Metastasis remains the primary driver of cancer-related mortality. To spread, cancer cells escape the primary tumor site, traverse heterogeneous tissues and the extracellular matrix (ECM), evade the immune system, and establish secondary tumor sites. Throughout this journey, cells constantly interact with a microenvironment that mechanically resists, relaxes, and remodels in response to force. These mechanical interactions shape how cells adhere, generate traction, and preserve structural integrity, thereby influencing the trajectory of disease progression.
In this talk, I present our work across scales to understand how mechanics regulates cell migration, immune dynamics, and tumor evolution, systematically combining theory and experiments. At the single-cell level, we demonstrate that the time-dependent properties of the ECM modulate cancer cell migration patterns and immune cell dynamics. By altering the lifetimes of cell-matrix adhesions, matrix viscoelasticity drives a transition from sub-diffusive to super-diffusive migration, fundamentally changing how cancer cells navigate their microenvironment. Next, we explore how immune-synapse mechanics is modulated by the ECM mechanical properties. We show that the interplay between receptor engagement and integrin-mediated adhesions regulates force generation, spreading, and downstream signaling in T cells.

Moving to the multicellular scale, we address the mechanics of the tumor as a collective system. We introduce a mechano-electro-osmotic framework to show how metabolic gradients and ion transport drive osmotic swelling. This process generates a residual stress in solid tumors, producing distinct spatial patterns in cell morphology. We corroborate these predictions with experiments across multiple cancer cell systems, spanning in vitro and patient-derived tumor models, providing a plausible physical pathway linking solid stress to localized DNA damage and genomic instability within tumors.

Building on these mechanistic insights, we turn to the nucleus, where mechanical cues can reshape chromatin organization and gene regulation. I will briefly discuss our ongoing work developing multimodal generative AI tools that integrate chromatin conformation, chromatin accessibility, and gene expression to learn shared representations of genome organization. This framework provides an integrated view of chromatin architecture and a quantitative window into the physical principles that shape it.
Together, these studies reveal how mechanical constraints couple to core cellular processes across scales, from adhesion-mediated migration and immune synapse function to stress generation in multicellular tumors. More broadly, they point to general physical principles by which cells sense, transmit, and adapt to forces within living materials, shaping disease progression and therapeutic response.