Badri Narayanan Narasimhan

Hormone receptor positive (HR+) breast cancer is the most common breast cancer subtype globally and remains a leading cause of cancer-related death in women. Black women diagnosed HR+ breast cancer experience significantly worse outcomes than White women, a disparity that persists even after accounting for factors such as healthcare access and educational attainment. Understanding the biological mechanisms underlying these differences has been limited by the underrepresentation of Black patients in genomic datasets. To address this gap, we generated an HR+ breast cancer transcriptomic dataset enriched for Black patients while controlling for access to healthcare and education level. Tumors from Black women showed enrichment of tumor microenvironment-related signatures, including increased collagen deposition and prognostically unfavorable T-cell landscapes. Data from in vitro and in vivo experimental models showed that race-aligned collagen deposition patterns were driven, at least in part, by tumor cell-intrinsic signaling and promoted metastatic phenotypes associated with poorer outcomes. Further analysis of the patient transcriptomic dataset revealed that unfavorable T-cell signatures previously attributed to race or ancestry were more strongly associated with poverty burden. Across multiple independent datasets, STAT4 emerged as a potential master regulator of this poverty-associated immune phenotype. Collectively, these findings suggest that molecular features of breast tumors are shaped by both biological and structural factors linked to self-identified race and socioeconomic disadvantage. These results demonstrate that integrating social determinants of health with molecular analyses can reveal mechanisms contributing to cancer outcome disparities and provide a foundation for the development of more effective and equitable precision oncology approaches.

Single cells confined by the extracellular matrix can exhibit rotational motion, yet the physical mechanisms underlying its onset and persistence remain unclear. Here, we address this gap with a cellular phase field model that couples cell deformation, cell polarization governed by stochastic excitable dynamics, and confinement. We identify the confinement strength as a bifurcation parameter determining three regimes: Strong confinement prevents rotation through spatial constraints, intermediate confinement induces stochastic transitions between rotating and nonrotating states, and weak confinement allows persistent rotations. For the intermediate regime, we develop a semi-Markovian renewal process framework that characterizes the stochastic dynamics through dwell time statistics, transition probabilities, and first-passage times. For the weak confinement regime, we reveal that a mechanochemical feedback enables coherent rotations despite internal noise through the reduction of local excitability mediated by mechanical contraction. We formalize this feedback analytically using Kramers escape theory. Experiments on epithelial MCF10A cells in Matrigel demonstrate three types of cell dynamics that recapitulate those observed in each confinement regime. Our results establish a theoretical approach for understanding single-cell rotations under confinement, with implications for controlling single-cell dynamics by tuning extracellular matrix properties.

In native extracellular matrices (ECM), cells utilize matrix metalloproteinases (MMPs) to degrade and remodel their microenvironment. Accordingly, synthetic matrices have been engineered to permit MMP-mediated cleavage, facilitating cell spreading, migration, and interactions. However, the interplay between matrix degradability and mechanical properties remains underexplored. We hypothesized that MMP activity induces immediate mechanical alterations in the ECM, which are subsequently detected by cells. We observed that both fibrillar collagen and synthetic degradable matrices exhibit enhanced stress relaxation following MMP exposure. Cells responded to these variations in relaxation by modulating their spreading and focal adhesions. Furthermore, we demonstrated that stress relaxation and cell spreading can be precisely controlled through the rational design of matrix degradability. These findings establish a fundamental link between matrix degradability and stress relaxation, with potential implications for a broad spectrum of biological applications.

Collagenolytic degradation is a process fundamental to tissue remodeling. The microarchitecture of collagen fibril networks changes during development, aging, and disease. Such changes to microarchitecture are often accompanied by changes in matrix degradability. In a matrix, the pore size and fibril characteristics such as length, diameter, number, orientation, and curvature are the major variables that define the microarchitecture. In vitro, collagen matrices of the same concentration but different microarchitectures also vary in degradation rate. How do different microarchitectures affect matrix degradation? To answer this question, we developed a computational model of collagen degradation. We first developed a lattice model that describes collagen degradation at the scale of a single fibril. We then extended this model to investigate the role of microarchitecture using Brownian dynamics simulation of enzymes in a multi-fibril three dimensional matrix to predict its degradability. Our simulations predict that the distribution of enzymes around the fibrils is non-uniform and depends on the microarchitecture of the matrix. This non-uniformity in enzyme distribution can lead to different extents of degradability for matrices of different microarchitectures. Our simulations predict that for the same enzyme concentration and collagen concentration, a matrix with thicker fibrils degrades more than that with thinner fibrils. Our model predictions were tested using in vitro experiments with synthetic collagen gels of different microarchitectures. Experiments showed that indeed degradation of collagen depends on the matrix architecture and fibril thickness. In summary, our study shows that the microarchitecture of the collagen matrix is an important determinant of its degradability.

Collagenolytic degradation is a process fundamental to tissue remodeling. The microarchitecture of collagen fibril networks changes during development, aging, and disease. Such changes to microarchitecture are often accompanied by changes in matrix degradability. In vitro , collagen matrices of the same concentration but different microarchitectures also vary in degradation rate. How do different microarchitectures affect matrix degradation? To answer this question, we developed a computational model of collagen degradation. We first developed a lattice model that describes collagen degradation at the scale of a single fibril. We then extended this model to investigate the role of microarchitecture using Brownian dynamics simulation of enzymes in a multi-fibril three dimensional matrix to predict its degradability. Our simulations predict that the distribution of enzymes around the fibrils is non-uniform and depends on the microarchitecture of the matrix. This non-uniformity in enzyme distribution can lead to different extents of degradability for matrices of different microarchitectures. Our model predictions were tested using in vitro experiments with synthesized collagen gels of different microarchitectures. Experiments showed that indeed degradation of collagen depends on the matrix architecture and fibril thickness. In summary, our study shows that the microarchitecture of the collagen matrix is an important determinant of its degradability.

Orientational control of anisotropic plasmonic nanoparticles is an attractive proposition to generate dynamic plasmonic responses. Particularly, the use of light as a stimulus to modulate the orientation is extremely useful owing to its spatiotemporal operative ability. This work showcases a light‐mediated approach to tune the orientational features of gold nanorods in DNA‐engineered hydrogel materials. The strategy relies on the use of visible‐light‐induced photothermal effects to cause deformation of the hydrogel matrix, resulting in temperature‐controlled polarization‐dependent optical responses whose anisotropy features are highly adaptive to the nature of DNA crosslinks. The visible‐light‐mediated approach showcased here can open novel avenues to create dynamic light‐responsive materials with reconfigurable plasmonic responses.