Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.
Highlights
Survival of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) has remained poor for many decades[1]
ADAM12 associates with activated pancreatic cancer stroma and poor-prognosis molecular subclasses We identified ADAM12 in a previous screen for stromal targets of tumor-derived SHH24
To further delineate the source of ADAM12 expression, we measured its expression by species-specific qPCR in patient-derived xenografts (PDXs)[28]
Summary
Survival of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) has remained poor for many decades[1]. The vast majority of patients are diagnosed with advanced disease, precluding resection of the tumor. Treatment options for these patients are limited and clinical trials typically demonstrate only partial. Research on PDAC has shifted focus from tumor cells to the abundant non-malignant compartment known as the stroma. This stroma consists of extracellular matrix proteins, cancer- associated fibroblasts (CAFs), and immune cells[3]. The stroma typically forms the vast majority of tumor bulk and contributes to chemoresistance by acting as a barrier to the delivery of chemotherapeutics. Non-mechanical tumor promoting properties have been attributed to the stroma as well[4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
