MBOAT7-Driven Phosphatidylinositol Remodeling Promotes the Progression of Clear Cell Renal Carcinoma

Abstract

The most common kidney cancer, clear cell Renal Cell Carcinoma (ccRCC) is closely associated with obesity. In fact, the "clear cell" variant of RCC is given this name due to large lipid droplets within the tumor cells. Although it is well appreciated that renal lipid metabolism is altered in ccRCC, the mechanisms driving this are not well understood. Leveraging a shotgun lipidomics approach we have identified a lipid signature for ccRCC that includes an increase in arachidonic acid-enriched phosphatidylinositols (AA-PI). In parallel, we found that ccRCC tumors have increased expression of the acyltransferase enzyme membrane bound O-acyltransferase domain containing 7 (MBOAT7) that contributes to AA-PI synthesis. In ccRCC patients, MBOAT7 expression increases with tumor grade, and increased MBOAT7 expression correlates with poor survival. Genetic deletion of MBOAT7 in ccRCC cells decreases proliferation and induces cell cycle arrest, and MBOAT7 -/cells fail to form tumors in vivo. RNAseq of MBOAT7 -/cells identified alterations in cell migration and extracellular matrix organization, which were functionally validated in migration assays. Our work highlights the accumulation of AA-PI in ccRCC and demonstrate a novel way to decrease the AA-PI pool in ccRCC by limiting MBOAT7. Our data reveal that metastatic ccRCC is associated with altered AA-PI metabolism, and identify MBOAT7 as a novel target in advanced ccRCC.

Severe consequences of a high-lipid diet include hydrogen sulfide dysfunction and enhanced aggression in glioblastoma

“…To characterize the lipid landscape of the HFD-versus chow-fed brain and tumor, we employed a mass spectrometry-based shotgun lipidomic analysis method that enables identification of multiple structurally distinct lipid species. This method, which we adopted without alteration, was originally published by Gromovsky et al (58) and later optimized by Neumann et al (59).…”

Identification of a Novel Lipid Metabolism-Related Gene Signature in Prognosis of Bladder Cancer

“…Heinrichs found that MBOAT7 might contribute to GC susceptibility through in ammation [28]. MBOAT7 was overexpressed in renal cancer cell and high MBOAT7 expression was associated with poor prognosis in ccRCC [29].CCDC58 may play a tumor-promoting role in endometrial cancer. Aldo-keto reductase 1 member B1 (AKR1B1) could be involved in various signaling pathways, such as epithelial to mesenchymal transition (EMT) [30], in ammatory responses [31], and mTOR pathway [32].…”

Research Progress of Tumor Microenvironment Targeted Therapy for Clear Cell Renal Cell Carcinoma

“…Trastuzumab and panitumab can reduce the expression of Syndecan-4, thus inhibiting tumor development and development; and After zoledronate treatment, tumor growth and migration were inhibited, but Syndecan-4 expression was increased, Therefore, the role of Syndecan-4 needs further researchs. 40 Neumann et al 41 identified a key new lipid metabolic dependence in ccRCC, and indicated that inhibition of membrane phosphatidylinositol (PI) lipid remodeling driven by membrane bound O-acyltransferase domain containing 7 (MBOAT7) might have therapeutic potential for patients with ccRCC. This follows that therapies targeting the ECM are feasible.…”