Metabolomics reveals that CAF-derived lipids promote colorectal cancer peritoneal metastasis by enhancing membrane fluidity

Abstract

Patients with peritoneal metastasis (PM) of colorectal cancer (CRC) have poorer overall survival outcomes than those without PM. Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and mediate CRC progression and PM. It is imperative to identify and develop novel therapeutic targets for PM-CRC driven by CAFs. Using lipidomics, we reveal that the abundance of phosphatidylcholine (PC) with unsaturated acyl chains was increased in clinical PM-CRC specimens. Additionally, we found that CAFs were present at a higher relative abundance in primary PM-CRC tumors and that membrane fluidity in CRC cells was increased after incubation with CAF-conditioned medium (CM) through three independent methods: lipidomics, fluorescence recovery after photobleaching (FRAP), and generalized polarization. Then, we found that increased membrane fluidity can enhance glucose uptake and metabolism, as supported by real-time bioenergetics analysis and U-13 C glucose labeling. Interestingly, stearoyl-CoA desaturase 1 (SCD), the rate-limiting enzyme in the biosynthesis of unsaturated fatty acids (uS-FAs), was expressed at low levels in PM and associated with poor prognosis in CRC patients. Importantly, by untargeted metabolomics analysis and fatty acid ([U-13 C]-stearic acid) tracing analyses, we found that CRC cells take up lipids and lipid-like metabolites secreted from CAFs, which may compensate for low SCD expression. Both in vitro and in vivo experiments demonstrated that sodium palmitate (C16:0) treatment could decrease the CAF-induced change in cell membrane fluidity, limit glucose metabolism, suppress cell invasiveness, and impair tumor growth and intraperitoneal dissemination. An increased C16:0 concentration was shown to induce apoptosis linked to lipotoxicity. Furthermore, C16:0 effectively enhanced the antitumor activity of 5-fluorouracil (5-FU) in vitro and was well tolerated in vivo. Taken together, these findings suggest that adding the saturated fatty acid (S-FA) C16:0 to neoadjuvant chemotherapy may open new opportunities for treating PM-CRC in the future.

SLC11A1 associated with tumor microenvironment is a potential biomarker of prognosis and immunotherapy efficacy for colorectal cancer

“…The tumor immune microenvironment is defined as the density, type, and location of tumor-infiltrating immune cells, which have a great influence on the development of CRC ( Amicarella et al, 2017 ). An increasing number of studies have recognized the specific functions of macrophages and CAFs in CRC development ( Peng et al, 2022 ; Yi et al, 2022 ). Activated fibroblast-derived CAFs are the most abundant cell type in the TME.…”

Chewing the fat: How lipidomics is changing our understanding of human health and disease in 2022

“…Bibliometric analyses of clinical lipidomics publications in 2022 using Scopus search terms “lipidomics” AND “clinic*” on 15 th December 2022 …”

“…[170][171][172][173] Lipidomic analyses have revealed cancer-specific lipid dysregulations that could potentially serve as promising biomarkers for screening purposes, 174,175 as demonstrated by Lee et al in a plasma analysis of 140 human samples that could differentiate five cancers (liver, lung, gastric, colorectal, and thyroid). 176 It is therefore of no surprise with its known lipid dysregulation and urgency that oncology was the biggest application area in 2022, where the following cancers were studied: bladder, 177 brain, 155 breast, [178][179][180][181][182] colorectal, [183][184][185][186][187][188] endometrial, 189 gallbladder, 190 gastric, 191 kidney, 192 liver, [193][194][195][196][197] lungs, 156,[198][199][200] nasopharyngeal, 201 ovarian, 202 paediatric, 203 prostate, 204,205 and skin. 206 To maximize the survival rates of cancer patients, it is important to identify cancer at its early stages, where tumours can be surgically removed or treated with milder drug regimens.…”

Fight the Cancer, Hit the CAF!

“…Accordingly, exogenous lipid intake can support the rapid proliferation of tumor cells due to the upregulation of genes associated with EMT [ 73 ]. Furthermore, lipids released by CAF, including long-chain and unsaturated fatty acids, phospholipids, diacylglycerols and cholesterol esters, can change plasma membrane viscosity of CRC promoting malignancy by increasing glucose uptake and, subsequently, glycolysis [ 74 ]. Moreover, lipids derived from CAF have been shown to increase membrane fluidity also in breast cancer cells, that, among other features, can be viewed as an overall promotion of tumor progression and invasion [ 75 ].…”