bims-ecemfi 2025-11-02 papers

NPJ Syst Biol Appl. 2025 Oct 29. 11(1): 120

MMP9 shapes cell mechanics to enable collective invasion in cancer.

Asadullah, Sarbajeet Dutta, Sumon Kumar Saha, Anisha Karmakar, Nikita Sharma, Sudikshaa Vijayakumar, Shamik Sen.

Cooperation among phenotypically distinct sub-populations within a tumor plays a key role in cancer progression. In this study, we investigated how proteolytic heterogeneity supports collective cancer invasion. In invasive MDA-MB-231 breast cancer cells which exhibit considerable variability in MMP9 expression, we show that MMP9 knockdown cells are notably smaller and softer than control cells. A computational model revealed that the invasiveness of mixed clusters containing both proteolytic and non-proteolytic cells depends on cell-cell adhesion, with non-proteolytic cell invasion requiring close proximity to proteolytic neighbors. When we assigned non-proteolytic cells the same size and stiffness as proteolytic ones, the overall invasiveness declined-highlighting that small size and deformability of non-proteolytic cells are essential for sustained collective invasion. We validated these predictions experimentally using spheroid invasion assays showing that mixed spheroids of control and MMP9 knockdown cells are the most invasive. Together, our findings demonstrate that interplay between MMP9 expression and biophysical properties enables collective invasion through enrichment of and matrix degradation by high MMP9 expressing cells at the invasive front, and squeezing of low MMP9 expressing cells through the remodeled matrix.

DOI: https://doi.org/10.1038/s41540-025-00601-2

ACS Appl Mater Interfaces. 2025 Oct 29.

Collective Mechanical Memory Encoded by Long-Lasting Supracellular Cytoskeletal Structures in Multicellular Spheroids.

Jiwon Kim, Hyuntae Jeong, Young-Woo Jeon, Chanhong Min, Ian Y Wong, Jennifer H Shin.

Animal cells can sense and "remember" the stiffness of their extracellular environment, resulting in sustained changes in form and function. Such "mechanical memory" has been previously explored using individual cells and attributed to epigenetic changes and transcriptional activity. However, it is unclear whether such memory is retained across collective cells. Here, we report that collective cells sustain mechanical memory through self-organized actin-CK18 networks spanning multiple cell lengths, even under dramatically changing mechanical environments, such as those encountered during cancer metastasis. As a case study, we modeled ovarian cancer metastasis and found that cells initially cultured on different stiffness retained distinct migratory phenotypes throughout the environmental transitions of the metastasis model. Notably, soft-primed cells, in particular, demonstrated stronger cell-cell adhesions than stiff-primed cells. Upon aggregation into multicellular spheroids, mimicking malignant spheroids found in patient ascites, the soft-primed spheroids exclusively developed a dense cage-like supracellular actin-CK18 structure at their peripheral surfaces. Furthermore, these soft-primed spheroids exhibited impeded collective invasion, instead becoming confined by the long-lasting cytoskeletal cage. Inhibition of gap junctions attenuated the formation of cytoskeletal cages, indicating that dynamic intercellular communication via gap junctions is essential for maintaining collective mechanical memory. This work demonstrates a collective mechanism of mechanical memory that is not solely dependent on epigenetic and transcriptional activation, advancing our understanding of the elevated metastatic potential of tumor cell clusters originating in stiffened matrices.

Keywords: Mechanical memory; collective migration; cytoskeletal network; gap junction; substrate stiffness

DOI: https://doi.org/10.1021/acsami.5c16693

FEBS J. 2025 Oct 29.

A guide to the types, structures, and multifaceted functions of matrix metalloproteinases in cancer.

Zoi Piperigkou, Sylvia Mangani, Spyros Kremmydas, Nikolaos E Koletsis, Nikos K Karamanos.

Matrix metalloproteinases (MMPs) represent a diverse family of zinc-dependent matrix remodeling enzymes that play critical roles in both physiological and pathological processes, including cancer progression. Their enzymatic activity in matrix remodeling underpins key aspects of cellular physiology; however, uncontrolled remodeling determines several pathological conditions, such as osteoarthritis, fibrosis, and cancer. Several cell functional properties, among them cell proliferation, apoptosis, migration, adhesion, and invasion, are affected by certain MMPs. Moreover, MMPs guide critical steps during cancer progression, including cell behavior, epithelial-to-mesenchymal transition, pre-metastatic niche formation, angiogenesis, and immune surveillance. However, the roles of MMPs in cancer are complex and context-dependent, with certain family members demonstrating opposing functions that vary with tumor stage, anatomic site, enzyme localization, and substrate specificity. These dual roles present both opportunities and challenges for therapeutic targeting and diagnostic applications of MMPs. While early clinical trials of MMP inhibitors (MMPIs) yielded disappointing outcomes, advances in preclinical models have improved our knowledge of MMP biology and continue to inform the design of more effective and selective MMPIs. This guide on the types, structures, and functions of MMPs gives an overview of MMP structural domains, matrix substrates, and specific functions, summarizing their main roles in normal and pathophysiological conditions, with a particular emphasis on cancer progression. New insights into pharmacological targeting, diagnostic applications, and progress on clinical trials are also presented here and critically discussed. This guide revisits the concept of the multifaceted biological functions of MMPs, critically examines the limitations of previous therapeutic attempts, and explores future directions for the development of effective MMP-based molecular targeting.

Keywords: biomarkers; cancer; extracellular matrix; matrix metalloproteinases; pre‐metastatic niche; proteolytic network

DOI: https://doi.org/10.1111/febs.70296

Nat Biotechnol. 2025 Oct 28.

A single-chain derivative of an integrin-activating antibody potentiates organoid growth in Matrigel and collagen hydrogels.

Wim B M de Lau, Joost J A P M Wijnakker, Gijs J F van Son, Daniel Krueger, Daisong Wang, Matthijs S Abendroth, Robin Schreurs, Claudia Y Janda, Fenna L H van Rijt, Benjamin J P Chalopin, Emma Bokobza, Johan H van Es, Timothy A Springer, Arnoud Sonnenberg, Hans Clevers.

Current methods of culturing human epithelial organoids from adult stem cells may not be compatible with clinical applications as they rely on xenogeneic, chemically undefined or non-standardized components such as the basement membrane extract Matrigel. Matrigel provides a source of extracellular matrix molecules, including laminins and collagen IV, which interact with β1 integrins expressed on organoid cells. Here we describe a single-chain (sc) version of antibody TS2/16 that allosterically activates integrin β1 function in organoids. The addition of monomeric scTS2/16 to organoid medium results in up to a fivefold increase in the yield of all gastrointestinal organoids grown in Matrigel. Moreover, scTS2/16 supports a six- to sevenfold increase in the yield of these organoids when cultured in collagen I hydrogels, both in 3D and 2D. Collagen I is well defined, available in clinical-grade formulations and, when combined with scTS2/16, may support the clinical application of epithelial organoids derived from gastrointestinal tissues and other epithelial sources.

DOI: https://doi.org/10.1038/s41587-025-02874-8