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Staff member

Juan Francisco Abenza Martínez

Staff member publications

Conti, Sefora, Venturini, Valeria, Cañellas-Socias, Adrià, Cortina, Carme, Abenza, Juan F., Stephan-Otto Attolini, Camille, Middendorp Guerra, Emily, Xu, Catherine K., Li, Jia Hui, Rossetti, Leone, Stassi, Giorgio, Roca-Cusachs, Pere, Diz-Muñoz, Alba, Ruprecht, Verena, Guck, Jochen, Batlle, Eduard, Labernadie, Anna, Trepat, Xavier, (2024). Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells Nature Communications 15, 3363

Colorectal cancer (CRC) tumors are composed of heterogeneous and plastic cell populations, including a pool of cancer stem cells that express LGR5. Whether these distinct cell populations display different mechanical properties, and how these properties might contribute to metastasis is poorly understood. Using CRC patient derived organoids (PDOs), we find that compared to LGR5- cells, LGR5+ cancer stem cells are stiffer, adhere better to the extracellular matrix (ECM), move slower both as single cells and clusters, display higher nuclear YAP, show a higher survival rate in response to mechanical confinement, and form larger transendothelial gaps. These differences are largely explained by the downregulation of the membrane to cortex attachment proteins Ezrin/Radixin/Moesin (ERMs) in the LGR5+ cells. By analyzing single cell RNA-sequencing (scRNA-seq) expression patterns from a patient cohort, we show that this downregulation is a robust signature of colorectal tumors. Our results show that LGR5- cells display a mechanically dynamic phenotype suitable for dissemination from the primary tumor whereas LGR5+ cells display a mechanically stable and resilient phenotype suitable for extravasation and metastatic growth.

JTD Keywords:


Kennedy, KE, Abenza, JF, Rossetti, L, Trepat, X, Villoslada, P, Garcia-Ojalvo, J, (2024). Parametric modeling of mechanical effects on circadian oscillators Chaos 34, 013135

Circadian rhythms are archetypal examples of nonlinear oscillations. While these oscillations are usually attributed to circuits of biochemical interactions among clock genes and proteins, recent experimental studies reveal that they are also affected by the cell's mechanical environment. Here, we extend a standard biochemical model of circadian rhythmicity to include mechanical effects in a parametric manner. Using experimental observations to constrain the model, we suggest specific ways in which the mechanical signal might affect the clock. Additionally, a bifurcation analysis of the system predicts that these mechanical signals need to be within an optimal range for circadian oscillations to occur.

JTD Keywords: Circadian rhythm, Clocks, Coherence, Synchronization


Abenza, JF, Rossetti, L, Mouelhi, M, Burgués, J, Andreu, I, Kennedy, K, Roca-Cusachs, P, Marco, S, García-Ojalvo, J, Trepat, X, (2023). Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD Journal Of Cell Biology 222, e202209120

Autonomous circadian clocks exist in nearly every mammalian cell type. These cellular clocks are subjected to a multilayered regulation sensitive to the mechanochemical cell microenvironment. Whereas the biochemical signaling that controls the cellular circadian clock is increasingly well understood, mechanisms underlying regulation by mechanical cues are largely unknown. Here we show that the fibroblast circadian clock is mechanically regulated through YAP/TAZ nuclear levels. We use high-throughput analysis of single-cell circadian rhythms and apply controlled mechanical, biochemical, and genetic perturbations to study the expression of the clock gene Rev-erbα. We observe that Rev-erbα circadian oscillations are disrupted with YAP/TAZ nuclear translocation. By targeted mutations and overexpression of YAP/TAZ, we show that this mechanobiological regulation, which also impacts core components of the clock such as Bmal1 and Cry1, depends on the binding of YAP/TAZ to the transcriptional effector TEAD. This mechanism could explain the impairment of circadian rhythms observed when YAP/TAZ activity is upregulated, as in cancer and aging.© 2023 Abenza et al.

