Alterations in extracellular matrix (ECM) architecture and stiffness are hallmarks of aggressive pancreatic cancer progression. However, the mechanisms by which ECM biomechanical properties regulate malignant biological behavior remain unknown. Here, we reveal that calmodulin-dependent protein kinase doublecortin-like kinase 1 (DCLK1) integrates biomechanical signaling and promotes pancreatic cancer cell progression. DCLK1 expression and activation are selectively induced under conditions of high biomechanical stress mediated through the piezo-type mechanosensitive ion channel component 1 (PIEZO1)/calcium/hippocalcin-like protein 1 (HPCAL1) pathway. Consistently, in solid tumor experiments, DCLK1 overexpression under low stiffness conditions facilitates rapid tumor progression and chemoresistance, whereas using calcium inhibitors can partially reverse the adverse effects of DCLK1 overexpression. Conversely, under high stiffness conditions, DCLK1 knockdown inhibits tumor growth and enhances chemosensitivity but attenuates the sensitizing effect of combined calcium inhibitor treatment on chemotherapy efficacy. Mechanistically, DCLK1 interacts with phosphatidylinositol-4-phosphate 5-kinase type 1 alpha (PIP5K1A) by inhibiting its threonine phosphorylation, thereby facilitating PIP5K1A membrane localization. This activates the downstream phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway, promoting cancer cell proliferation and chemoresistance. Collectively, these findings establish DCLK1 functions as a context-specific amplifier, exacerbating aggressive tumor progression and chemotherapy resistance in pancreatic cancer. Targeting the calcium/DCLK1 signaling axis may therefore enhance the efficacy of adjuvant therapies in pancreatic cancer.
Zhang et al. (Mon,) studied this question.