Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

• Published in: Scientific reports 2020-02, Vol.10 (1), p.3490-3490, Article 3490
• Main Authors: Wang, Yuliang, Ma, Shuyi, Ruzzo, Walter L.
• Format: Article
• Language: English
• Subjects: 631/114; 631/45; 631/553; 631/67; 692/4028; Amino acids; Arachidonic Acid - metabolism; Cysteine - metabolism; Databases, Factual; Desaturase; Fatty acids; Gene expression; Genomes; Heterogeneity; Humanities and Social Sciences; Humans; Lipid metabolism; Male; Metabolic networks; Metabolic Networks and Pathways - genetics; Metabolism; multidisciplinary; Organic Anion Transporters - antagonists & inhibitors; Organic Anion Transporters - metabolism; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Science; Science (multidisciplinary); Spatial heterogeneity; Stearoyl-CoA Desaturase - antagonists & inhibitors; Stearoyl-CoA Desaturase - metabolism; Succinic Acid - metabolism; Suramin; Suramin - chemistry; Suramin - metabolism; Therapeutic targets; Tumor Microenvironment; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-60384-w

Spatial heterogeneity is a fundamental feature of the tumor microenvironment (TME), and tackling spatial heterogeneity in neoplastic metabolic aberrations is critical for tumor treatment. Genome-scale metabolic network models have been used successfully to simulate cancer metabolic networks. However, most models use bulk gene expression data of entire tumor biopsies, ignoring spatial heterogeneity in the TME. To account for spatial heterogeneity, we performed spatially-resolved metabolic network modeling of the prostate cancer microenvironment. We discovered novel malignant-cell-specific metabolic vulnerabilities targetable by small molecule compounds. We predicted that inhibiting the fatty acid desaturase SCD1 may selectively kill cancer cells based on our discovery of spatial separation of fatty acid synthesis and desaturation. We also uncovered higher prostaglandin metabolic gene expression in the tumor, relative to the surrounding tissue. Therefore, we predicted that inhibiting the prostaglandin transporter SLCO2A1 may selectively kill cancer cells. Importantly, SCD1 and SLCO2A1 have been previously shown to be potently and selectively inhibited by compounds such as CAY10566 and suramin, respectively. We also uncovered cancer-selective metabolic liabilities in central carbon, amino acid, and lipid metabolism. Our novel cancer-specific predictions provide new opportunities to develop selective drug targets for prostate cancer and other cancers where spatial transcriptomics datasets are available.