Dataset Information

Inhibition of Alternative Complement Pathway May Cause Secretion of Factor B, Enabling an Early Detection of Pancreatic Cancer

ABSTRACT: This study aims to elucidate the cellular mechanisms underlying the secretion of factor B (CFB), recognized for its dual role as an early biomarker of pancreatic ductal adenocarcinoma (PDAC) and as the initiating substrate for the alternative complement pathway (ACP), a crucial component of the innate immune system. Employing parallel reaction monitoring analysis, we substantiated CFB's consistent ~2-fold elevated expression in PDAC patients compared to both healthy donors (HD) and chronic pancreatitis (CP) patients, thereby affirming its status as a cancer biomarker, as previously established through ELISA methods. In contrast to CFB expression, we observed heightened ACP activity in the patients of CP and other benign cancer compared to both HD and PDAC patients, prompting further exploration of a potential functional link between ACP and PDAC. To investigate the cellular secretion mechanism of CFB, we conducted protein-protein interaction analyses involving key complement proteins and their regulatory factors within the ACP cascade. These analyses encompassed blood samples from PDAC patients spanning various disease stages, alongside cancer cell lines. Our findings unveiled an intricate control system governing the ACP and its regulatory factors, including KRAS mutation, adrenomedullin (AM), and factor H (CFH). Notably, AM emerged as a pivotal player in CFB secretion, activating CFH and thereby promoting its predominant binding to C3b over CFB. Mechanistically, our data propose that KRAS mutation stimulates AM expression, subsequently enhancing CFH activity in the fluid phase through binding. This heightened AM-CFH interaction evidently conferred a greater affinity for C3b over CFB, potentially leading to suppression of the ACP cascade. This sequence of events likely culminated in the release of ductal CFB into plasma during the early stages of PDAC. Thus, our findings illuminate an intriguing trade-off between suppressed ACP activity and the early detection of PDAC.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Pancreatic Ductal Adenocarcinoma

SUBMITTER: Jin-Young Cho

LAB HEAD: Young-Ki Paik

PROVIDER: PXD047043 | Pride | 2024-05-21

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 71

Publications

Inhibition of the Alternative Complement Pathway May Cause Secretion of Factor B, Enabling an Early Detection of Pancreatic Cancer.

Lee Min Jung MJ Cho Jin-Young JY Bae Sumi S Jung Hye Soo HS Kang Chang Moo CM Kim Sung Hyun SH Choi Hye Jin HJ Lee Choong-Kun CK Kim Hoguen H Jo Daewoong D Paik Young-Ki YK

Journal of proteome research 20240202 3

This study aims to elucidate the cellular mechanisms behind the secretion of complement factor B (CFB), known for its dual roles as an early biomarker for pancreatic ductal adenocarcinoma (PDAC) and as the initial substrate for the alternative complement pathway (ACP). Using parallel reaction monitoring analysis, we confirmed a consistent ∼2-fold increase in CFB expression in PDAC patients compared with that in both healthy donors (HD) and chronic pancreatitis (CP) patients. Elevated ACP activit ...[more]

PMID: 38306169

Similar Datasets

Project description:Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. Most drugs that pass preclinical tests fail in these patients, emphasizing the need of appropriate preclinical models to test novel anticancer strategies. We developed four orthotopic mouse models employing primary human PDAC cells expressing Firefly and Gaussia luciferases, enabling bioluminescence monitoring of tumor growth and metastasis formation. Additional tumor characterization was performed using MR and high frequency ultrasound imaging. Genomic and immunohistochemical analysis revealed c-Met amplification and overexpression in one of four models. Analysis of c-Met inhibitors in vitro showed that crizotinib had the most potent effect. Moreover, we demonstrated synergistic effects between crizotinib and gemcitabine M-bM-^@M-^S the standard of care therapeutic in PDAC patients - in vitro and in vivo. Importantly, crizotinib reduced the cytidine deaminase activity in PDAC cells causing prolonged activity of gemcitabine due to diminished metabolic inactivation, as measured by LC-MS/MS. This might at least in part explain the observed prolonged survival of concomitantly treated mice with PDAC tumors and metastases. In conclusion, our orthotopic PDAC models enabled PDAC tumor imaging, and showed genetic, histopathological and metastatic features similar to their originator tumors. This allowed the identification of c-Met as a potential therapeutic target in PDAC, and revealed a cytidine deaminase-mediated synergistic mechanism between crizotinib and gemcitabine, a combination of drugs that warrants further investigation for the potential treatment of PDAC patients. 12 test samples in total [4 PDAC models (PDAC-1, PDAC-2, PDAC-3, PDAC-4; in three panel: primary human PDAC, primary tumor culture and mouse sample)] and reference sample (healthy control (mix/pool of healthy volunteers DNA) were analyzed as following (8 hybridizations); PDAC-1 primary human-Cy3 vs PDAC-4 cultured cells -Cy5 PDAC-1 cultured cells-Cy3 vs PDAC-4 mouse-Cy5 PDAC-1 mouse-Cy3 vs reference-Cy5 PDAC-2 primary human-Cy3 vs reference-Cy5 PDAC-2_cultured cells-Cy3 vs PDAC-2 mouse-Cy5 PDAC-3_primary human-Cy3 vs reference-Cy5 PDAC-3_cultured cells-Cy3 vs PDAC-3 mouse-Cy5 PDAC-4 primary human-Cy5 vs reference-Cy3 Normalized log2 ratio of (sample/references) data were calculated for 12 samples [*txt files on Series records]. Description of experimental/analysis design in r-program to generate 12 samples from 8 raw data files is provided in README.txt [Series supplementary file]

			Action	DRS
	1CP_PRM_01.raw	Raw
	1CP_PRM_02.raw	Raw
	1CP_PRM_03.raw	Raw
	1CP_PRM_04.raw	Raw
	1HD_PRM_01.mzML	Mzml