Tumor-derived Lysophosphatidic Acid Blunts Protective Type-I Interferon Responses in Ovarian Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA754392 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15443822_1.fastq.gz | Fastqsanger.gz | |||
| SRR15443822_2.fastq.gz | Fastqsanger.gz | |||
| SRR15443823_1.fastq.gz | Fastqsanger.gz | |||
| SRR15443823_2.fastq.gz | Fastqsanger.gz | |||
| SRR15443824_1.fastq.gz | Fastqsanger.gz |
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Project description:Lysophosphatidic acid (LPA) is a bioactive lipid enriched in highly immunosuppressive neoplasms like ovarian cancer (OvCa). While LPA is known to enhance the tumorigenic capacity of malignant cells, the immunomodulatory role of this phospholipid in cancer remains largely unexplored. Here, we report that LPA operates as a negative regulator of type-I interferon (IFN) responses in OvCa. Ablation of the LPAgenerating enzyme autotaxin in OvCa cells reprogrammed the tumor immune microenvironment, extended host survival, and improved the effects of therapies that elicit protective responses driven by type-I IFN. Mechanistically, LPA sensing by dendritic cells triggered PGE2 synthesis that suppressed type-I IFN signaling via autocrine EP4 engagement. Moreover, we identified an LPA-controlled, immune-derived gene signature associated with weak responses to combined PARP inhibition and PD-1 blockade in OvCa patients. Controlling LPA production or sensing in tumors may therefore be useful to improve cancer immunotherapies that rely on robust induction of type-I IFN.
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Project description:Lysophosphatidic acid (LPA) is a bioactive lipid enriched in the tumor microenvironment of immunosuppressive malignancies such as ovarian cancer. Although LPA enhances the tumorigenic attributes of cancer cells, the immunomodulatory activity of this phospholipid messenger remains largely unexplored. Here, we report that LPA operates as a negative regulator of type I interferon (IFN) responses in ovarian cancer. Ablation of the LPA-generating enzyme autotaxin (ATX) in ovarian cancer cells reprogrammed the tumor immune microenvironment, extended host survival, and improved the effects of therapies that elicit protective responses driven by type I IFN. Mechanistically, LPA sensing by dendritic cells triggered PGE2 biosynthesis that suppressed type I IFN signaling via autocrine EP4 engagement. Moreover, we identified an LPA-controlled, immune-derived gene signature associated with poor responses to combined PARP inhibition and PD-1 blockade in patients with ovarian cancer. Controlling LPA production or sensing in tumors may therefore be useful to improve cancer immunotherapies that rely on robust induction of type I IFN.SignificanceThis study uncovers that ATX-LPA is a central immunosuppressive pathway in the ovarian tumor microenvironment. Ablating this axis sensitizes ovarian cancer hosts to various immunotherapies by unleashing protective type I IFN responses. Understanding the immunoregulatory programs induced by LPA could lead to new biomarkers predicting resistance to immunotherapy in patients with cancer. See related commentary by Conejo-Garcia and Curiel, p. 1841. This article is highlighted in the In This Issue feature, p. 1825.
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Project description:total RNA from mouse (male c57BL/6) spleen labeled with Cy3 vs total RNA from mouse (male c57BL/6) B cells treated with Lysophosphatidic Acid labeled with Cy5- time course with repeats Keywords: ordered
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Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD), closely associated with obesity, can progress to metabolic dysfunction-associated steatohepatitis when the liver undergoes overt inflammatory damage. A-kinase anchoring protein 1 (AKAP1) has been shown to control lipid accumulation in brown adipocytes. However, the role of AKAP1 signaling in hepatic lipid metabolism and MASLD remains poorly understood. Here, we showed that hepatocyte-specific AKAP1 deficiency exacerbated hepatic steatosis and steatohepatitis in male mice subjected to a high-fat diet and fast-food diet, respectively. Mechanistically, AKAP1 directly phosphorylated and inactivated glycerol-3-phosphate acyltransferase 1 (GPAT1) in a PKA-dependent manner, thus suppressing lysophosphatidic acid (LPA) production. Increased endogenous LPA in hepatocytes promoted hepatocellular triglyceride (TG) synthesis and initiated pronounced inflammatory response in Kupffer cells. Restoring hepatic AKAP1 or repressing LPA levels via GPAT1 knockdown alleviated MASLD exacerbation. Overall, AKAP1 plays a protective role against MASLD by inhibiting GPAT1 activity, highlighting the potential of targeting AKAP1/PKA/GPAT1 signalosome for MASLD therapy.
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Project description:Lysophosphatidic acid (LPA) acts through high-affinity G protein-coupled receptors to mediate a plethora of physiological and pathological activities associated with tumorigenesis. LPA receptors and autotaxin (ATX/LysoPLD), the primary enzyme producing LPA, are aberrantly expressed in multiple cancer lineages. However, the role of ATX and LPA receptors in the initiation and progression of breast cancer has not been evaluated. We demonstrate that expression of ATX or each edg family LPA receptor in mammary epithelium of transgenic mice is sufficient to induce a high frequency of late-onset, estrogen receptor (ER)-positive, invasive, and metastatic mammary cancer. Thus, ATX and LPA receptors can contribute to the initiation and progression of breast cancer.
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