Dataset Information

Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages

ABSTRACT: In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor progression by creating an immunosuppressive environment through cytokine secretion and antigen presentation. While previous studies have demonstrated that CAFs exhibit distinct metabolic profiles compared to normal fibroblasts, it remains unclear how these metabolic programs influence the immune landscape within tumors and which factors drive metabolic reprogramming in CAFs. Here, we found that glutamine synthesis by CAFs promotes the polarization of pro-tumorigenic tumor-associated macrophages (TAMs), and supports tumor growth by altering TAM composition, highlighting the pivotal role of CAFs in shaping the immunosuppressive TME. Mechanistically, we found that tumor-derived palmitic acid activates a signaling cascade involving Toll-like receptor 4 (TLR4), Syk, and NF-κB in fibroblasts, leading to inflammatory CAF polarization, and IL-6-induced glutamine synthesis. These findings uncover a novel metabolic symbiosis whereby tumor cells manipulate TAM polarization through CAF-mediated glutamine metabolism, presenting potential therapeutic targets for cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE297727 | GEO | 2025/05/26

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Cancer-associated fibroblasts (CAFs) are one of the components in tumor microenvironment (TME) that can facilitate tumor progression, invasion, and metastasis directly through tumor-CAF interactions, or indirectly by crosstalking with tumor infiltrating immune cells and inducing immunosuppressive TME. Indeed, high stromal signature has been associated with reduced therapeutic efficacy and resistance to Immune Checkpoint Blockade. AEBP1 is highly expressed in myofibroblast cells whose expression is further upregulated in activated fibroblasts and the extracellular matrix (ECM)-producing CAFs. AEBP1 has two alternatively spliced isoforms that the extracellular isoform binds to collagen and promotes collagen remodeling, and the intracellular isoform modulates transcription and signaling. We observed expression of both isoforms of AEBP1 in primary human CAFs. Our data showed that combined knock out (KO) of both isoforms of AEBP1 by gene editing technology decreased CAF proliferation, collagen gel contractility and CAF-mediated tumor cell proliferation in vitro. Pan AEBP1 KO mouse fibroblasts also showed reduced activity in vitro and in vivo in the co-implantation mouse model. We found that knocking out both isoforms of AEBP1 downregulated the collagen biosynthesis and ECM organization related pathways in both mouse fibroblasts and primary human CAFs through RNA sequencing studies. In addition, loss of AEBP1 in fibroblasts impacted tumor cell phenotypes resulting in significant decrease of tumor cells with,with epithelial-mesenchymal transition signature in the co-implantation mouse model. Furthermore, AEBP1 KO in CAFs enhanced the anti-PD-1 induced effector T cell activity and the anti-PD-1 efficacy in this co-implantation model. Altogether, our results demonstrate that AEBP1 is important in regulating CAF function in the TME. Inhibiting AEBP1, therefore, may be a novel strategy in targeting CAF tumor-supporting activity and overcoming cancer resistance to anti-PD-1 immunotherapy.

Project description:Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, MPM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several cancer types. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on MPM cells. Methods: Meso-CAFs were isolated from surgical specimens of MPM patients and analyzed by comparative genomic hybridization, transcriptomics and proteomics. Human MPM cell lines were retrovirally transduced with GFP. The impact of Meso-CAFs on tumor cell growth, migration, and response to pathway inhibitors and cisplatin was investigated in 2D and 3D co-culture models by videomicroscopy and automated image analysis. Results: Meso-CAFs possess normal genomes without gene copy number aberrations typical for MPM cells. They express CAF markers and lack MPM marker expression. Their proteome and secretome profiles clearly differ from normal lung fibroblasts with particularly strong differences in the fraction of actively secreted proteins. The presence of Meso-CAFs in co-culture resulted in increased proliferation and migration of MPM cells. A similar effect on cell growth was induced by conditioned medium. Met/PI3K or WNT signaling inhibition abolished the Meso-CAF-mediated growth stimulation. While Meso-CAFs reduced the efficacy of EGFR inhibition in co-cultures, they did not provide protection of tumor cells against cisplatin. Conclusion: Our study provides the first characterization of human patient-derived Meso-CAFs and demonstrates a strong impact of Meso-CAFs on tumor cell growth and migration, two key aspects of MPM aggressiveness, indicating a substantial role of Meso-CAFs in driving MPM progression. Moreover, we show that Meso-CAFs significantly influence drug response and identify signaling pathways required for Meso-CAF-mediated growth stimulation. These data could be relevant for improving therapeutic strategies in MPM.

Dataset Information

Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets