Disrupting Collagen-Mediated Prosurvival Pathways in Pancreatic Cancer
Abstract
We investigated the role of the Discoidin Domain Receptor 1 (DDR1), a collagen receptor kinase, in Pancreatic Ductal Adenocarcinoma (PDAC). Hypothesis: DDR1 mediates the pro-malignant effects of collagen in PDAC progression. DDR1 mediates the crosstalk between mutant Kras addicted PDAC cells with collagen and activate signaling pathways that promote tumor cell survival and malignancy (MEK resistance). Aims: 1. Evaluate the Role of DDRs in Resistance to MEK Inhibition and their Effectiveness as Potential Therapeutic Targets in the KPC Mouse Model and 2. Establish the Anti-Tumor Effect of Single or Combinatorial Lethality of DDR1 Inhibition on Human PDX and Matched Organoid Cultures. Major Findings: We characterized DDR expression in multiple PDAC cell lines, with the majority displaying DDR1 but not DDR2 expression. DDR1 inhibition had no impact on cell proliferation or survival in the presence of soluble collagen I in PDAC cell lines with mutated Ras. However, inhibition was observed in PDAC cells with wild type Ras. In 3D collagen I gels in vitro, DDR1 expression significantly inhibited cell proliferation. Sensitivity to MEK inhibition was not correlated with levels of DDR expression in human PDAC cell lines. DDR1 inhibition increased the sensitivity of PDAC cell lines to Trametinib inhibition. DDR1b expression increased gemcitabine sensitivity in MiaPaCa-2 cells cultured in 3D collagen I gels. DDR1 is critical for tumor development and progression in the KPC mouse model of PDAC because DDR1 deficiency restricts tumor growth and metastases. DDR1b significantly promoted tumor growth of human MiaPaCa-2 cells when implanted within collagen 1 in mice. DDR1b expression and activation in these tumors is associated with activation of Src/PDPK1/AKT activity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2021
- Accession Number
- AD1170604
Entities
People
- Rafael Fridman
Organizations
- Wayne State University