Tumor invasion marks the first and most decisive step in cancer metastasis, enabling malignant cells to breach surrounding tissues and spread to distant organs. This complex process involves not only biochemical signaling but also intricate biomechanical interactions within the tumor microenvironment.
A recent review published in Genes & Diseases by researchers from Beihang University, Shandong First Medical University, and the Second People's Hospital of Dezhou offers a comprehensive examination of how biomechanical forces within the tumor microenvironment regulate cancer invasion and metastasis.
While genetic and biochemical signaling pathways have traditionally dominated cancer research, the authors emphasize that solid stress, tissue stiffness, and microstructural deformation also play decisive roles in tumor behavior. The authors highlight that tumor cells, when subjected to mechanical compression and spatial confinement, undergo membrane deformation, cytoskeletal remodeling, and alterations in surface topology to escape confined environments. This mechanoadaptive response enables cancer cells to invade adjacent tissues without relying solely on genetic mutations or enzymatic degradation.
The review defines the biomechanical signature of tumor cells as a multifaceted interplay between cell membrane topology, actin cytoskeletal remodeling, and mechanical stress adaptation. Curvature-sensing proteins such as BAR and ERM family members translate mechanical stimuli into intracellular signaling that modulates adhesion and motility. Furthermore, the concept of mechanical memory, whereby cancer cells retain invasive traits even after mechanical stimuli are removed, offers insight into how mechanical conditioning contributes to long-term metastatic potential.
The review also underscores the importance of three-dimensional (3D) tumor models that replicate physiological mechanics more accurately than conventional 2D cultures. Advanced technologies such as microfluidic systems and bioprinted spheroids provide valuable platforms to investigate how mechanical forces influence tumor cell behavior, extracellular matrix (ECM) dynamics, and intratumoral heterogeneity.
Importantly, these biomechanical insights open new avenues for developing "migrastatic" therapies, which target mechanical signaling pathways to inhibit invasion and metastasis. By modulating cytoskeletal tension, membrane curvature, or ECM stiffness, researchers aim to restore mechanical homeostasis and suppress cancer dissemination at its earliest stages.
The authors conclude that integrating mechanobiology with molecular oncology is key to achieving a holistic understanding of tumor invasion. Future research focusing on mechanosensitive proteins, nuclear deformation, and mechano-epigenetic regulation will be instrumental in identifying novel biomarkers and therapeutic targets to combat metastatic disease.
Reference
Title of Original Paper: The biomechanical signature of tumor invasion
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101771
