The Agpat4/LPA axis in colorectal cancer cells regulates antitumor responses via p38/p65 signaling in macrophages

Zhang, David; Shi, Rongchen; Xiang, Wei; Kang, Xin; Tang, Bo; Li, Chuan; Gao, Linfeng; Zhang, Xuan; Zhang, Lili; Dai, Rongyang; Miao, Hongming

doi:10.1038/s41392-020-0117-y

Cited by 42 publications

(40 citation statements)

References 41 publications

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“…The first intermediate is lysophosphatidate which is regulated by GPAT and LPAAT enzymes. Lysophosphatidate levels are lower in human colorectal cancer tissues relative to those in paracarcinoma tissues, which was associated with increased mRNA levels of LPAATγ (AGPAT3) and LPAATδ (AGPAT4) [ 228 ]. The lower levels of lysophosphatidate may be due to increased efflux of lysophosphatidate from cancer tissue and thereby act in a paracrine fashion to influence local immune cell function [ 228 ].…”

Section: Tumor Fatty Acid Metabolism Pathways and Their Role In Cancementioning

confidence: 99%

“…The next intermediate is phosphatidate, which is regulated by LPAAT, LPIN, and DGK enzymes as well as PLD (see review [ 231 ]), which governs a range of signaling pathways [ 29 – 32 ]. The increased levels of LPAAT in colorectal cancer [ 228 ] would be expected to increase the conversion of lysophosphatidate to phosphatidate. However, LPIN1, one of three members of the LPIN family, is highly expressed in ovarian cancer [ 232 ], hepatocellular carcinoma [ 233 ], and breast cancer [ 234 , 235 ], and therefore causing an increased conversion of phosphatidate to DG and resulting in no accumulation of PA. Knockdown of LPIN1 reduced incorporation of extracellular palmitate into glycerophospholipids, indicating reduced synthesis and remodeling, which resulted in impaired basal-like triple-negative breast cancer cell viability and orthotopic xenograft growth [ 234 ].…”

Section: Tumor Fatty Acid Metabolism Pathways and Their Role In Cancementioning

confidence: 99%

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The diversity and breadth of cancer cell fatty acid metabolism

2021

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Tumor cellular metabolism exhibits distinguishing features that collectively enhance biomass synthesis while maintaining redox balance and cellular homeostasis. These attributes reflect the complex interactions between cell-intrinsic factors such as genomic-transcriptomic regulation and cell-extrinsic influences, including growth factor and nutrient availability. Alongside glucose and amino acid metabolism, fatty acid metabolism supports tumorigenesis and disease progression through a range of processes including membrane biosynthesis, energy storage and production, and generation of signaling intermediates. Here, we highlight the complexity of cellular fatty acid metabolism in cancer, the various inputs and outputs of the intracellular free fatty acid pool, and the numerous ways that these pathways influence disease behavior.

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Section: Tumor Fatty Acid Metabolism Pathways and Their Role In Cancementioning

confidence: 99%

Section: Tumor Fatty Acid Metabolism Pathways and Their Role In Cancementioning

confidence: 99%

The diversity and breadth of cancer cell fatty acid metabolism

2021

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“…Impeding M2 polarization to promote anti-tumor immune responses has gained clinical interest (e.g. CSF1 inhibition) and also preclinical studies of genetic TAM reprogramming are promising [40,41].…”

Section: Tumor-associated Macrophagesmentioning

confidence: 99%

Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook

et al. 2020

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Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging the overall survival (OS) of advanced stage patients. Over the recent years IO therapy has been broadly integrated into the first-line setting of non-oncogene driven NSCLC, either in combination with chemotherapy, or in selected patients with PD-L1high expression as monotherapy. Still, a significant proportion of patients suffer from disease progression. A better understanding of resistance mechanisms depicts a central goal to avoid or overcome IO resistance and to improve patient outcome. We here review major cellular and molecular pathways within the tumor microenvironment (TME) that may impact the evolution of IO resistance. We summarize upcoming treatment options after IO resistance including novel IO targets (e.g. RIG-I, STING) as well as interesting combinational approaches such as IO combined with anti-angiogenic agents or metabolic targets (e.g. IDO-1, adenosine signaling, arginase). By discussing the fundamental mode of action of IO within the TME, we aim to understand and manage IO resistance and to seed new ideas for effective therapeutic IO concepts.

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“…12 We established PC models with CRC cells or melanoma cells in previous studies and found that PC progression was intensively regulated by the microenvironment of the visceral fat. 10,11,14 Fat tissues are infiltrated by a variety of immune cells, among which macrophages play central roles in regulating local and systemic inflammation and the immune status. 15 A high-fat diet (HFD), which contains high levels of saturated fatty acids, can convert adipose tissue macrophages (ATMs) from the M2-like phenotype (CD11c − CD206 + ) to the M1-like (CD11c + CD206 − ) phenotype and induce chronic inflammation in fat tissues and other organs.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dietary fats suppress the peritoneal seeding of colorectal cancer cells through the TLR4/Cxcl10 axis in adipose tissue macrophages

Xiang

Shi

Zhang

et al. 2020

Sig Transduct Target Ther

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Peritoneal carcinomatosis (PC) of colorectal cancer (CRC) is a terminal phase of malignancy with no effective strategies for the prevention of this condition. Here we established PC models in mice by intraperitoneal engraftment of CRC cells and revealed an unexpected role for a high-fat diet (HFD) in preventing metastatic seeding in the visceral fat. Mechanistically, the HFD stimulated the activation of adipose tissue macrophages (ATMs) toward an M1-like phenotype and enhanced ATM tumor phagocytosis in a TLR4-dependent manner. Furthermore, the TLR4–Cxcl10 axis in ATMs promoted T cell recruitment, and M1-like macrophages stimulated T cell activation in tumor-seeded fats. The inhibitory effect of the HFD on tumor seeding was abolished with the ablation of macrophages, inactivation of T cells, or blockade of the TLR4–Cxcl10 axis in macrophages. Finally, we showed that a HFD and conventional chemotherapeutic agents (oxaliplatin or 5-fluorouracil) synergistically improved the survival of tumor-seeded mice. Collectively, our findings demonstrate that peritoneal seeding of CRC can be suppressed by short-term treatment with a HFD in the early phase, providing a novel concept for the management of these patients in the clinic.

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The Agpat4/LPA axis in colorectal cancer cells regulates antitumor responses via p38/p65 signaling in macrophages

Cited by 42 publications

References 41 publications

The diversity and breadth of cancer cell fatty acid metabolism

The diversity and breadth of cancer cell fatty acid metabolism

Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook

Dietary fats suppress the peritoneal seeding of colorectal cancer cells through the TLR4/Cxcl10 axis in adipose tissue macrophages

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