JTD Keywords: activation, dynamics, forces, growth, hippo pathway, liver, platform, time, transcription, Gene-expression


Andreu, I, Granero-Moya, I, Chahare, NR, Clein, K, Molina-Jordan, M, Beedle, AEM, Elosegui-Artola, A, Abenza, JF, Rossetti, L, Trepat, X, Raveh, B, Roca-Cusachs, P, (2022). Mechanical force application to the nucleus regulates nucleocytoplasmic transport Nature Cell Biology 24, 896-905

Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied forces. Such forces can lead to the nuclear translocation of proteins, but whether force controls nucleocytoplasmic transport, and how, remains unknown. Here we show that nuclear forces differentially control passive and facilitated nucleocytoplasmic transport, setting the rules for the mechanosensitivity of shuttling proteins. We demonstrate that nuclear force increases permeability across nuclear pore complexes, with a dependence on molecular weight that is stronger for passive than for facilitated diffusion. Owing to this differential effect, force leads to the translocation of cargoes into or out of the nucleus within a given range of molecular weight and affinity for nuclear transport receptors. Further, we show that the mechanosensitivity of several transcriptional regulators can be both explained by this mechanism and engineered exogenously by introducing appropriate nuclear localization signals. Our work unveils a mechanism of mechanically induced signalling, probably operating in parallel with others, with potential applicability across signalling pathways.; Andreu et al. show that force regulates nucleocytoplasmic transport by weakening the permeability barrier of nuclear pore complexes, affecting passive and facilitated diffusion in different ways.

JTD Keywords: Activation, Inhibitor, Matrix, Mechanotransduction, Nesprins, Nucleoporins, Permeability barrier, Pore complex, Proteins, Transmission


Uroz, Marina, Garcia-Puig, Anna, Tekeli, Isil, Elosegui-Artola, Alberto, Abenza, Juan F., Marín-Llauradó, Ariadna, Pujals, Silvia, Conte, Vito, Albertazzi, Lorenzo, Roca-Cusachs, Pere, Raya, Ángel, Trepat, Xavier, (2019). Traction forces at the cytokinetic ring regulate cell division and polyploidy in the migrating zebrafish epicardium Nature Materials 18, 1015-1023

Epithelial repair and regeneration are driven by collective cell migration and division. Both cellular functions involve tightly controlled mechanical events, but how physical forces regulate cell division in migrating epithelia is largely unknown. Here we show that cells dividing in the migrating zebrafish epicardium exert large cell–extracellular matrix (ECM) forces during cytokinesis. These forces point towards the division axis and are exerted through focal adhesions that connect the cytokinetic ring to the underlying ECM. When subjected to high loading rates, these cytokinetic focal adhesions prevent closure of the contractile ring, leading to multi-nucleation through cytokinetic failure. By combining a clutch model with experiments on substrates of different rigidity, ECM composition and ligand density, we show that failed cytokinesis is triggered by adhesion reinforcement downstream of increased myosin density. The mechanical interaction between the cytokinetic ring and the ECM thus provides a mechanism for the regulation of cell division and polyploidy that may have implications in regeneration and cancer.

JTD


Pardo-Pastor, Carlos, Rubio-Moscardo, Fanny, Vogel-González, Marina, Serra, Selma A., Afthinos, Alexandros, Mrkonjic, Sanela, Destaing, Olivier, Abenza, Juan F., Fernández-Fernández, José M., Trepat, Xavier, Albiges-Rizo, Corinne, Konstantopoulos, Konstantinos, Valverde, Miguel A., (2018). Piezo2 channel regulates RhoA and actin cytoskeleton to promote cell mechanobiological responses Proceedings of the National Academy of Sciences of the United States of America 115, (8), 1925-1930

The actin cytoskeleton is central to many cellular processes involving changes in cell shape, migration, and adhesiveness. Therefore, there is a great interest in the identification of the signaling pathways leading to the regulation of actin polymerization and assembly into stress fibers (SFs). However, to date it is not well understood how the mechanical interactions between cells and their environment activate the assembly of SFs. Here, we demonstrate that the mechanosensitive Piezo2 channel is required to sense physical cues from the environment to generate a calcium signal that maintains RhoA active and the formation and orientation of SFs and focal adhesions. Besides, this Piezo2-initiated signaling pathway has implications for different hallmarks of cancer invasion and metastasis.

JTD Keywords: Mechanotransduction, Calcium signaling, RhoA, Actin stress fibers, Cancer