Fatty acid transport protein 2 reprograms neutrophils in cancer

Ruzzo

2020

Sci Rep

Spatial heterogeneity is a fundamental feature of the tumor microenvironment (TME), and tackling spatial heterogeneity in neoplastic metabolic aberrations is critical for tumor treatment. Genomescale 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 malignantcell-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.Cancer cells reprogram their metabolism to fulfill the energetic and biosynthetic needs of proliferation, invasion and migration 1 . This is exemplified in prostate cancer, the second most common cancer in American men after melanoma 2 . Previous studies have uncovered profound metabolic dysregulation in multiple pathways, particularly in fatty acid and lipid metabolism 3,4 . Discovering novel cancer-specific metabolic aberrations has significant translational applications, because cancer-associated metabolic dysfunctions can be exploited to advance cancer detection (e.g., 18 F-FDG (Fludeoxyglucose) imaging based on elevated glycolysis in cancer 5 ) and treatment (e.g., L-asparaginase in treating acute lymphoblastic leukemia 6 ).Cancer metabolic reprograming is profoundly impacted by spatial heterogeneity, a fundamental feature of the tumor microenvironment (TME) 7 . Heterogeneous distributions of blood vessels and stromal tissues create uneven spatial gradients of nutrients and metabolic byproducts, which significantly shape the phenotypes of many cell types in the TME 8 . Recent technologies, such as spatial transcriptomics 9,10 and Slide-seq 11 have enabled transcriptomic profiling of hundreds of locations within tissue sections with high spatial resolution (2-100 μm), and have been used to study multiple types of malignancies, including prostate cancer, breast cancer, pancreatic cancer, and melanoma 9,10,12-14 . These spatially-resolved datasets provide novel opportunities to dissect spatial metabolic heterogeneity i...

Section: Resultsmentioning

confidence: 99%

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

Ruzzo

2020

Sci Rep

“…Therefore, STAT1 may have opposite effects on MDSCs under different conditions. In addition, a recent study indicated that STAT5, which is stimulated by GM-CSF, upregulates the expression of fatty acid transport protein 2 (FATP2) and exerts suppressive activity through the synthesis of prostaglandin E (PGE) [29].…”

Section: Stat Signaling Pathwaymentioning

confidence: 99%

“…A study of the mechanism showed that T-MDSCs but not splenic MDSCs increase lipid uptake, which reveals that the fatty acid translocase CD36, induced by tumor-derived cytokines (G-CSF and GM-CSF) and targeted by the STAT3 and STAT5 signaling pathways, is relevant to FAO and immunosuppression of T-MDSCs [78]. Furthermore, fatty acid transport protein 2 (FATP2) is a long-chain fatty acid transporter that was reported to be overexpressed in mouse and human PMN-MDSCs but not M-MDSCs, is controlled via GM-CSF and STAT5, and exerts suppressive function by means of arachidonic acid uptake and synthesis of PGE2, which was blocked after FATP2 inhibition [29]. Liver X receptors (LXRs) are vital nuclear hormone receptor family transcription factors that participate in lipid homeostasis in mammals.…”

Section: Lipid Metabolismmentioning

confidence: 99%

“…Multiple myeloma PMN-MDSCs are induced by multiple myeloma-related mesenchymal stem cells to have high expression of ARG1 and exert immunosuppressive function in tumor [103] Multiple myeloma PMN-MDSCs limit the anti-tumor response of T cells by increase the expression of ARG1 and other suppressive molecules, which is correlated with the expression of IL-18 [104] Head and neck cancer and urological cancers Overexpression of fatty acid transport protein 2 (FATP2) in PMN-MDSCs is conductive to tumor growth by the synthesis of PGE2 [29] Lymphomas are malignant tumors derived from the lymphatic hematopoietic system and are divided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) [106]. Several studies have uncovered that in NHL, including B cell NHL, diffuse large B cell lymphoma and NK/T cell NHL, increased expression of ARG1, IDO and iNOS in MDSCs is relevant to the enhancement of tumor growth and suppression of T cells [107][108][109][110].…”

Section: Arg1mentioning

confidence: 99%

“…Colony-stimulating factor 1 receptor (CSF-1R) is an important receptor for MDSC migration, and its inhibitor BLZ945 and anti-PD-1 combined with anti-PD-L1 can effectively cure cancer [133]. FATP2, which is overexpressed in PMN-MDSCs, improves cancer treatment efficacy by combination treatment with a FATP2 inhibitor and anti-CTLA-4 [29]. Several clinical trials are listed in Table 5.…”

Section: The Therapeutic Effects Of Targeting Mdscsmentioning

confidence: 99%

See 2 more Smart Citations

Metabolic Regulation of Myeloid-Derived Suppressor Cell Function in Cancer

Jia

et al. 2020

Cells

Myeloid-derived suppressor cells (MDSCs) are a group of immunosuppressive cells that play crucial roles in promoting tumor growth and protecting tumors from immune recognition in tumor-bearing mice and cancer patients. Recently, it has been shown that the metabolic activity of MDSCs plays an important role in the regulation of their inhibitory function, especially in the processes of tumor occurrence and development. The MDSC metabolism, such as glycolysis, fatty acid oxidation and amino acid metabolism, is rewired in the tumor microenvironment (TME), which enhances the immunosuppressive activity, resulting in effector T cell apoptosis and suppressive cell proliferation. Herein, we summarized the recent progress in the metabolic reprogramming and immunosuppressive function of MDSCs during tumorigenesis.

Suppressive Myeloid Cells Shape the Tumor Immune Microenvironment

Xiong

2021

Advanced Biology

Cancer is the outcome of the conflict between the host immune system and cancer cells. The crosstalk between immune cells and tumor cells within the tumor microenvironment (TME) influences tumor progression and metastasis. Many studies have clarified the cellular and molecular events that can induce cancer cells to escape immune surveillance, including those involving tumor‐induced myeloid cell‐mediated immunosuppression. Emerging evidence indicates that tumor‐infiltrating myeloid cells (TIMs) accelerate tumor growth and induce angiogenesis, metastasis, and therapy resistance once converted into potent immunosuppressive cells. Here, how tumor infiltrating myeloid cells participate in tumor immune evasion and the prospects of these cells in cancer immunotherapy are discussed.