In the realm of cellular biology, the ability of cancer cells to migrate swiftly and invade distant tissues remains a formidable challenge, complicating efforts to contain this devastating disease. A compelling new discovery from researchers at Kyushu University, Japan, illuminates an intricate physical mechanism driving the rapid movement of cancer cells, particularly emphasizing how these cells manipulate internal water pressure to facilitate their migration through the body. This breakthrough defies previously held notions about cell motility and opens promising avenues for therapeutic targeting in aggressive cancers.
Cancer’s lethality is largely rooted in metastasis—the spread of cancer cells from a primary tumor to distant sites within the body. Central to this process is the capacity of cancer cells to transmigrate through diverse tissue environments, often by bypassing constraints that hamper normal cells. Traditional understanding posited that cellular movement relies predominantly on adhesion to extracellular matrices, enabling cells to pull themselves forward through contraction mechanisms involving the cytoskeleton. However, many invasive cancer cells circumvent this strategy by adopting amoeboid migration, a mode characterized by transient membrane protrusions called blebs that allow cells to squeeze through tight, confining spaces without forming strong adhesions.
At the heart of this pioneering research is the enzyme calcium/calmodulin-dependent protein kinase II (CaMKII). Led by Professor Junichi Ikenouchi, the investigation reveals an unexpected but crucial role of CaMKII in orchestrating the physical forces that drive bleb formation and expansion. While CaMKII has long been recognized for its signaling functions within cells, particularly in neural contexts and calcium-mediated pathways, this study uncovers its mechanical influence—nucleating into large protein supercomplexes that act as an osmotic engine within migrating cancer cells.
The process begins as localized signals elevate internal calcium concentrations within the nascent bleb. In response to this surge, CaMKII undergoes a conformational transition, enabling it to polymerize alongside other proteins into a supercomplex structure. This assembly changes the intracellular osmolarity, creating a steep concentration gradient that actively draws water into the bleb. The hydrated expansion generates a localized increase in hydrostatic pressure, physically pushing the plasma membrane outward and fueling the rapid and forceful protrusions characteristic of amoeboid migration.
This osmotic-based force generation mechanism, termed “CODE” for CaMKII-based Osmotically-driven DEformation, presents a paradigm shift in how cell motility can be driven—not just by cytoskeletal motor proteins or adhesion dynamics but by the spatial reorganization of protein complexes that modulate cellular hydration and pressure. The discovery elucidates a mechanochemical feedback loop wherein biochemical signals modulate physical state changes within the cell, culminating in dynamic morphological transformations required for effective migration.
Prior assumptions attributed membrane bleb growth primarily to passive cytoplasmic pressure diffusing internally, but findings from Ikenouchi’s earlier investigations had already indicated that expanding blebs bear specialized molecular compositions, with markedly enriched calcium ions and signaling constituents distinct from surrounding cytoplasm. This new research now adds a mechanistic layer demonstrating that CaMKII supercomplex formation is not a mere byproduct but the driver of osmotic pressure changes, directly influencing cell shape and motility.
From the clinical standpoint, these insights are extremely significant. Amoeboid migration enables cancer cells to evade therapies targeting adhesion-dependent pathways, such as those inhibiting integrin interactions or extracellular matrix remodeling. By identifying the CODE mechanism as fundamental to this alternative migration style, novel interventions can be devised that specifically disrupt CaMKII supercomplex formation or the associated osmotic engine, potentially halting the invasive behavior of aggressive tumors that rely on amoeboid locomotion.
Beyond oncology, understanding how cells physically generate force by rearranging proteins internally to modulate osmotic pressure could transform regenerative medicine and tissue engineering. Tissue morphogenesis, wound healing, and stem cell migration may all hinge on similar mechanistic principles, where localized protein assembly translates biochemical stimuli into mechanical outputs. Manipulating these processes could allow for the engineering of tissues with enhanced regenerative capacities or improved cellular behaviors for therapeutic applications.
The Kyushu University team employed rigorous experimental methodologies, combining live-cell imaging to observe bleb dynamics, molecular biology assays to quantify CaMKII activity and complex formation, and biophysical measurements to verify osmotic gradients and pressure changes. Their interdisciplinary approach underscores the growing trend in molecular biophysics, where understanding cellular phenomena demands integrative perspectives bridging signaling pathways and mechanical forces.
This research advances the fundamental comprehension of cellular biomechanics by providing compelling evidence that protein-driven osmotic engines are operative within living cells, capable of orchestrating rapid morphological expansions necessary for migration. It challenges the classical view that motor proteins and cytoskeletal contractility are solely responsible for generating protrusive forces and introduces a novel category of intracellular force generators based on fluid dynamics controlled by protein assembly.
Importantly, this work also demonstrates how relatively simple physicochemical principles, such as osmotic pressure governed by solute concentration gradients, are harnessed by cells through sophisticated molecular machinery. CaMKII’s role as a nucleating agent of protein supercomplexes indicates that cellular architecture and function are intricately linked to phase transitions and spatial protein distributions, adding new dimensions to the study of intracellular organization.
The implications for therapeutic development are profound. Targeting the CODE mechanism offers a strategy to incapacitate cancer cell migration without adversely affecting other cellular processes reliant on conventional motility mechanisms. Such specificity could reduce side effects and improve outcomes in treating metastatic cancers. The identification of molecular inhibitors that disrupt CaMKII polymerization or osmotic supercomplex stability stands as an exciting frontier for drug discovery.
In summation, the elucidation of CaMKII-driven osmotic forces powering cancer cell bleb expansion reshapes our understanding of cell migration in oncogenesis. This innovative research not only uncovers a previously invisible layer of mechanobiology but also illuminates new therapeutic landscapes. As cancer continues to defy treatment through cellular plasticity and adaptive mechanisms, decoding such fundamental processes is vital in the quest to outmaneuver this disease at its core.
Subject of Research: Cells
Article Title: CaMKII nucleates an osmotic protein supercomplex to induce cellular bleb expansion
News Publication Date: February 3, 2026
Web References:
DOI: 10.1038/s44318-026-00703-5
Kyushu University: https://www.kyushu-u.ac.jp/en/
References:
Fujii, Y., Sakai, Y., Matsuzawa, K., & Ikenouchi, J. (2026). CaMKII nucleates an osmotic protein supercomplex to induce cellular bleb expansion. The EMBO Journal. https://doi.org/10.1038/s44318-026-00703-5
Image Credits: Junichi Ikenouchi / Kyushu University
Keywords
Cancer cell migration, amoeboid migration, bleb expansion, CaMKII, osmotic pressure, protein supercomplex, mechanobiology, metastasis, cellular biomechanics, cytoskeletal dynamics, cellular motility, molecular biophysics
Tags: amoeboid migration in cancercalcium/calmodulin-dependent protein enzymecancer cell migration mechanismscellular biology breakthroughschallenges in cancer treatmentinvasive cancer cell behaviorKyushu University cancer researchmetastasis and cancer spreadrole of cytoskeleton in motilitytherapeutic targeting of aggressive cancersunderstanding cancer cell dynamicswater pressure in cancer cells
