Research
Dr. Razidlo's lab team has two main focus areas of research related to cancer metastasis:
- Signaling pathways that regulate cytoskeletal remodeling
- Signals from the tumor microenvironment
Our goal is to understand how tumor cells invade and spread, particularly in pancreatic cancer, with the hope of designing therapies to stop the spread of cancer and improve patient survival.
Actin cytoskeletal dynamics
Actin cytoskeletal dynamics
Actin cytoskeletal dynamics
This lab image shows F-actin polymerized in vitro and imaged using fluorescence microscopy.
Signaling pathways that regulate cytoskeletal remodeling
Actin cytoskeletal dynamics
The dynamic actin cytoskeleton provides the structure for invasive protrusions. We're investigating the proteins that control actin polymerization, branching and bundling, and how they're activated in invasive cancer cells.
Activators of Rho GTPases
Activators of Rho GTPases
Activators of Rho GTPases
This lab image shows a pancreatic tumor cell ectopically expressing Vav1, an activator of Rac and Cdc42 GTPases. Vav1 expression induces an invasive phenotype.
Activators of RhoGTPases
Actin cytoskeletal dynamics are controlled by the small GTPases Rac, Cdc42 and Rho. These GTPases are molecular switches that are regulated by associated proteins — activation by guanine nucleotide exchange factors (GEFs) and inactivation by guanine nucleotide associated proteins (GAPs).
We're particularly interested in how GEFs are aberrantly activated in pancreatic cancers and the consequence for migratory processes. We've described that Vav1, a GEF for Rac and Cdc42 that's turned on in pancreatic cancers, can activate the pro-invasive machinery to upregulate invasive migration. This suggests that Vav1 may also be a potent therapeutic target to inhibit metastasis.
Remodeling of the extracellular matrix
Remodeling of the extracellular matrix
Remodeling of the extracellular matrix
This lab image shows a pancreatic tumor cell (red staining) plated on a green fluorescent extracellular matrix. Invasive structures called invadopodia (red actin puncta) degrade the fluorescent substrate, leading to a loss of fluorescent signal as the cell migrates across the matrix.
Remodeling of the extracellular matrix
Tumor cells form degradative structures called invadopodia that serve as sites for degradation of the extracellular matrix by matrix metalloproteinases. Our lab is investigating the mechanisms by which tumor cells form these actin-based, degradative protrusions through the concerted action of cytoskeletal, membrane and trafficking dynamics.
In addition, we have found that stromal cells robustly degrade and remodel the extracellular matrix by distinct mechanisms. This emphasizes the need to understand the contributions of the complex tumor microenvironment to design effective therapies to halt pro-invasive ECM remodeling.
Signals from the tumor microenvironment
Tumor microenvironment
Tumor microenvironment
Tumor microenvironment
This lab image shows a tissue section from a pancreatic tumor showing the ductal tumor cells surrounded by a complex stromal environment.
Cross-talk between tumor cells and the inflammatory microenvironment
Inflammatory signals are abundant in pancreatic tumors and can contribute to tumor progression and metastasis. Tumor cells also contribute to the inflammatory microenvironment, illustrating a complex cross-talk among cell types.
We're interested in how the inflammatory environment is modulated in pancreatic cancer and how inflammatory cytokines upregulate the invasive machinery in tumor cells.
Stromal lipids
Stromal lipids
Stromal lipids
This lab image shows pancreatic tumor cells stained for stored lipids (red) and a degradative compartment (green). Blue indicates the cell nuclei.
Metastatic invasion fueled by excess stromal lipids
Tumor cells accumulate lipids by multiple mechanisms, via increased synthesis and via uptake from the microenvironment. How do tumor cells control the balance between lipid storage and catabolism? How are stored lipids subsequently utilized for invasive migration? We're particularly interested in how this metabolic rewiring is regulated by prominent oncogenes in pancreatic cancer.
Related publications
Research funding
We're grateful for research funding from these organizations: