Low RASSF6 expression in pancreatic ductal adenocarcinoma is associated with poor survival

Abstract

Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However , the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapit-ulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (<151 days) and slow growth, differences in their growth were maintained during extensive pas-saging. Rapid growth was additionally associated with lymph node metastasis (P = 0.022). The association of lymphovascular invasion and lymph node metastasis with PDX formation and rapid growth may reflect an underlying biological mechanism that allows these tumors to adapt and grow in a new environment. While the ability of PDX tumors to mimic the cellular and non-cellular features of the parental tumor stroma provides a valuable model to study the interaction of PDAC cells with the tumor microenvironment, the association of PLOS ONE | https://doi.

Downregulation of lncRNA CASC2 facilitates osteosarcoma growth and invasion through miR‐181a

“…45,46 The expression of RASSF6 was downregulated in several tumours such as gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic ductal adenocarcinoma. [47][48][49] RASSF6 played as a tumour suppressor gene and suppressed tumour cell growth, invasion and migration and promoted the cell cycle and apoptosis. 48,50 In this study, we demonstrated that RASSF6 expression was downregulated in osteosarcoma tissues and cell lines and downregulated expression of RASSF6 was correlated with advanced TNM stage.…”

BCL‐XL binds and antagonizes RASSF6 tumor suppressor to suppress p53 expression

“…Humans have six C‐RASSFs, all of which are known as tumor suppressors (Avruch et al., ; Volodko, Gordon, Salla, Ghazaleh, & Baksh, ). RASSF6 is frequently suppressed by DNA hypermethylation in human cancers, and its low expression correlates with tumor progression and short disease‐free survival (Chen et al., ; Djos, Martinsson, Kogner, & Carén, ; Guo et al., ; Hesson et al., ; Liang et al., ; Richter, Pfeifer, & Dammann, ; Richter, Zimmermann, Haag, Walesch, & Dammann, ; Wen et al., ; Ye et al., ). These findings support that RASSF6 is a tumor suppressor.…”

Diagnostic value of selected markers and apoptotic pathways for pancreatic cancer

“…A very recent work also detected low expression of RASSF6 (Ras association domain family 6) in PDAC and associated it with poor survival [132]. Only 16.7% of patients’ tumor tissues were strongly positive for RASSF6 in immunostainings.…”