Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer

Abstract

Most patients with pancreatic ductal adenocarcinoma (PDA) present with metastatic disease at the time of diagnosis or will recur with metastases after surgical treatment. Semaphorin–plexin signaling mediates the migration of neuronal axons during development and of blood vessels during angiogenesis. The expression of the gene encoding semaphorin 3D (Sema3D) is increased in PDA tumors, and the presence of antibodies against the pleiotropic protein annexin A2 (AnxA2) in the sera of some patients after surgical resection of PDA is associated with longer recurrence-free survival. By knocking out AnxA2 in a transgenic mouse model of PDA (KPC) that recapitulates the progression of human PDA from premalignancy to metastatic disease, we found that AnxA2 promoted metastases in vivo. The expression of AnxA2 promoted the secretion of Sema3D from PDA cells, which coimmunoprecipitated with the co-receptor plexin D1 (PlxnD1) on PDA cells. Mouse PDA cells in which SEMA3D was knocked down or ANXA2-null PDA cells exhibited decreased invasive and metastatic potential in culture and in mice. However, restoring Sema3D in AnxA2-null cells did not entirely rescue metastatic behavior in culture and in vivo, suggesting that AnxA2 mediates additional prometastatic mechanisms. Patients with primary PDA tumors that have abundant Sema3D have widely metastatic disease and decreased survival compared to patients with tumors that have relatively low Sema3D abundance. Thus, AnxA2 and Sema3D may be new therapeutic targets and prognostic markers of metastatic PDA.

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

“…This model recapitulates PDAC tumour progression but is in a mixed 129/SvJae/C57BL/6 background. Therefore, the original KPC mouse was backcrossed into a C57BL/6 background for nine generations and pancreatic tumours from these mice were harvested to produce primary epithelial KPC lines, which were kindly provided by Dr Elizabeth Jaffee for use in these studies 19. Cells were maintained in RPMI 1640 supplemented with 10% heat‐inactivated fetal bovine serum, 1% minimum essential medium non‐essential amino acids, 1 mM sodium pyruvate, and 50 U/mL penicillin/streptomycin (Gibco, Gaithersburg, MD, USA), with incubators maintained at 37°C and 5% CO 2 .…”

Biological Effect and Mechanism of the miR-23b-3p/ANXA2 Axis in Pancreatic Ductal Adenocarcinoma

“…In addition, they found that semaphorin 3D (Sema3D) is responsible for directing axonal extension during neuron growth and development. ANXA2 promotes the secretion of Sema3D by PDAC cells, which may promote the infiltration of PDAC cells through neural invasion [15].…”

Annexins – insights from knockout mice

“…However, several possibly clinically relevant observations with this strain have been made in recent years (Table 3). Crossing a sophisticated mouse model for the development of pancreatic ductal adenocarcinoma (PDA) with the AnxA2 -/-strain revealed a prominent role for AnxA2 in metastatic events driven by pancreatic cancers (Foley et al, 2015). While primary pancreatic tumors from AnxA2-deficient animals and controls were comparable, the metastatic potential of the PDA tumors from AnxA2 KO animals was substantially reduced.…”

“…This may be relevant for pulmonary function, but may extend to other disorders associated with COL6 deficiency (Dassah et al, 2014). In addition, this could also be related to migratory and invasive properties of pancreatic cancer cells (Foley et al, 2015) (Table 3). A few studies in the AnxA2 KO strain have now also provided initial evidence that AnxA2 contributes to membrane organization and transport along endocytic routes.…”

“…It is unknown if this striking phenotype requires p11, but it appears unrelated to plasmin generation and neoangiogenesis. Yet it involves secretion and autocrine signaling of semaphorin 3D, suggesting a critical role for AnxA2 in exocytic pathways contributing to the aggressive behavior of pancreatic cancer cells (Foley et al, 2015).…”