Dataset Information

Multi-layered proteomic analysis for colorectal cancer

ABSTRACT: Matrix metalloproteinase-2 (MMP-2) plays a role in cell migration and invasion that involve degradation of extracellular matrix proteins as well as vascular remodeling. Increased expression of MMP-2 has often been observed in the tumors of colorectal cancer (CRC) patients. In order to unveil the perturbed proteomic signal during MMP-2-induced cancer progression, we analyzed MMP-2 dependent secretome change in HCT116 cancer cells by stable isotopic labeling with amino acids in cell culture (SILAC), together with the plasma proteome profile of CRC patients by label-free quantification according to disease progression from TNM stage I to IV. We also analyzed public database of CRC tissue proteome deposited by Clinical Proteomic Tumor Analysis Consortium (NCI/NIH). As a strategy for integrating the multi-layered proteomes, we first performed unsupervised hierarchical clustering on plasma and tissue proteomes according to TNM stage, and then Fisher’s exact test to find out which clusters were significantly represented by the secretome decreased by more than 1.5-fold upon MMP-2 knock down. The resultant cluster included CD9-ITGB1-ITGA7 protein complex as well as MMP-2. The proteins included in this cluster were mostly related to cell-cell communications and cell motility, and showed remarkable increased expression in tissue and plasma upon disease progression from TNM I to II. MMP-2 induced activation of FAK phospho-signaling in an activity-dependent manner. With the comparative and integrative multi-layered proteomic analysis, we suggest that high invasiveness featured in the disease progression of colorectal cancer with increased secretion of MMP-2 is because MMP-2 activates FAK signaling through CD9-integrin complex and consequently induces positive feedback of MMP-2 upregulation.

INSTRUMENT(S): LTQ Orbitrap, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Colon Cancer

SUBMITTER: Yumi Kwon

LAB HEAD: Cheolju Lee

PROVIDER: PXD018304 | Pride | 2021-08-26

REPOSITORIES: Pride

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Publications

Multi-layered proteogenomic analysis unravels cancer metastasis directed by MMP-2 and focal adhesion kinase signaling.

Kwon Yumi Y Park Seong-Jun SJ Nguyen Binh Thanh BT Kim Mi Jeong MJ Oh Sejin S Lee Hwanho H Park Narae N Kim Hyun Seok HS Kang Min-Jung MJ Min Byung Soh BS Lee Jin-Won JW Yang Eun Gyeong EG Lee Cheolju C

Scientific reports 20210824 1

The role of matrix metalloproteinase-2 (MMP-2) in tumor cell migration has been widely studied, however, the characteristics and effects of MMP-2 in clinical sample of metastatic colorectal cancer (CRC) remain poorly understood. Here, in order to unveil the perturbed proteomic signal during MMP-2 induced cancer progression, we analyzed plasma proteome of CRC patients according to disease progression, HCT116 cancer secretome upon MMP-2 knockdown, and publicly available CRC tissue proteome data. C ...[more]

PMID: 34429501

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

Dataset Information

Multi-layered proteomic analysis for colorectal cancer

Publications

Multi-layered proteogenomic analysis unravels cancer metastasis directed by MMP-2 and focal adhesion kinase signaling.

Similar Datasets

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