RSPO2 Enhances Canonical Wnt Signaling to Confer Stemness-Associated Traits to Susceptible Pancreatic Cancer Cells

Abstract

Cancer stem cells (CSC) present a formidable clinical challenge by escaping therapeutic intervention and seeding tumors through processes that remain incompletely understood. Here, we describe small subpopulations of pancreatic cancer cells with high intrinsic Wnt activity (Wnt high ) that possess properties indicative of CSCs, including drug resistance and tumor-initiating capacity, whereas cell populations with negligible Wnt activity (Wnt low ) preferentially express markers of differentiation. Spontaneous response to extrinsic Wnt signals induces signaling networks comprising ERK1/2 and epithelial-mesenchymal transition that subsequently confer cancer stemness traits to susceptible cells. Wnt enhancer R-Spondin 2 (RSPO2) seems to play a prominent upstream role in regulating this interplay. In this context, Wnt high cells were more likely to give rise to Wnt high progeny, tended to be more metastatic, and revealed higher levels of RSPO2 expression. Our studies reveal adaptive aspects of pancreatic cancer stemness arising from driver populations of CSCs that misappropriate functional and responsive elements of archetypical self-renewal pathways. Blocking such stemness-promoting pathways in conjunction with established chemotherapy could provide means to disrupt dynamic CSC process and present novel therapeutic targets and strategies. Cancer Res; 75(9); 1883-96. Ó2015 AACR.

Abnormal expression of mRNA, microRNA alteration and aberrant DNA methylation patterns in rectal adenocarcinoma

“…Our study indicated RSPO2 was significantly down-regulated in READ and kept the line with the published research, which demonstrates RSPO2 functions as a tumor suppressor; over-expression of it inhibits CRC cell proliferation and tumorigenicity [28]. RSPO2 is highly expressed in colon cancer stem cells and promotes the invasion of CRC cells through enhancing epithelial-mesenchymal transition [26]. The biological functions of RSPO2 in CRC and READ are unclear and the expression pattern of RSPO2 in READ regulated by DNA methylation modification and miRNA needs to be further investigated through experiments.…”

Expression and functional regulation of stemness gene Lgr5 in esophageal squamous cell carcinoma

“…Ilmer et al showed that RSPO2-enhanced canonical Wnt signaling contributes to cancer stemness in pancreatic cancer [50]. Lgr5 and RSPO2 are also associated with tumor aggressiveness, lymph node metastases, and Wnt/β-catenin activation in human papillary thyroid cancer [51].…”

Analysis of Important Gene Ontology Terms and Biological Pathways Related to Pancreatic Cancer

“…Take β -catenin as an example, β -catenin has been revealed to participate in the Wnt signaling pathway in various tumor subtypes [55, 56]. The initiation and progression of both pancreatic cancer and endometrial cancer have been confirmed to be associated with Wnt signaling pathway, implying that such two regulatory networks may have crosstalk and our extracted KEGG pathway (hsa05213) may actually contribute to the progression of pancreatic cancer [57–59]. As for the other three important solid tumor associated pathways, two of them, renal cell carcinoma and colorectal cancer associated pathways ( hsa05211 and hsa05210 ), contain functional regulatory genes and pathways that have been reported to contribute to pancreatic cancer at the same time.…”