Abstract
RUNX3 controls the balance between proliferation and metastasis in pancreatic ductal adenocarcinoma.
Major finding: RUNX3 controls the balance between proliferation and metastasis in pancreatic ductal adenocarcinoma.
Concept: RUNX3 expression is regulated by DPC4 gene dosage in a biphasic manner.
Impact: DPC4 and RUNX3 levels in primary tumors may predict survival and inform treatment decisions.
Pancreatic ductal adenocarcinoma (PDA) is an aggressive disease noted for its rapid metastatic potential. However, a minority of patients suffer instead from locally advanced disease that would benefit from alternative therapy. To better understand the mechanisms underlying these distinct disease presentations, Whittle and colleagues generated mice with heterozygous deletion of Smad4 (also known as Dpc4) in the context of oncogenic KrasG12D and mutant Trp53R172H (KPDC) to mimic genetic lesions commonly found in human PDA. KPDC mice developed fewer metastases than mice with wild-type Dpc4 (KPC), but had a greater primary tumor burden. Consistent with this finding, KPDC cells exhibited impaired basal and TGFβ-induced migration and invasion and increased proliferation. Mechanistically, heterozygous Dpc4 deletion resulted in reduced expression of the transcription factor runt-related transcription factor 3 (RUNX3), which was significantly higher in KPC tumors compared with KPDC tumors and in invasive KPC carcinomas compared with preinvasive lesions, indicating that RUNX3 expression correlates with metastatic potential. High levels of RUNX3 expression in murine and human PDA cells promoted cell migration and metastasis via upregulation of extracellular matrix (ECM) genes, including osteopontin (Spp1) and Col6a1, and inhibited proliferation via induction of Cdkn1a. In contrast, homozygous deletion of Dpc4 (KPDDC) resulted in enhanced metastatic potential similar to KPC mice, but even faster primary tumor growth and reduced survival compared with KPC and KPDC mice. RUNX3 and ECM gene expression were elevated in KPDDC cells, suggesting a biphasic dependency of metastatic potential upon DPC4 and RUNX3 levels. In patients with PDA, high RUNX3 levels correlated with poor survival, and SPP1 and COL6A1 levels were elevated in patients with distant recurrence after surgery. In summary, these data support a model in which DPC4 gene dosage modulates RUNX3 expression, which regulates the metastatic potential of tumor cells. Furthermore, analysis of RUNX3 levels in primary tumors may help guide treatment strategies in patients with PDA.