Abstract
Solid stress is a biomechanical abnormality of the tumor microenvironment that plays a crucial role in tumor progression. When it is applied to cancer cells, solid stress hinders their proliferation rate and promotes cancer cell invasion and metastatic potential. However, the underlying mechanisms of how it is implicated in cancer metastasis is not yet fully understood. Here, we used two pancreatic cancer cell lines and an established in vitro system to study the effect of solid stress-induced signal transduction on pancreatic cancer cell migration as well as the mechanism involved. Our results show that the migratory ability of cells increases as a direct response to solid stress. We also found that Growth Differentiation Factor 15 (GDF15) expression and secretion is strongly upregulated in pancreatic cancer cells in response to mechanical compression. Performing a phosphoprotein screening, we identified that solid stress activates the Akt/CREB1 pathway to transcriptionally regulate GDF15 expression, which eventually promotes pancreatic cancer cell migration. Our results suggest a novel solid stress signal transduction mechanism bringing GDF15 to the centre of pancreatic tumor biology and rendering it a potential target for future anti-metastatic therapeutic innovations.
Highlights
Solid stress - the mechanical forces per unit area generated by the solid phase of a tumor during progression - is a characteristic biomechanical abnormality of the tumor microenvironment that is rapidly gaining ground as an important regulator of cancer progression[1]
We showed that solid stress activates normal pancreatic fibroblasts enabling them to promote pancreatic cancer cell migration through the secretion of Growth Differentiation Factor-15 (GDF15), which is strongly elevated in fibroblasts as a response to mechanical compression[12]
We aimed to investigate the effect of solid stress on the migration of two distinct pancreatic cancer cell lines, MIA PaCa-2 and BxPC-3, using a previously-described in vitro transmembrane pressure device[1,5,8,11,12,20]
Summary
Solid stress - the mechanical forces per unit area generated by the solid phase of a tumor during progression - is a characteristic biomechanical abnormality of the tumor microenvironment that is rapidly gaining ground as an important regulator of cancer progression[1]. It is well known that solid stress inhibits tumor growth, induces cell apoptosis and regulates tumor morphology[4,5,6,7], while a limited number of studies has shown that solid stress can enhance the metastatic potential of cancer cells[6,8,9,10]. It has been proposed that mechanical compression (5.0 mmHg) in combination with Interleukin-6 (IL-6) treatment activates the Akt/Gsk-3β/β-catenin signaling pathway to induce epithelial-to-mesenchymal transition (EMT) in renal cell carcinoma[11]. We showed that solid stress activates normal pancreatic fibroblasts enabling them to promote pancreatic cancer cell migration through the secretion of Growth Differentiation Factor-15 (GDF15), which is strongly elevated in fibroblasts as a response to mechanical compression[12]. We conclude that solid stress signal transduction is mediated by an Akt-dependent mechanism that eventually promotes GDF15-induced pancreatic cancer cell migration
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