Elucidating the role of tissue biophysics in organ colonization

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Our research aims to unravel the biophysical principles governing cancer metastasis, a critical challenge in oncology. Current treatments are often ineffective against emergent lesions, highlighting the need to understand how cancer cells target and colonize specific organs. While biophysical traits like viscoelasticity and cell adhesion are known to influence cancer progression, their interplay with organotropism is not fully understood, particularly due to the limitations of murine models in dissecting the physical microenvironment's role. Our program addresses this by developing a versatile platform for studying metastatic cells and their dynamic microenvironments. Our central hypothesis posits that tumor cells must adapt to mechanical and topographical challenges to establish new metastatic sites. We utilize a cutting-edge biomimetic 3D culture system and optical techniques like Optical Trap, offering a more physiologically relevant environment than traditional 2D cultures. Additionally, we developed a human metastasis model leveraging larval zebrafish for ethical, efficient, and rapid preclinical validation. Our methodologies include intravital microscopy for real-time cellular dynamics and sophisticated mechanical mapping for precise quantification of the cellular microenvironment. These multimodal approaches provide sub-cellular resolution phenotyping of cell behavior in both 3D cultures and living animals, allowing us to dissect the role of physical properties like stiffness, viscoelasticity, and interstitial fluid flow in organ-targeting tropism. Recent findings demonstrate that biophysical cues regulate organotropic spread in zebrafish. We've also shown that integrins and motor proteins, through transcriptional regulation of cell sensing machinery, are crucial for cell exit and adaptation during organ colonization. Key Findings: a) Dynamic Tuning of Mechanical Properties During Organ Colonization: We observed that cancer cells become softer and more liquid-like upon exiting the vasculature, facilitating initial passage. However, they stiffen and become more solid-like after infiltrating the new organ, which may be vital for survival and proliferation. This dynamic change was conserved across human breast and melanoma cell lines and patient tissues. Our high-throughput analysis of patient samples further revealed that external hydrodynamic forces in capillary mimetics regulate cancer cell mechanical properties, indicating that blood flow actively shapes the mechanics of circulating tumor cells and their metastatic potential. These findings suggest that disseminated cancer cells exhibit a continuous and adaptable landscape of mechano-phenotypes. b) Transcriptional Regulation of Mechanical Phenotype Conserved Across Different Cancers: Our investigations unveiled a crucial YAP-mediated mechanical phenotype essential for extravasation of human breast and melanoma cells (immortalized and primary) in vivo. Specifically, YAP translocation from the nucleus to the cytoplasm softens cells and increases their deformability. While these softer cells can home to the brain, they ultimately fail to extravasate. Reducing mechanical heterogeneity within cancer cell populations significantly curtails extravasation, highlighting the therapeutic potential of targeting mechanical adaptability. This dynamic mechanical landscape is not solely intrinsically programmed but modulated by YAP-mediated mechanosensing of external hydrodynamic flow. Contrary to the widely accepted postulate that softer cells are more invasive, our results suggest a more complex interplay of mechanical properties and nuclear dynamics, with nuclear repositioning being equally critical for cellular entrance into tissue. This nuanced understanding is crucial for developing targeted strategies to prevent metastatic spread. This research significantly advances our understanding of the biophysical cues driving cancer metastasis, opening new avenues for therapeutic interventions targeting the mechanical adaptability of cancer cells, irrespective of cancer type. Future research will explore the intricate relationship between mechano-genetic regulation and organ-specific colonization. A critical question remains: is this precise regulation pre-programmed at the primary tumor site, or does it dynamically emerge within a clonal population in response to the unique mechanical and biochemical pressures of a distant microenvironment? To address this, we are currently simulating mechanical cues to prime cells based on our in vivo measurements. Ultimately, understanding these mechano-genetic feedback loops is crucial for developing novel therapeutic strategies to prevent metastatic progression.