Assessment of the stromal contribution to Sonic Hedgehog‐dependent pancreatic adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. It is typically detected at an advanced stage, at which the therapeutic options are very limited. One remarkable feature of PDAC that contributes to its resilience to treatment is the extreme stromal activation seen in these tumors. Often, the vast majority of tumor bulk consists of non-tumor cells that together provide a tumor-promoting environment. One of the signals that maintains and activates the stroma is the developmental protein Sonic Hedgehog (SHH). As the disease progresses, tumor cells produce increasing amounts of SHH, which activates the surrounding stroma to aid in tumor progression. To better understand this response and identify targets for inhibition, we aimed to elucidate the proteins that mediate the SHH-driven stromal response in PDAC. For this a novel mixed-species coculture model was set up in which the cancer cells are human, and the stroma is modeled by mouse fibroblasts. In conjunction with next-generation sequencing we were able to use the sequence difference between these species to genetically distinguish between the epithelial and stromal responses to SHH. The stromal SHH-dependent genes from this analysis were validated and their relevance for human disease was subsequently determined in two independent patient cohorts. In non-microdissected tissue from PDAC patients, in which a large amount of stroma is present, the targets were confirmed to associate with tumor stroma versus normal pancreatic tissue. Patient survival analysis and immunohistochemistry identified CDA, EDIL3, ITGB4, PLAUR and SPOCK1 as SHH-dependent stromal factors that are associated with poor prognosis in PDAC patients. Summarizing, the presented data provide insight into the role of the activated stroma in PDAC, and how SHH acts to mediate this response. In addition, the study has yielded several candidates that are interesting therapeutic targets for a disease for which treatment options are still inadequate.

Identification of potential biomarkers and analysis of prognostic values in head and neck squamous cell carcinoma by bioinformatics analysis

“…Moreover, Masugi et al26 found that knockdown of ITGB4 reduced the migration and invasion and that upregulation of ITGB4 promoted cell scattering and motility in pancreatic ductal adenocarcinoma cells. Besides, our study shows that ITGB4 was associated with poor prognosis in HNSCC; similar results have also been shown in pancreatic ductal adenocarcinoma patients 27. Together, we speculate that ITGA6 and ITGB4 in ECM–receptor interaction signaling pathway may play a significant role in HNSCC.…”

Stromal SPOCK1 supports invasive pancreatic cancer growth

“…Furthermore, stromal cells have been described to act as chaperones for tumor cells that disseminate from the primary tumor, presumably providing a niche for malignant cells that would otherwise be vulnerable during transit (Coleman et al ., ). In addition, we and others have previously shown that the stroma provides a wide array of ligands that act in trans to support tumor cell growth (Damhofer et al ., ).…”

“…We have previously performed a screen for stromal targets of tumor cell-derived Sonic Hedgehog (SHH), a developmental protein important for the maintenance of stroma in PDAC (Damhofer et al, 2013). From this screen, several extracellular genes were identified that were prognostic, and likely to support tumor growth.…”

Inhibition of c-Myc by 10058-F4 induces growth arrest and chemosensitivity in pancreatic ductal adenocarcinoma

“…The efficacy, pharmacokinetics, 219 tissue distribution and metabolism of 10058-F4 was analyzed in a 220 prostate cancer xenografts previously [19] and no significant 221 anticancer effect was found after treatment of mice with either 222 20 or 30 mg/kg 10058-F4 due to its rapid metabolism and low 223 concentration in tumors. Dense fibrotic stromal matrix (desmo-224 plasia), which is mainly composed of extracellular matrix, 225 activated fibroblasts and inflammatory cells, is one histological 226 feature of PDAC and together can comprise up to 90% of the tumor 227 volume [20]. Given the poorer vascular and blood perfusion 228 induced by desmoplasia in PDAC, it is reasonable to explain the 229 negative effect of 10058-F4 in vivo.…”