High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program

Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden. Saturated fat intake (SFI) is also associated with an enhanced MYC transcriptional signature in prostate cancer patients. The SFI-induced MYC signature independently predicts prostate cancer progression and death. Finally, switching from a high-fat to a low-fat diet, attenuates the MYC transcriptional program in mice. Our findings suggest that in primary prostate cancer, dietary SFI contributes to tumour progression by mimicking MYC over expression, setting the stage for therapeutic approaches involving changes to the diet

Multiplex Immunofluorescence in Formalin-Fixed Paraffin-Embedded Tumor Tissue to Identify Single-Cell–Level PI3K Pathway Activation

Abstract Purpose: Identifying cancers with high PI3K pathway activity is critical for treatment selection and eligibility into clinical trials of PI3K inhibitors. Assessments of tumor signaling pathway activity need to consider intratumoral heterogeneity and multiple regulatory nodes. Experimental Design: We established a novel, mechanistically informed approach to assessing tumor signaling pathways by quantifying single-cell–level multiplex immunofluorescence using custom algorithms. In a proof-of-concept study, we stained archival formalin-fixed, paraffin-embedded (FFPE) tissue from patients with primary prostate cancer in two prospective cohort studies, the Health Professionals Follow-up Study and the Physicians’ Health Study. PTEN, stathmin, and phospho-S6 were quantified on 14 tissue microarrays as indicators of PI3K activation to derive cell-level PI3K scores. Results: In 1,001 men, 988,254 tumor cells were assessed (median, 743 per tumor; interquartile range, 290–1,377). PI3K scores were higher in tumors with PTEN loss scored by a pathologist, higher Gleason grade, and a new, validated bulk PI3K transcriptional signature. Unsupervised machine-learning approaches resulted in similar clustering. Within-tumor heterogeneity in cell-level PI3K scores was high. During long-term follow-up (median, 15.3 years), rates of progression to metastases and death from prostate cancer were twice as high in the highest quartile of PI3K activation compared with the lowest quartile (hazard ratio, 2.04; 95% confidence interval, 1.13–3.68). Conclusions: Our novel pathway-focused approach to quantifying single-cell–level immunofluorescence in FFPE tissue identifies prostate tumors with PI3K pathway activation that are more aggressive and may respond to pathway inhibitors. </jats:sec

Supplementary Data from Multiplex Immunofluorescence in Formalin-Fixed Paraffin-Embedded Tumor Tissue to Identify Single-Cell–Level PI3K Pathway Activation

All supplementary tables and figures</p

Table S8 from Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate

Function and effect of aberrations of differentially expressed genes between Cribriform and Noncribriform</p

Figure S3 from Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate

Examples of PTEN Immunostaining of Tissue Microarray (TMA) Cores, HPFS/ PHS Prostate Cancer Cohorts.</p

Table S9, S10 from Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate

Table S9: Differentially methylated CpG islands in invasive cribriform vs Noncribriform; Table S10: mRNA expression of the differentially hypermethylated in cribriform with concomitant reduction of mRNA expression.</p

Figure S1 from Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate

(A) Cribriform carcinoma, (B) Noncribriform carcinoma.</p

Figure S4 from Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate

Invasive Cribriform Carcinoma is Associated with High Gleason Score and Tumor Stage.</p