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NNMT inhibition in cancer-associated fibroblasts restores antitumor immunity

ABSTRACT: Cancer-associated fibroblasts (CAFs) play a pivotal cancer-supportive role, yet CAF-targeted therapies remain elusive. Through spatial transcriptomics and single-cell RNA sequencing, we identified nicotinamide N-methyltransferase (NNMT) as a central CAF regulator in high-grade serous ovarian cancer (HGSOC) patients. Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumor. Using high-throughput screening, we developed a potent, specific NNMT inhibitor that reduces tumor burden in multiple murine cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated MDSC recruitment and reinvigorating CD8⁺ T cell activation. Our findings establish NNMT as an essential CAF regulator and promising therapeutic target to mitigate immunosuppression in the tumor microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292661 | GEO | 2025/05/09

REPOSITORIES: GEO

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NNMT inhibition in cancer-associated fibroblasts restores antitumor immunity.

Project description:Cancer-associated fibroblasts (CAFs) play a pivotal cancer-supportive role, yet CAF-targeted therapies remain elusive. Through spatial transcriptomics and single-cell RNA sequencing, we investigated the role of nicotinamide N-methyltransferase (NNMT) in high-grade serous ovarian cancer (HGSOC). Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumor. NNMT knockout in immunocompetent mice impaired tumor growth in syngeneic ovarian, breast, and colon tumor models through enhanced CD8+ T cell activation. Using high-throughput screening, we developed a potent and specific NNMT inhibitor that reduces tumor burden and metastasis in multiple murine cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated MDSC recruitment and reinvigorating CD8⁺ T cell activation. Our findings establish NNMT as a central CAF regulator and promising therapeutic target to mitigate immunosuppression in the tumor microenvironment.

2025-05-09 | GSE295028 | GEO

Proteomics reveals NNMT as a master metabolic regulator of cancer associated fibroblasts

Project description:High-grade serous carcinoma has a poor prognosis, owing primarily to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer, but a systematic examination of both the tumour and stromal compartments is critical in understanding ovarian cancer metastasis. We developed a label- free proteomic workflow to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment. The tumour proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene- expression changes in the tumour stroma. This work supports the use of ultra-low-input proteomics to identify candidate drivers of disease phenotypes. NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma that may be therapeutically targeted.

2019-04-18 | PXD006396 | Pride

RNA sequencing of NNMT overexpression in 3T3 fibroblasts

Project description:High grade serous carcinoma (HGSC) arising from either the fallopian tube or ovary has a poor prognosis primarily due to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer (OvCa)1,2, but a systematic examination of both the tumor and stromal compartments is critical to understanding OvCa metastasis. We developed a label-free proteomic workflow to analyze as few as 5,000 formalin-fixed, paraffin embedded cells microdissected from each compartment. The tumor proteome was comparatively stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and the proteins it regulates. Stromal NNMT expression was necessary and sufficient for several functional aspects of the cancer associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT supported OvCa migration, proliferation, and in vivo growth and metastasis. Expression of NNMT in CAFs led to a depletion of S-adenosyl methionine (SAM) and a reduction in histone methylation associated with extensive gene expression changes in the tumor stroma. This work supports the use of ultra-low input proteomics to identify candidate drivers of disease phenotypes and reveals that NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma and a novel treatment target.

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H3K27 ChIP-sequencing of NNMT overexpression in normal fibroblasts

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Microarray analysis of NNMT overexpression and knockdown in stromal cells

Project description:Analysis of gene expression in human CAFs with control (shCtrl) or shRNA against NNMT (shNNMT) expression or normal fibroblasts expressing control (Ctrl) or NNMT overexpression (NNMT) constructs. Cells were infected with lentivirus to express the indicated shRNA construct. Hypothesis is that knockdown of NNMT will affect expression of genes via regulation of histone methylation status.

2019-05-01 | GSE112497 | GEO

H3K9me3, H3K27me3, H3K27ac and H3K4me3 ChIP-sequencing in SUM159PT NNMT-WT, NNMT-KOd and NNMT KOs breast cancer cells.

Project description:The cellular heterogeneity within a tumor can be determined by core genetic and epigenetic programs that operate in certain cells (tumor initiating cells – TICs), providing them with the degree of plasticity needed for induction of metastasis and resistance to therapy. Here we show that the metabolic enzyme nicotinamide N-methyl transferase (NNMT) promotes TIC plasticity in Estrogen Receptor (ER) alpha negative breast cancer. NNMT downregulation delays tumor formation and its full depletion impairs metastasis formation in mice. Mechanistically, NNMT loss increases deposition of H3K9-me2/3 and H3K27-me3 at the promoter of genes involved in stem cell regulation, shutting down their expression and upregulating luminal differentiation genes. This study reveals a major function of NNMT in maintaining core epigenetic programmes that promote TIC self-renewal and metastasis and that repress luminal differentiation.

