CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

Molecular Cell, Год журнала: 2023, Номер 83(22), С. 4062 - 4077.e5

Опубликована: Ноя. 1, 2023

Abnormal increases in cell size are associated with senescence and cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the remain unknown. We address this question using CDK4/6 inhibitors, arrest G0/G1 licensed treat advanced HR+/HER2- breast cancer. demonstrate that CDK4/6-inhibited overgrow during G0/G1, causing p38/p53/p21-dependent withdrawal. Cell withdrawal is triggered biphasic p21 induction. first wave caused osmotic stress, leading p38- size-dependent accumulation of p21. inhibitor washout results some entering S-phase. Overgrown experience replication resulting a second promotes G2 or subsequent G1. propose levels integrate signals overgrowth-triggered stresses determine fate. This model explains how hypertrophy can drive why inhibitors have long-lasting effects patients.

Язык: Английский

---

Cell size homeostasis is tightly controlled throughout the cell cycle

PLoS Biology, Год журнала: 2024, Номер 22(1), С. e3002453 - e3002453

Опубликована: Янв. 5, 2024

To achieve a stable size distribution over multiple generations, proliferating cells require means of counteracting stochastic noise in the rate growth, time spent various phases cell cycle, and imprecision placement plane division. In most widely accepted model, is thought to be regulated at G1/S transition, such that smaller than critical pause end G1 phase until they have accumulated mass predetermined threshold, which point proceed through rest cycle. However, based solely on specific checkpoint G1/S, cannot readily explain why with deficient control mechanisms are still able maintain very distribution. Furthermore, model would not easily account for variation during subsequent anticipated G1/S. address questions, we applied computationally enhanced quantitative microscopy (ceQPM) populations cultured human lines, enables highly accurate measurement dry individual throughout From these measurements, evaluated factors contribute maintaining homeostasis any Our findings reveal accurately maintained, despite disruptions normal machinery or perturbations growth. Control generally confined regulation length. Instead imposed lines examined, find coefficient (CV) population begins decline well before transition continues S G2 phases. Among different types tested, detailed response growth differs. general, when it falls below exponential natural increase CV effectively constrained. We both mass-dependent cycle modulation reducing within population. Through interplay coordination 2 processes, emerges. Such previously unappreciated general principles cells. These same regulatory processes might also operative terminally differentiated Further dynamical studies should lead better understanding underlying molecular control.

Язык: Английский

---

Understanding the cell: Future views of structural biology

Cell, Год журнала: 2024, Номер 187(3), С. 545 - 562

Опубликована: Фев. 1, 2024

Determining the structure and mechanisms of all individual functional modules cells at high molecular detail has often been seen as equal to understanding how work. Recent technical advances have led a flush high-resolution structures various macromolecular machines, but despite this wealth detailed information, our cellular function remains incomplete. Here, we discuss present-day limitations structural biology highlight novel technologies that may enable us analyze functions directly inside cells. We predict progression toward cell will involve shift conceptualizing 4D virtual reality using digital twins. These capture segments in highly enriched detail, include dynamic changes, facilitate simulations processes, leading experimentally testable predictions. Transferring biological questions into algorithms learn from existing data explore solutions ultimately unveil

Язык: Английский

---

Mechanical compressive forces increase PI3K output signaling in breast and pancreatic cancer cells

Life Science Alliance, Год журнала: 2025, Номер 8(3), С. e202402854 - e202402854

Опубликована: Янв. 2, 2025

Mechanical stresses, including compression, arise during cancer progression. In solid cancer, especially breast and pancreatic cancers, the rapid tumor growth environment remodeling explain their high intensity of compressive forces. However, sensitivity compressed cells to targeted therapies remains poorly known. cells, pharmacological PI3K inactivation decreased cell number induced apoptosis. These effects were accentuated when we applied 2D compression forces in mechanically responsive cells. Compression selectively overexpression isoforms PI3K/AKT pathway activation. Furthermore, transcriptional inhibition converged control expression an autophagy regulator, GABARAP, whose level was inversely associated with inhibitor under compression. alone blocked flux all tested whereas basal activity restored only non-responsive This study provides direct evidence for role compression-induced mechanotransduction. promotes apoptosis or autophagy, explaining importance survival

