Engineering approaches for understanding mechanical memory in cancer metastasis

APL Bioengineering, Год журнала: 2024, Номер 8(2)

Опубликована: Апрель 10, 2024

Understanding cancer metastasis is crucial for advancing therapeutic strategies and improving clinical outcomes. Cancer cells face dynamic changes in their mechanical microenvironment that occur on timescales ranging from minutes to years exhibit a spectrum of cellular transformations response these cues. A facet this adaptive the concept memory, which mechanosensitive cell behavior function persists even when cues are altered. This review explores evolving landscape during metastasis, emphasizing significance memory its influence behavior. We then focus engineering techniques being utilized probe cells. Finally, we highlight promising translational approaches poised harness new therapies, thereby frontiers bioengineering applications research.

Язык: Английский

---

Tumor Biomechanics Alters Metastatic Dissemination of Triple Negative Breast Cancer via Rewiring Fatty Acid Metabolism

Advanced Science, Год журнала: 2024, Номер 11(23)

Опубликована: Апрель 11, 2024

Abstract In recent decades, the role of tumor biomechanics on cancer cell behavior at primary site has been increasingly appreciated. However, effect latter stages metastatic cascade, such as seeding secondary sites and outgrowth remains underappreciated. This work sought to address this in context triple negative breast (TNBC), a type known aggressively disseminate all disease progression. Using mechanically tuneable model systems, mimicking range stiffness's typically found within tumors, it is that, contrary expectations, cells exposed softer microenvironments are more able colonize tissues. It shown that heightened survival driven by enhanced metabolism fatty acids TNBC microenvironments. demonstrated uncoupling cellular mechanosensing through integrin β1 blocking antibody effectively causes stiff primed behave like their soft counterparts, both vitro vivo. first show may be contributing changes outcome imprinting greater metabolic flexibility conferring discrete advantages.

Язык: Английский

---

Mechanical forces amplify TCR mechanotransduction in T cell activation and function

Applied Physics Reviews, Год журнала: 2024, Номер 11(1)

Опубликована: Янв. 19, 2024

Adoptive T cell immunotherapies, including engineered receptor (eTCR) and chimeric antigen (CAR) have shown efficacy in treating a subset of hematologic malignancies, exhibit promise solid tumors, many other potential applications, such as fibrosis, autoimmunity, regenerative medicine. While immunoengineering has focused on designing biomaterials to present biochemical cues manipulate cells ex vivo vivo, mechanical that regulate their biology been largely underappreciated. This review highlights the contributions force several receptor–ligand interactions critical function, with central focus TCR–peptide-loaded major histocompatibility complex (pMHC). We then emphasize role forces (i) allosteric strengthening TCR–pMHC interaction amplifying ligand discrimination during recognition prior activation (ii) extracellular matrix. describe approaches design eTCRs, CARs, exploit TCR mechanosensitivity order potentiate manufacturing function adoptive immunotherapy.

Язык: Английский

---

Cellular mechanical memory: a potential tool for mesenchymal stem cell-based therapy

Stem Cell Research & Therapy, Год журнала: 2025, Номер 16(1)

Опубликована: Март 31, 2025

Abstract Recent studies have shown that mechanical properties such as extracellular matrix stiffness, fluid flow, weight loading, compression, and stretching can affect cellular functions. Some examples of cell responses to could be the migration cancer cells from rigid soft surfaces or differentiation fibroblasts into myofibroblasts. Cellular changes modify insertion proteins in (ECM), causing an increase tissue stiffness with functional consequences. In general, physical factors any kind phenotype culture conditions vivo tissues. Cells sense stimuli by applying force restructuring their shape functions response resistance stimuli. Furthermore, triggers develop a “memory” for altering plasticity adaptation. This phenomenon is called memory (CMM), singular feature mesenchymal stem (MSCs). Controlled targeting CMM may resolve scarcity viable needed based therapy (CBT) implement concerning research, fibrosis, senescence. review focusses on mesodermal lineage, MSCs, chondrocytes, role potential target CBT.

Язык: Английский

---

Mechanomemory of nucleoplasm and RNA polymerase II after chromatin stretching by a microinjected magnetic nanoparticle force

Cell Reports, Год журнала: 2024, Номер 43(7), С. 114462 - 114462

Опубликована: Июль 1, 2024

Increasing evidence suggests that the mechanics of chromatin and nucleoplasm regulate gene transcription nuclear function. However, how sense respond to forces remains elusive. Here, we employed a strategy applying directly cell via microinjected 200-nm anti-H2B-antibody-coated ferromagnetic nanoparticle (FMNP) an anti-immunoglobulin G (IgG)-antibody-coated or uncoated FMNP. The behaved as viscoelastic gel-like structure was softer at loading frequencies 0.1–5 Hz. Protein diffusivity chromatin, nucleoplasm, RNA polymerase II (RNA Pol II) activity were upregulated in chromatin-stretching-dependent manner stayed for tens minutes after force cessation. Chromatin stiffness increased, but mechanomemory duration decreased, with substrate stiffness. These findings may provide mechanism upregulation have implications on functions.

