A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma is a disease of extremely poor prognosis for which there are no reliable markers of asymptomatic disease. To identify pancreatic cancer biomarkers, we focused on a genomic interval proximal to the most common fragile site in the human genome, chromosome 3p12, which undergoes smoking-related breakage, loss of heterozygosity, and homozygous deletion as an early event in many epithelial tumors, including pancreatic cancers. Using a functional genomic approach, we identified a seven-gene panel (TNC, TFPI, TGFBI, SEL-1L, L1CAM, WWTR1, and CDC42BPA) that was differentially expressed across three different expression platforms, including pancreatic tumor/normal samples. In addition, Ingenuity Pathways Analysis (IPA) and literature searches indicated that this seven-gene panel functions in one network associated with cellular movement/morphology/development, indicative of a “migration signature” of the 3p pathway. We tested whether two secreted proteins from this panel, tenascin C (TNC) and tissue factor pathway inhibitor (TFPI), could serve as plasma biomarkers. Plasma ELISA assays for TFPI/TNC resulted in a combined area under the curve (AUC) of 0.88 and, with addition of CA19-9, a combined AUC for the three-gene panel (TNC/TFPI/CA19-9), of 0.99 with 100% specificity at 90% sensitivity and 97.22% sensitivity at 90% specificity. Validation studies using TFPI only in a blinded sample set increased the performance of CA19-9 from an AUC of 0.84 to 0.94 with the two-gene panel. Results identify a novel 3p pathway–associated migration signature and plasma biomarker panel that has utility for discrimination of pancreatic cancer from normal controls and promise for clinical application.

Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma

“…Promising tumour markers derived from the PDAC tumour stroma, including matricellular proteins such as OPN, have previously been reported [24][25][26][27][28][29]. We have previously reported that collagen fragments derived from the basement membrane (BM) are elevated in PDAC patients at the time of diagnosis [28,29], and that type IV collagen has a role in PDAC cell survival and migration [20].…”

Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization

“…In breast cancer, TN-C expression is correlated with disease progression and relapse by metastasis to the lung and is a potential biomarker for the disease (135, 136). Similarly, TN-C has also been noted as a biomarker for pancreatic, bladder, colorectal cancers, and glioma (137–141). Therapeutic inhibition of TN-C is a possible treatment strategy in these models as well, which was illustrated in a mouse breast cancer model when cells treated with shRNA against TN-C produced fewer metastases (135).…”

Targeting MRCK and LIMK kinases for cancer therapy

“…Therefore, expression of key regulators might be expected to be elevated in invasive and metastatic cancer. MRCKa was identified in breast cancer as part of a gene expression signature linked to poor prognosis and increased incidence of metastasis under five years (7), and one of a seven gene panel with significantly elevated expression in pancreatic adenocarcinoma compared to normal pancreas (8). Invasiveness of MDA MB 231 breast cancer cells was inhibited by knockdown of either ROCK or MRCK kinases, but the most effective treatment was combined ROCK and MRCK knockdown or inhibition (9,10).…”