts. Critically, increased aerobic glycolysis has not been a Leitmotiv in localized #prostatecancer but is rather associated with aggressive disease. (6/17)