Язык: Английский

---

How to Keep Myofibroblasts under Control: Culture of Mouse Skin Fibroblasts on Soft Substrates

Journal of Investigative Dermatology, Год журнала: 2024, Номер 144(9), С. 1923 - 1934

Опубликована: Июль 29, 2024

Язык: Английский

---

Cell–matrix feedback controls stretch-induced cellular memory and fibroblast activation

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(12)

Опубликована: Март 18, 2025

Mechanical stretch can activate long-lived changes in fibroblasts, increasing their contractility and initiating phenotypic transformations. This activation, critical to wound healing procedures such as skin grafting, increases with mechanical stimulus for cells cultured two-dimensional but is highly variable three-dimensional (3D) tissue. Here, we show that static of 3D tissues either increase or decrease fibroblast activation depending upon recursive cell–extracellular matrix (ECM) feedback demonstrate control this through integrated vitro mathematical models. ECM viscoelasticity, signaling dynamics, cell mechanics combine yield a predictable, nonmonotonic, relationship between long-term activation. Results determine how retain memory have direct implications improving outcomes grafting procedures.

Язык: Английский

---

Mechanomemory after short episodes of intermittent stresses induces YAP translocation via increasing F-actin

APL Bioengineering, Год журнала: 2025, Номер 9(2)

Опубликована: Апрель 18, 2025

How forces and mechanics influence regulate living cells remains elusive. Mechanomemory, the response to a mechanical perturbation that persists after is removed, believed be key understanding impact of on cell functions. Recently, our lab has demonstrated presence mechanomemory lasts for ∼30 min applying external stress via integrins. Herein, we test hypothesis applications short intermittent episodes exert long-term effects process mechanotransduction. An Arginine-Glycine-Aspartic acid (RGD)-peptides-coated 4-μm magnetic bead was bound integrin receptors apply stresses surface Chinese Hamster Ovary cell. At same magnitude frequency (15 Pa at 0.3 Hz), multiple cycles externally applied 2 or 10 with 15 intervals, 30 plus load-free interval increased nuclear translocation YAP (Yes-Associated Protein) Ctgf gene expression, like by 60 continuous stress, but did not. Short durations F-actin in cytoplasm, which coincided elevated translocation. Inhibiting actomyosin not microtubules blocked stress-induced nucleus. Cells soft substrates translocate more than stiff load release. These results highlight stresses-induced cytoplasmic biological functions

Язык: Английский

---

Confinement primes cells for faster migration by polarizing active mitochondria

Nanoscale Advances, Год журнала: 2023, Номер 6(1), С. 209 - 220

Опубликована: Ноя. 22, 2023

Mechanical cues in the tumor microenvironment interplay with internal cellular processes to control cancer cell migration. Microscale pores present tissue confer varying degrees of confinement on migrating cells, increasing matrix contact and inducing cytoskeletal rearrangement. Previously, we observed that increased collagen significantly migration speed cell-induced strains within matrix. However, effects this future are not fully understood. Here, use a microtrack platform determine effect priming MDA-MB-231 cells for fast We show through confined track results accumulation migratory machinery, including actin active mitochondria, front breast cells. By designing microtracks allow first navigate region high confinement, then low assessed whether changes behavior. Indeed, maintain their attained even after exiting indicating memory previous fuel Active mitochondria location at leave confinement. Furthermore, knocking out vinculin disrupt focal adhesions disrupts mitochondrial localization seen upon release from Together, these data suggest may facilitate post-confinement. better understanding how contributes migration, can identify potential therapeutic targets inhibit metastasis.

Язык: Английский

---

A high throughput cell stretch device for investigating mechanobiology in vitro

APL Bioengineering, Год журнала: 2024, Номер 8(2)

Опубликована: Июнь 1, 2024

Mechanobiology is a rapidly advancing field, with growing evidence that mechanical signaling plays key roles in health and disease. To accelerate mechanobiology-based drug discovery, novel vitro systems are needed enable perturbation of cells format amenable to high throughput screening. Here, both stretch device 192-well silicone flexible linear plate were designed fabricated meet technology needs for cell stretch-based applications. demonstrate the utility automation screening, dispensing, liquid handling, content imaging, sequencing platforms employed. Using this system, an assay was developed as biological validation proof-of-concept readout A mechano-transcriptional response characterized using focused gene expression profiling measured by RNA-mediated oligonucleotide Annealing, Selection, Ligation Next-Gen sequencing. articular chondrocytes, signature containing responsive genes relevant cartilage homeostasis disease identified. The possibility integration other sensitive types (e.g., cardiovascular, airway, bladder, gut, musculoskeletal), combination alternative phenotypic readouts protein expression, proliferation, or spatial alignment), broadens scope allows wider adoption research community. This stress fills unmet need screening support discovery areas.

Язык: Английский

---