CAREER: Connecting biology and mechanics through a multiscale modeling of pubertal mammary gland development

This research will advance our understanding of the mechanism that governs the emergence of complex biological networks. It proposes novel approaches for combining laboratory experiments and multiscale mathematical modeling to characterize branching morphogenesis in the mammary gland. Branching morphogenesis is a process by which the female mammary gland develops its tree-like structure during puberty.

It governs the formation of other tree-like organs such as the lungs, salivary gland, and kidney. Defects in branching morphogenesis can lead to hypertension, chronic kidney failure, and poor lung function. Mechanisms that control branching morphogenesis are circumvented or altered during the development and progression of breast cancer.

Understanding the mechanisms that generate branched organs may identify novel ways to treat breast cancer, regenerate organ function, or design artificial organs to combat diseases. At puberty, branching morphogenesis generates an extensive network of mammary gland epithelium ducts. The epithelium ductal network is connected at its base to the nipple and plays a key role in milk synthesis and secretion for neonates.

Molecular and mechanical factors in the tissue environment are important for normal branching morphogenesis. Majority of the research in this area has focused on identifying key molecular factors and the mechanisms by which they regulate branching morphogenesis. How mechanical signaling regulates branching morphogenesis remains largely unknown.

The mathematical models proposed in this research will contribute to bridging this gap. This project will build novel multiscale mathematical models to predict how the interactions between mechanical and cellular signaling regulate the formation of the mammary ductal network.

Branching morphogenesis occurs through two stages: the first stage is via successive rounds of elongation and splitting of the tip of individual ducts (i.e., tip bifurcation) and the second stage is via budding along the sides of existing ducts (i.e., side branching). Increased extracellular matrix (ECM) stiffness is known to increase the sites for epithelium ductal branch initiation.

However, how the mechanical signaling originating from the ECM affects branch elongation, tip bifurcation and side branching is not fully understood. This project will (1) combine optimal transport theory, agent-based models, and data from laboratory experiments to predict how interactions between ECM and epithelium cells regulate ductal branch elongation and tip bifurcation in the mammary gland, (2) apply topological data analysis and multifractal analysis to predict the role of tensional force and ECM stiffness on ductal tip bifurcation and side branching in the mammary gland.

Findings from this research will improve our understanding of how biomechanical forces affect ductal network formation. This CAREER project will contribute to the training of undergraduate and graduate students at San Diego State University (SDSU), a Hispanic Serving Institution. It will integrate mathematical biology research activities in the undergraduate curriculum at SDSU and train students early in their career to approach scientific inquiry in a way that crosses scientific disciplines.

Furthermore, this project will provide a summer workshop to guide local teachers-leaders in creating teaching modules that integrate quantitative research and foster critical thinking in high school students in high-need urban schools.

This award is jointly funded by the MPS-DMS-Mathematical Biology program, BIO-MCB-Cellular Dynamics and Function program, and MPS-PHY-Physics of Living Systems (PoLS) program.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.