β-catenin-activated autocrine PDGF/Src signaling is a therapeutic target in pancreatic cancer

Abstract

K-ras mutation and p53 loss are the most prevalent genetic alterations in pancreatic cancer. In addition to these two alterations, pancreatic tumors frequently contain a third genetic defect. Mutations in the WNT/ß-catenin signaling molecules occur in 15-20% of pancreatic cancer patients and co-exist with K-ras mutation and p53 loss. However, the contribution of the WNT/ß-catenin pathway in pancreatic tumorigenesis is still unclear. Methods: We generated Pdx1-CreKras G12D p53 L/+ APC L/+ (KPA) mice and compared their phenotypes with Pdx1-CreKras G12D p53 L/+ (KPC) mice. The signaling pathways specifically activated in the KPA mice were investigated and the therapeutic effect by targeting the activated pathways was evaluated. We finally validated our findings in human blood and tumor samples. Results : Survival of the KPA mice was shorter than that of the KPC mice. The KPA cancer cells are highly invasive and exhibit distorted morphology in organoid culture with extensive invadopodia formation and elevated matrix metalloproteinase (MMP) activity. The platelet-derived growth factor (PDGF) pathway is upregulated in the KPA cancer cells, and PDGF production induced by ß-catenin triggers constitutive activation of the Src kinase via the PDGF receptor in the cells. Serum PDGF concentration of the KPA mice is much higher than that of the normal and KPC mice. The Src inhibitor dasatinib effectively inhibits tumor growth and metastasis of the KPA cancer cells. Patient's serum PDGF level is significantly correlated with the expression of PDGF and phosphor-Src in tumors and elevated PDGF/phosphor-Src level in tumors predicts increased recurrence and poor survival. Moreover, mutations of the WNT/ß-catenin signaling molecules are higher in patients with elevated PDGF/phosphor-Src level. Conclusion: ß-catenin activation, coupled with K-ras mutation and p53 loss, activates an autocrine PDGF/Src signaling in pancreatic cancer and defines a subset of patients who might be sensitive to Src inhibition. In addition, serum PDGF level could be a reliable biomarker for patient selection in clinic.

Tumor Cellular and Microenvironmental Cues Controlling Invadopodia Formation

“…In particular, the transcriptional induction of PDGFRα and downstream activation of Src driven by the EMT-related transcription factor Twist1, is essential for invadopodia formation and matrix degradation, as well as in vivo metastasis, indicating that the reactivation of developmental machinery, such as the EMT, in tumor metastasis might act in cooperation via invadopodia (Eckert et al, 2011). In pancreatic cancer, β-catenin activation, coupled with K-ras mutation and p53 loss, activates an autocrine PDGF signaling with highly invasive properties of tumor cells, capable to form invadopodia and to digest ECM (Kuo et al, 2019). Finally, signals from an activated tyrosine kinase receptor Met might also increase invadopodia biogenesis in basal-like breast and gastric carcinoma cells, dependent on tyrosine phosphorylation of cortactin (Rajadurai et al, 2012).…”

Terphenyllin Suppresses Orthotopic Pancreatic Tumor Growth and Prevents Metastasis in Mice

“…Pancreatic cancer is a highly lethal and devastating disease with early metastasis and poor prognosis. Although the extensive molecular analyses of PC have indicated the strong genetic heterogeneity of this disease, some common molecular alterations have been characterized and validated as potential molecular targets for developing anti-PC therapeutic agents (Qie and Diehl, 2016;Cicenas et al, 2017;Waters and Der, 2018;Kuo et al, 2019;Qin et al, 2019). Despite the improvements in chemotherapy and targeted therapy and the considerable progress in increasing overall survival, there are very limited treatment options for PC patients, especially for those with locally advanced disease or metastasis (Werner et al, 2013;Rebelo et al, 2017;Neoptolemos et al, 2018).…”

“…However, FOLFIRINOX has recently been associated with increased toxicity, mainly febrile neutropenia and diarrhea (Lambert et al, 2017). Numerous studies have unraveled the common molecular alterations occurring in PC, such as mutations in Kras, p53, and BRCA1 (Nag et al, 2013;Cicenas et al, 2017;Waters and Der, 2018), aberrant activation of wnt/bcatenin signaling and keap1/Nrf2 signaling (Qin et al, 2018;Kuo et al, 2019;Qin et al, 2019), and amplification and overexpression of MDM2, cyclin D1, USP7, and MDR1 (Qie and Diehl, 2016;Robey et al, 2018;Wang et al, 2019b;Dong et al, 2020;Qi et al, 2020), which play critical roles in the initiation, progression, metastasis, and chemoresistance of PC. Many targeted agents have been developed and evaluated in the preclinical and clinical settings (Karandish and Mallik, 2016).…”

Inactivation of APC Induces CD34 Upregulation to Promote Epithelial-Mesenchymal Transition and Cancer Stem Cell Traits in Pancreatic Cancer

“…A typical PDAC model was engineered to express Kras G12D and delete P53 specifically in the pancreas by crossing with the Pdx1-Cre strain. Kras G12D activation alone caused the development of PanINs of different grades which, combined with the loss of p53, produced a rapid progression to PDAC [ 29 , 30 , 31 ]. Notably, although the genetic lesions in this model were present in all pancreatic lineages, the resulting neoplastic changes showed an exclusively ductal phenotype, suggesting either that these mutant alleles drive transdifferentiation of multiple pancreatic cell lineages to a ductal character or that such lesions produce oncogenic change exclusively in the ductal progenitor lineage to dominate PDAC development [ 12 , 31 , 32 ].…”