Язык: Английский

---

Mechanical interactions between tissue layers underlie plant morphogenesis

Nature Plants, Год журнала: 2025, Номер unknown

Опубликована: Март 26, 2025

Язык: Английский

---

Physical basis of the cell size scaling laws

eLife, Год журнала: 2023, Номер 12

Опубликована: Май 2, 2023

Cellular growth is the result of passive physical constraints and active biological processes. Their interplay leads to appearance robust ubiquitous scaling laws relating linearly cell size, dry mass, nuclear size. Despite accumulating experimental evidence, their origin still unclear. Here, we show that these can be explained quantitatively by a single model size regulation based on three simple, yet generic, defining altogether Pump-Leak model. Based quantitative estimates, clearly map coarse-grained parameters with dominant cellular components. We propose mass density homeostasis arises from between proteins small osmolytes, mainly amino acids ions. Our predicts this naturally fail, both at senescence when DNA RNAs are saturated RNA polymerases ribosomes, respectively, mitotic entry due counterion release following histone tail modifications. same laws, further results osmotic balance envelope large pool metabolites, which dilutes chromatin counterions do not scale during growth.

Язык: Английский

---

Epithelial tissue confinement inhibits cell growth and leads to volume-reducing divisions

Developmental Cell, Год журнала: 2023, Номер 58(16), С. 1462 - 1476.e8

Опубликована: Июнь 19, 2023

Cell proliferation is a central process in tissue development, homeostasis, and disease, yet how regulated the context remains poorly understood. Here, we introduce quantitative framework to elucidate growth dynamics regulate cell proliferation. Using MDCK epithelial monolayers, show that limiting rate of expansion creates confinement suppresses growth; however, this does not directly affect cycle. This leads uncoupling between rates division epithelia and, thereby, reduces volume. Division becomes arrested at minimal volume, which consistent across diverse vivo. nucleus approaches minimum volume capable packaging genome. Loss cyclin D1-dependent cell-volume regulation results an abnormally high nuclear-to-cytoplasmic ratio DNA damage. Overall, demonstrate by interplay regulation.

Язык: Английский

---

Compressive stresses in cancer: characterization and implications for tumour progression and treatment

Nature reviews. Cancer, Год журнала: 2024, Номер 24(11), С. 768 - 791

Опубликована: Окт. 10, 2024

Язык: Английский

---

The uniformity and stability of cellular mass density in mammalian cell culture

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Окт. 12, 2022

Cell dry mass is principally determined by the sum of biosynthesis and degradation. Measurable change in occurs on a time scale hours. By contrast, cell volume can minutes altering osmotic conditions. How changes are coupled fundamental question size control. If were proportional to during growth, would always maintain same cellular density, defined as dividing volume. The accuracy stability against perturbation this proportionality has never been stringently tested. Normalized Raman Imaging (NoRI), measure both protein lipid density directly . Using new technique , we have able investigate response pharmaceutical physiological perturbations three cultured mammalian lines. We find remarkably narrow distribution within cells, that is, significantly tighter than variability or distribution. measured independent cycle. be modulated extracellular osmolytes disruptions cytoskeleton. Yet, surprisingly resistant pharmacological synthesis degradation, suggesting there must some form feedback control homeostasis when altered. such starvation senescence induce significant shifts density. begun shed light how why remains fixed yet sensitive transitions state.

Язык: Английский

---

Volume growth in animal cells is cell cycle dependent and shows additive fluctuations

eLife, Год журнала: 2022, Номер 11

Опубликована: Янв. 27, 2022

The way proliferating animal cells coordinate the growth of their mass, volume, and other relevant size parameters is a long-standing question in biology. Studies focusing on cell mass have identified patterns as function time cycle phase, but little known about volume growth. To address this question, we improved our fluorescence exclusion method measurement (FXm) obtained 1700 single-cell trajectories HeLa cells. We find that, during most cycle, close to exponential proceeds at higher rate S-G2 than G1. Comparing data with mathematical model, establish that cell-to-cell variability arises from constant-amplitude fluctuations steps rather underlying specific rate. hypothesize such ‘additive noise’ could emerge processes regulate adaptation biophysical cues, tension or osmotic pressure.

Язык: Английский

---