Durotaxis and negative durotaxis are processes in which cell migration is directed by extracellular stiffness. Durotaxis is the tendency of cells to migrate toward stiffer areas, while negative durotaxis occurs when cells migrate toward regions with lower stiffness. The mechanisms of both processes are not yet fully understood. Additionally, the connection between durotaxis and negative durotaxis remains unclear. In this review, we compare the mechanisms underlying durotaxis and negative durotaxis, summarize the basic principles of both, discuss the possible reasons why some cell types exhibit durotaxis while others exhibit negative durotaxis, propose mechanisms of switching between these processes, and emphasize the challenges in the investigation of durotaxis and negative durotaxis.

Directed cell migration towards a softer environment is called negative durotaxis. The mechanism and pathological relevance of negative durotaxis in tumor progression still requires in-depth investigation. Here, we report that YAP promotes the negative durotaxis of melanoma. We uncovered that the RhoA-myosin II pathway may underlie the YAP enhanced negative durotaxis of melanoma cells. Acral melanoma is the most common subtype of melanoma in non-Caucasians and tends to develop in a stress-bearing area. We report that acral melanoma patients exhibit YAP amplification and increased YAP activity. We detected a decreasing stiffness gradient from the tumor to the surrounding area in the acral melanoma microenvironment. We further identified that this stiffness gradient could facilitate the negative durotaxis of melanoma cells. Our study advanced the understanding of mechanical force and YAP in acral melanoma and we proposed negative durotaxis as a new mechanism for melanoma dissemination.

Small GTPases regulate cytoskeletal dynamics, cell motility, and division under precise spatiotemporal control. Different small GTPases exhibit cross talks to exert feedback response or to act in concert during signal transduction. However, whether and how specific cytoskeletal components’ feedback to upstream signaling factors remains largely elusive. Here, we report an intriguing finding that disruption of the Arp2/3-branched actin specifically reduces RhoA activity but upregulates its total protein abundance. We further dissect the mechanisms underlying these circumstances and identify the altered cortactin/p190RhoGAP interaction and weakened CCM2/Smurf1 binding to be involved in GTP-RhoA reduction and total RhoA increase, respectively. Moreover, we find that cytokinesis defects induced by Arp2/3 inhibition can be rescued by activating RhoA. Our study reveals an intricate feedback from the actin cytoskeleton to the small GTPase. Our work highlights the role of Arp2/3-branched actin in signal transduction aside from its function in serving as critical cytoskeletal components to maintain cell morphology and motility.

The migrasome, an organelle that forms behind migrating cells, is connected to the cell body by a retraction fiber. Once released from the retraction fiber, the migrasome transforms into an extracellular vesicle and plays important roles in cell communication, development, angiogenesis, and disease. To date, the biogenesis, regulation of formation, cargo transportation, and physiological functions of migrasomes remain largely unknown. In this review, we summarize the current understanding of the mechanisms underlying migrasome formation and regulation, describe the evidence suggesting that migrasomes serve various physiological functions, compare the differences between migrasomes and other extracellular vesicles, emphasize the limitations in studying migrasomes, and discuss the potential of migrasomes in disease diagnosis and treatment.

Acral melanoma is the most common subtype of melanoma in non-Caucasians and tends to develop in stress-bearing area. Previous study showed that 12.3% acral melanoma patients harbored YAP amplification. Altered mechano-microenvironment has been observed in multiple cancers and mechanical force has been shown to trigger YAP activation. However, whether mechanical force and/or YAP promote acral melanoma tumorigenesis and metastasis is unresolved. Here, we report that acral melanoma patients exhibit YAP amplification and increased YAP activity. The over-activation of YAP promotes the transformation of melanocytes. We detected a decreasing stiffness gradient from the tumor to the surrounding area in the acral melanoma microenvironment. We further identified that this stiffness gradient could facilitate anti-durotaxis of melanoma cells. We uncovered that the RhoA-myosin II pathway may underlie the YAP enhanced anti-durotaxis of melanoma cells. Our study advanced the understanding of mechanical force and YAP in acral melanoma and we proposed anti-durotaxis as a new mechanism for melanoma dissemination. Funding Information: This work was supported by funding from the National Key R&D Program of China (2017YFA0506500), the Clinical Medicine Plus X-Young Scholars Project of Peking University (PKU2019LCXQ017) for C.W.; the National Natural ScienceFoundation of China (81972568) for Xuan Meng. Declaration of Interests: MISSING. Ethics Approval Statement: This study was approved by the Research Ethics Committee, Peking University Third Hospital, Beijing, China. Animal studies were conducted according to guidelines approved by the Biomedical Ethics Committee of Peking University (approval no. LA2014136). All protocols in this study were performed in accordance with the Declaration of Helsinki.