2023-04-13 | GSE114875 | GEO

DNA methylation analysis of NNMT overexpression and knockdown in stromal cells

Project description:Genome-wide DNA methylation profiling in response to overexpression or knockdown of NNMT in stromal cells. The Illumina MethylationEPIC array was used to profiled genome-wide methylation of normal fibroblasts expressing a control construct or NNMT overexpression construt and cancer-associated fibroblasts (CAFs) expressing an shCtrl or shNNMT construct. Two biological replicates of each experimental group were profiled following growth in 10 micromolar methionine growth media for 21 days.

2019-05-01 | GSE126672 | GEO

Microarray analysis of knockdown of nicotinamide N-methyltransferase (NNMT) in human cancer-associated fibroblasts

Project description:Analysis of gene expression in human CAFs with control (shCtrl) or shRNA against NNMT (shNNMT) expression. Cells were infected with lentivirus to express the indicated shRNA construct. Hypothesis is that knockdown of NNMT will affect expression of genes via regulation of histone methylation status.

2022-05-01 | GSE98267 | GEO

Comprehensive proteomic profiling of the differences between Cancer Associated Fibroblasts and KRAS mutated cancer cell lines

Project description:Cancer associated fibroblasts (CAFs) are a key component of tumors. We aimed to profile the proteome of cancer cell lines representing three common cancer types (lung, colorectal and pancreatic) and a representative CAF cell line from each tumor type to gain insight into CAF function and identify new CAF biomarkers. We used liquid chromatography and tandem mass spectrometry to evaluate the proteome of 9 cancer and 3 CAF cell lines. Functions of selected differentially expressed proteins in CAF cell lines were studied using siRNA and expression of new CAF biomarkers identified in cell lines were studied by immunohistochemistry in 30 human tumor specimens. Of the 9460 proteins evaluated, functional enrichment analysis revealed N-glycan biosynthesis and extracellular membrane proteins to be upregulated in CAFs and not in cancer cells. 85 proteins had 16-fold higher expression in CAFs compared to cancer cells. These included previously known CAF markers like ACTA2, FAP and SDC2. Novel biomarkers overexpressed in CAFs were noted, including HSPB6 and PTGS1. SiRNA knockdown of these genes encoding these proteins did not reduce contractility in lung CAFs, suggesting they were not crucial to this function despite high expression. Immunohistochemical analysis of 30 tumor samples (10 lung, 10 colorectal and 10 pancreatic) showed HSPB6 and PTGS1 expression were restricted to the stroma. An unbiased analysis of the differences in the proteome of cancer cells compared to CAFs revealed increased expression of HSPB6 and PTGS1 in CAFs.

2024-08-22 | PXD054500 | Pride

Differential proteomic profiling between Cancer Associated Fibroblasts and KRAS mutated cancer cell lines

Project description:Purpose Cancer-associated fibroblasts (CAFs) are a key component of tumors. We aimed to profile the proteome of cancer cell lines representing three common cancer types (lung, colorectal and pancreatic) and a representative CAF cell line from each tumor type to gain insight into CAF function and identify new CAF biomarkers. Experimental Design We used isobaric labeling, liquid chromatography and mass spectrometry to evaluate the proteome of 9 cancer and 3 CAF cell lines. Functions of selected differentially expressed proteins in CAF cell lines were further investigated using siRNA and the expression levels of candidate novel CAF biomarkers were evaluated by immunohistochemistry in 30 human tumor specimens. Results Of the 9460 proteins evaluated, functional enrichment analysis revealed N-glycan biosynthesis and extracellular membrane proteins to be upregulated in CAFs and not in cancer cells. 85 proteins had 16-fold higher expression in CAFs compared to cancer cells. These included previously known CAF markers like ACTA2, FAP and SDC2. Novel biomarkers overexpressed in CAFs were noted, including HSPB6 and PTGS1. SiRNA knockdown of these genes encoding these proteins did not reduce contractility in lung CAFs, suggesting they were not crucial to this function despite high expression. Immunohistochemical analysis of 30 tumor samples (10 lung, 10 colorectal and 10 pancreatic) showed HSPB6 and PTGS1 expression were restricted to the stroma. Conclusions An unbiased analysis of the differences in the proteome of cancer cells compared to CAFs revealed increased expression of HSPB6 and PTGS1 in CAFs.

2023-08-21 | PXD040360 | Pride

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