Metastasis, the process by which cancer cells spread from the primary tumour to other parts of the body, is a major concern in cancer research and is the leading cause of mortality among patients with this disease. The migration of cancer cells within the body involves complex interactions with surrounding tissues and extracellular matrices.
New research from Pennsylvania State University delves into recent scientific findings on the role of microtubules and microtubule-associated motors in cancer cell metastasis, shedding light on their potential importance in understanding and combating this deadly phenomenon.
Metastasis formation is not a linear process. It involves the migration of cancer cells from the primary tumour, their invasion into healthy tissue and the formation of secondary tumours. This migration is not random, instead it follows pathways of least resistance and is guided by various cues in the microenvironment, including anisotropically aligned collagen fibres, a phenomenon known as 'contact guidance'.
An interesting aspect of cancer cell migration is the reduction in actomyosin contractility, a process that makes cells more 'fluid'. This change raises questions about the mechanical forces that facilitate tumour cell movement, especially when actomyosin contractility is impaired. It is in this context that microtubules and microtubule-associated motors come into play.
A growing body of evidence suggests that microtubules and their associated motors play a direct role in cancer cell locomotion. For instance, when actomyosin-mediated contractility is reduced, cytoplasmic dynein motors become crucial for the migration of some tumour cells, particularly in collagen-rich matrices. These motors are involved in the development of cell protuberances along collagen fibres and play a role in microtubule organisation, cell shape and contact guidance.
Microtubules are not only structural components. In fact, they actively contribute to the cells' ability to perceive and interact with their environment. They act as support structures that help the cell align with its environment, and their mechanical properties are crucial to several cellular functions, including the contraction of myofibrils within cardiac myocytes.
A key finding is the role of dynein in supporting cancer cell migration when actomyosin contractility is inhibited. Specifically, the study shows that while non-muscle myosin II (NMII) contractility and dynein motility coexist, each motor group is able to maintain tumour cell migration along the 2D network of biomimetic collagen 'fibres'.
Furthermore, the study finds that tumour cells require the simultaneous activity of the dynein and myosin motors during 3D migration confined in granular gelatin-based hydrogels, suggesting, for the first time, a fundamental mechanochemical-biological difference between the confined and unconfined modes of metastasis.
The extracellular matrix (ECM) plays a crucial role in cancer cell migration. Several studies have focused on 3D collagen gels as biomimetic models for studying metastasis. However, the structural and mechanical complexity of these gels presents challenges for detailed mechanistic-biological research. Understanding whether actomyosin adhesion and contractility alone are sufficient to coordinate the migration of tumour cells into the intricate 3D collagen matrices is an as yet unresolved challenge.
The study results revealed that the interaction between actomyosin and microtubules is crucial for cancer cell migration. While actomyosin motors are traditionally associated with cell alignment with the ECM and migration within fibrillar collagen matrices, the fluid polymerisation dynamics of Arp2/3's branched F-actin network and the presence of intact microtubules play an equally significant role. In 3D collagen matrices, dynein activity contributes to the development of low-contractility protuberances, which are essential for cell migration.
Findings suggest that microtubules and dynein motors complement or even replace the contractility of actomyosin, providing mechanical forces for cell adhesion and protrusion along collagen guidance cues. The role of these components varies between metastatic and non-metastatic cells, with dynein, dynactin and microtubules forming a coherent system of force generation and transmission in metastatic cells.
In non-metastatic cells, the motility of dynein mainly facilitates cell adhesion and migration through radial protrusions, resulting in less efficient migration.
Interestingly, the study suggests that the mechanical antagonism between dynein and kinesin-1, two microtubule-associated motors, could influence microtubule organisation, cell contact guidance and reactivity to adhesion cues. Dynein and kinesin-1 show opposite directional preferences along microtubules, and their balance is crucial for cancer cell migration.
This research sheds light on the complex mechanisms underlying cancer cell migration and metastasis. It highlights the essential role of microtubules and dynein motors, especially when actomyosin contractility is impaired.
According to the study authors, this discovery marks a paradigm shift in many respects. Until now, dynein has never been considered to be involved in providing the mechanical force for tumour cell motility, i.e. their ability to move on their own. The study shows instead that by targeting dynein, one can effectively block the motility of these cells and thus stop metastatic spread.
This suggests a completely new method for cancer management. Instead of killing cancer cells with radiation or chemotherapy, the cells can be paralysed. Cell 'paralysis' could prove to be an effective treatment strategy for cancer compared to chemotherapy treatments, because after surgical removal of the main tumour, it could prevent the cancer from spreading without damaging healthy tissues and cells.
The researchers noted that any potential clinical treatment is still a long way off, as no human or animal studies have yet been conducted.