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CD99 is a novel prognostic stromal marker in non-small cell lung cancer

ABSTRACT: The delicate interaction between cancer cells and the surrounding stroma plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumour-stroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer. A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened utilising the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern. The corresponding antibodies were applied on a tissue microarray, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99was associated with good prognosis in the univariate (p=0.037) and multivariate (p=0.039) analyses. The association was independent from the total proportion of tumour stroma, the fraction of inflammatory cells, and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p=0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The result supports the concept that stromal properties have a significant impact on tumourigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE33363 | GEO | 2012/06/06

SECONDARY ACCESSION(S): PRJNA149025

REPOSITORIES: GEO

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CD99 is a novel prognostic stromal marker in non-small cell lung cancer

Project description:The delicate interaction between cancer cells and the surrounding stroma plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumour-stroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer. A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened utilising the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern. The corresponding antibodies were applied on a tissue microarray, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99was associated with good prognosis in the univariate (p=0.037) and multivariate (p=0.039) analyses. The association was independent from the total proportion of tumour stroma, the fraction of inflammatory cells, and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p=0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The result supports the concept that stromal properties have a significant impact on tumourigenesis. Tissue from five tumors were compared to corressponding microdissected tissue from the same tissue sample

2012-06-05 | E-GEOD-33363 | biostudies-arrayexpress

Defining the Tumor Microenvironment by Integration of Im-munohistochemistry and Extracellular Matrix Targeted Imaging Mass Spectrometry

Project description:Breast stroma plays a significant role in breast cancer risk and progression yet remains poorly understood. In breast stroma, collagen is the most abundantly expressed protein and its increased deposition and alignment contributes to progression and poor prognosis. Collagen post-translation modifications such as hydroxylated-proline (HYP) control deposition and stromal organization. The clinical relevance of collagen HYP site modifications in cancer processes remains undefined due to technical issues accessing collagen from formalin-fixed, paraffin-embedded (FFPE) tissues. We previously developed a targeted approach for investigating collagen and other extracellular matrix proteins from FFPE tissue. Here, we hypothesized that immunohistochem-istry staining for fibroblastic markers would not interfere with targeted detection of collagen stroma peptides and could reveal peptide regulation influenced by specific cell types. Our initial work demonstrated that stromal peptide peak intensities when using MALD-IMS following IHC staining (αSMA, FAP, P4HA3 and PTEN) were comparable to serial sections of non-stained tissue. Analysis of histology-directed IMS using PTEN on breast tissues and TMAs revealed heteroge-neous PTEN staining patterns and suggestive roles in stromal protein regulation. This study sets the foundation for investigations of target cell types and their unique contribution to collagen regulation within extracellular matrix niches.

2022-02-15 | PXD028107 | Pride

Identification of stromally expressed molecules in the prostate by Tag profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate

Project description:The stromal microenvironment plays key roles in prostate development and cancer. Cancer associated fibroblasts (CAFs) and other stromal cells stimulate tumourigenesis via several mechanisms including the expression of pro-tumourigenic factors. Mesenchyme (embryonic stroma) controls prostate organogenesis, and in some circumstances can re-differentiate prostate tumours. Epithelia are regulated by powerful paracrine signalling from the stroma in both development and disease, and identification of these stromal signals is important. We have applied next-generation Tag profiling to fetal human prostate, normal human prostate fibroblasts (NPFs) and CAFs to identify molecules expressed in prostatic stroma Each sample was used for Tag library construction, by Solexa Inc

2011-10-22 | E-GEOD-25018 | biostudies-arrayexpress

Identification of stromally expressed molecules in the prostate by Tag profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate

2011-10-22 | GSE25018 | GEO

Resident stroma recruits myeloid-derived suppressor cells via CCL2/CCR2 axis in oral squamous cell carcinoma

Project description:In the tumour microenvironment (TME), stroma components play a vital role in tumour development. Myeloid-derived suppressor cells (MDSC) recruited by tumour cells in TME support tumour development. However, the influence of stroma on MDSC is unclear. Here we aimed to unveil the roles of stroma in the recruitment of MDSC in oral squamous cell carcinoma (OSCC). We created xenograft OSCC models on GFP+ bone marrow transplanted nude mice. We co-xenografted human OSCC cells line (HSC-2) with three different types of stromal cells, including human dermal fibroblasts (HDF) or patient-derived stromal cells (PDS1 and PDS2) isolated from two OSCC patients, or without stromal cells. Tumour/stroma co-xenograft models recruited significantly higher numbers of GFP+ bone marrow (BM) cells than the tumour cells alone xenografted group. However, only patient-derived stroma xenograft (PDSX) models promoted GR1/CD11b/Arg1 triple-positive MDSC, which was the main population influenced by stromal character and depended on the stroma secreted CCL2. In vitro inhibition of CCL2 synthesis in PDS cocultures also resulted in significantly decreased migration of BM cells than in HDF coculture and HSC-2 alone culture. Moreover, CCR2+ MDSC infiltrated considerably higher in PDSX models. Taken together, we demonstrated that stromal cells are responsible for MDSC recruitment and stroma secreted CCL2 play an essential role in MDSC recruitment in OSCC.

2021-08-18 | GSE164374 | GEO

Gene expression profile at single cell levels of post natal day 7 mouse cerebellar subdural meningeal cells

Project description:The microenvironment exerts a profound control on tumor initiation in many tissues. In brain tumors, this process is under studied, in particular how stromal signals exert effects on cancer signaling in pre-tumor cells. In the cerebellum, canonical Wnt signalling mediated by Norrin/Frizzled4 (Fzd4) activation in endothelial cells in the meninges exerts a potent inhibitory effect on preneoplasia and tumour progression in mouse models of Sonic hedgehog medulloblastoma (Shh-MB). Single cell transcriptome profiling and deep phenotyping of the meninges during the critical period of preneoplasia development revealed that Norrin/Fzd4 signalling maintains the activation of meningeal macrophages (mMΦs), characterized by Lyve1 and CXCL4 expression. mMΦ depletion during this critical period phenocopies the enhanced preneoplasia and tumourigenesis caused by Ndp loss. CXCL4 mediates the anti-tumourigenesis effect of mMΦs, as it antagonizes CXCL12/CXCR4 signaling in granule neuron progenitors, the MB cell of origin, to reduce cell cycle progression and promote migration away from the pre-tumour niche. Taken together, these findings are the first demonstration that mMΦs are key mediators of chemokine-regulated anti-cancer cross talk between the stroma and pre-tumour cells in the control of MB initiation.

2023-08-28 | GSE226805 | GEO

Spatial Profiling Identifies Prognostic Features of Response to Adjuvant Therapy in Triple Negative Breast Cancer (TNBC)

Project description:Nanostring DSP was performed on 25 TMA cores from TNBC patients with separate tumour and stroma compartment samples De proteins were identified in tumour and stromal compartments

2022-11-29 | GSE218973 | GEO

Prognostic Gene Expression Signature of Carcinoma Associated Fibroblasts in Non-Small Cell Lung Cancer [expression profiling_NSCLC stroma]

Project description:The tumor microenvironment strongly influences cancer development, progression and metastasis. The role of carcinoma-associated fibroblasts (CAFs) in these processes and their clinical impact has not been studied systematically in non-small cell lung carcinoma (NSCLC). We established primary cultures of CAFs and matched normal fibroblasts (NFs) from 15 resected NSCLC. We demonstrate that CAFs have greater ability than NFs to enhance the tumorigenicity of lung cancer cell lines. Microarray gene expression analysis of the 15 matched CAF and NF cell lines identified 46 differentially expressed genes, encoding for proteins that are significantly enriched for extracellular proteins regulated by the TGF-beta signaling pathway. We have identified a subset of 11 genes that formed a prognostic gene expression signature, which was validated in multiple independent NSCLC microarray datasets. Functional annotation using protein-protein interaction analyses of these and published cancer stroma-associated gene expression changes revealed prominent involvement of the focal adhesion and MAPK signalling pathways. Fourteen (30%) of the 46 genes also were differentially expressed in laser-capture micro-dissected corresponding primary tumor stroma compared to the matched normal lung. Six of these 14 genes could be induced by TGF-beta1 in NF. The results establish the prognostic impact of CAF-associated gene expression changes in NSCLC patients. 30 samples: 15 primary lung tumor stroma, 15 normal lung parenchyma

2011-04-08 | E-GEOD-22863 | biostudies-arrayexpress

Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes: a Proof-of-Concept synthetic lethal study

Project description:An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which binds multiple binding partners to suppress tumourigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD11, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of ‘druggable’ targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify synthetic lethal compounds with LIMD1 loss in lung cancer cells. PF-477736 was shown to selectively target LIMD1 deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 is effective in treating LIMD1-/- tumors in subcutaneous xenograft models, with no significant effect in LIMD1+/+ cells. We have identified a novel drug tool with significant preclinical characterization that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.

2022-02-16 | PXD023674 | Pride

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

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