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High sensitivity receptor screen and global phosphoproteomics identifies podoplanin as a regulator of cancer associated fibroblast physiology

ABSTRACT: Cancer-associated fibroblasts (CAFs) are increasingly recognized as key regulatory cells in the tumor microenvironment, with the ability to engage in crosstalk both with tumor and immune cells. Still, the molecular determinants that orchestrate the interactions between CAFs and infiltrating immune cells remain poorly understood. To elucidate the surface interactome that underlines cell communication, we build an extensive library of single transmembrane (STM) receptors coupled to high avidity cell-based screens, and identify the neutrophil and Treg surface protein CD177 as a novel functional modulator of the mechanoreceptor podoplanin (PDPN). Functionally, CD177 exerts a profound effect on the phosphoproteome of CAFs that results in modulation of actomyosin contractility and energy homeostasis. In human colorectal tumors, CD177+ cells can interact closely with PDPN+ CAFs, indicating that this interaction may have effects on the local tumor environment. Starting from a powerful technology for target discovery, our study defines a molecular bridge between CAFs and immune cells in the tumor microenvironment and reveals PDPN as a central modulator of fibroblast mechanophysiology.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: erik verschueren

PROVIDER: MSV000083594 | MassIVE | Mon Mar 18 15:01:00 GMT 2019

REPOSITORIES: MassIVE

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Project description:The better prognosis of patients with Epstein-Barr virus-positive gastric carcinoma than those with EBV-negative GC is correlated with the degree of recruitment of inflammatory tumor infiltrating cells (TIL) to the vicinity of tumor cells. We hypothesized that the better prognosis would associate with less genetic or epigenetic alterations in EBV(+)GC, or EBV infection should deregulate immune modulator proteins, of which secretion recruit TIL. Therefore we performed mRNA expression profilings in EBV(-)GC and EBV(+)GC, each of which was pair wise compared with their normal control. We found that EBV(+)GC had much more molecular homogeneity with focused alterations in immune modulator genes; The Pearson correlation matrix analyses demonstrated that EBV(+)GC tumor showed remarkably high tumor homogeneity. While EBV(-)GC had considerable number genes that are differentially expressed genes from their normal counterparts, EBV(+)GC showed only a handful, almost 20 fold less number of DEG than EBV(-)GC under the same p value cutoff (p<0.001). Gene ontology and pathway analyses showed that while pathways of cation homeostasis, digestion and ion transport were commonly deregulated in both GC types, genes for chromatin assembly, prostaglandin receptor activity, pattern specification process are selectively deregulated in EBV(-)GC tumors. In contrast, pathways or genes for cytokine activity, immune response and lipoprotein particle clearance are selectively deregulated in EBV(+)GC tumors. These results demonstrate that EBV(+)GC inherently evolves to high homogeneity with fewer changes in gene expression and these secret immune modulatory chemokines could recruit reactive immune cells to EBV(+)GC, leading to favorable microenvironment for cancer suppression. All patients underwent the surgery for advanced gastric carcinoma (GC) except one patient with early GC. The EBV-presence in the GC was verified by in situ EBV-encoded small RNA (ERER) staining.. The 14 paired EBV(-)GC patients and 12 paired EBV(+)GC patients were selected for this study. Tumor tissue (T)and normal tissues (N) from distant sites from tumor areas were dissected, frozen at -80C and were subjected to RNA purification, mRNA array profiling analyses.

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High sensitivity receptor screen and global phosphoproteomics identifies podoplanin as a regulator of cancer associated fibroblast physiology

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