BMS76 CELL MOTILITY IN

BMS76 – Cell Motility in Physiology and Pathology

BMS76 – CELL MOTILITY IN

PHYSIOLOGY AND PATHOLOGY

Opleiding: Master Biomedical Sciences

Onderwijsinstelling: Radboudumc

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BMS76 – Cell Motility in Physiology and Pathology Content Intracellular mechanisms of cell movement......................................................................................4 Molecular mechanisms of actin organization as driver of migration...................................................................4 Molecular actin filament organization/dynamics...........................................................................................4 Mechanisms of filament assembly..................................................................................................................5 Contraction......................................................................................................................................................6 Tail detachment...............................................................................................................................................7 Environmental guidance of cell movement and modes of migration.................................................7 Environmental guidance of cell movement..........................................................................................................7 Haptokinesis as environmental guidance mechanism for cell migration.......................................................7 Taxis as environmental guidance mechanism for cell migration....................................................................7 Cell migration modes and transitions...................................................................................................................8 Single amoeboid..............................................................................................................................................8 Single mesenchymal........................................................................................................................................8 Plasticity – mesenchymal-amoboid transistion..............................................................................................8 Cell migration in wound healing and morphogenesis......................................................................10 Steps of wound healing.......................................................................................................................................10 Signaling pathways involved and cell migration strategies................................................................................10 Experimental approaches to study wound healing.............................................................................................11 Scratch assay.................................................................................................................................................11 Lens ex vivo wound repair model.................................................................................................................11 Normal vs. chronic wound..................................................................................................................................12 Morphogenesis....................................................................................................................................................12 Cell migration in immune defense and angiogenesis.......................................................................13 Protrusion-based migration in immune cells......................................................................................................13 Cell migration in angiogenesis.............................................................................................................................14 Migrating cells in cancer..................................................................................................................14 The metastatic cascade.......................................................................................................................................14 Plasticity of invasion programs...........................................................................................................................15 Organ colonization..............................................................................................................................................16 Migrating cells in inflammation and immunotherapy......................................................................17 Principles of leukocyte recruitment into tissues and cell-cell interaction..........................................................17 Immunotherapy in cancer...................................................................................................................................17

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BMS76 – Cell Motility in Physiology and Pathology iRATs...............................................................................................................................................19 iRAT Week 1: Basic mechanisms of cell movements..........................................................................................19 iRAT Week 2: Cell migration in physiology..........................................................................................................21 iRAT Week 3: Cell migration in disease...............................................................................................................23

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BMS76 – Cell Motility in Physiology and Pathology Intracellular mechanisms of cell movement Molecular mechanisms of actin organization as driver of migration Mesenchymal migration is a mode of cell movement where cells with a fibroblast-

like shape move through a tissue matrix. It occurs in several steps:

1.Polarization: The cell establishes a "front" and "back," setting a direction for movement.

2.Protrusion: The cell membrane extends at the leading edge. Actin

filaments push the membrane outward, forming structures that help the cell explore and anchor the ECM.

3.Adhesion: Stable attachments form between the cell and the ECM.

Integrin proteins cluster at focal adhesions, providing anchor points for traction.

4.Contraction: The cell body moves forward. Myosin motor proteins pull

actin filaments at the rear, contracting the cell and advancing it.

5.Tail retraction: The cell’s rear detaches, completing the movement cycle.

Rear focal adhesions dissemble, allowing the cell to move forward freely.Molecular actin filament organization/dynamics Actin monomers (G-actin) assemble into dynamic filaments (F-actin) through a process regulated by ATP. When G-actin monomers bind ATP, they are more likely to join the growing "plus" (barbed) end of an actin filament, promoting elongation. Once incorporated, actin’s ATPase activity hydrolyzes ATP to ADP, which stabilizes the filament but gradually reduces the affinity of actin subunits for each other. At the opposite "minus" (pointed) end, older ADP-bound actin monomers disassemble more readily. This polarized assembly leads to a phenomenon called treadmilling, where ATP-actin monomers add at the plus end while ADP-actin monomers disassemble at the minus end, allowing the filament to maintain a steady length while continuously cycling monomers through.

Profilin: binds to G-actin monomers, enhancing their ability to

bind ATP and directing them toward the barbed end, thus promoting filament elongation.

Cofilin: binds to ADP-actin subunits within older segments of

the filament, inducing a conformational change that increases the rate of disassembly at the pointed end.There are several inhibitors that specifically target actin

polymerization and depolymerization:

Phalloidin: This compound binds tightly to F-actin,

stabilizing actin filaments and preventing their depolymerization.

Jasplakinolide: Jasplakinolide promotes actin

polymerization by stabilizing F-actin and enhancing nucleation, the initial step of filament formation. This leads to excessive actin polymerization and a rigid actin network that resists normal depolymerization.

Cytochalasin D: By binding to the barbed (plus) end of

actin filaments, cytochalasin D prevents the addition of new actin monomers.

Latrunculin A: This inhibitor binds to G-actin monomers,

preventing them from incorporating into F-actin.

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