Mission
The Nia Lab’s overall research goal is to combine the principles of engineering and physical sciences with molecular biology in health and disease to answer key questions in normal lung physiology and in lung diseases, such as cancer and infection. We aim to leverage in vivo platforms as well as our ex vivo crystal ribcage platforms to probe lung biology from single cell to whole-organ, and in the context of cancer, discover new vulnerabilities of cancer cells, and propose new treatment strategies. Our overall questions are:
- How do lung mechanics and dynamic functions affect the physical forces (stresses) in the tumor microenvironment during cancer development, progression, and treatment?
- How is immune activity modulated by dynamic lung function during disease and injury?
- How are circulation and respiration coupled in the lung at the single capillary scale?
We are a highly multi-disciplinary lab. To tackle the above problems, we utilize multiple approaches including multi-scale lung mechanobiology using the crystal ribcage, intravital and in vitro imaging, cell biology, mathematical modeling, and artificial intelligence.
Probing the whole, functional mouse lung via “crystal ribcage”
Understanding the the dynamics of lung disease pathogenesis and treatment response requires probing the lung at cellular resolution in real-time. We introduce the crystal ribcage: a transparent ribcage that (i) allows multiscale optical imaging of the lung in health and disease from whole-organ to single cell, (ii) enables modulation of lung biophysics and immunity through intravascular, intrapulmonary, intraparenchymal, and optogenetic interventions, and (iii) preserves the 3-D architecture, air-liquid interface, cellular diversity, and respiratory-circulatory functions of the lung. Utilizing these unprecedented capabilities on murine models of primary and metastatic lung tumors, respiratory infection, pulmonary fibrosis, emphysema, and acute lung injury we probed how disease progression remodels the respiratory-circulatory functions at the single alveolus and capillary levels.
In cancer, we have identified the earliest stage of tumorigenesis that compromises alveolar and capillary functions, a key state with consequences on tumor progression and treatment response. In pneumonia, we mapped mutual links between the recruited immune cells and the alveolar-capillary functions. We found that neutrophil migration is strongly and reversibly responsive to vascular pressure with implications for understanding of how lung physiology, altered by disease and anatomical location, affects immune cell activities. The crystal ribcage and its broad applications presented here will facilitate further studies of real-time remodeling of the alveoli and capillaries during pathogenesis of nearly any pulmonary disease, leading to the identification of new targets for treatment strategies.
Physical vs. biological microenvironment at the interface of tumor-host tissue
Biological and physical interactions at the interface of tumor and host tissue play critical roles in progression and invasion of tumors, and, importantly, in tumor immunity – as immune cell infiltration is often localized at the invasive margin of the tumors, limiting the ability to mount a significant response against the cancer cells. Most tumors experience physical resistance to growth from the surrounding tissue in the form of compressive forces, which is equally applied on the surrounding normal tissue at the tumor-brain interface. This physical resistance to growth appears to be higher in tumors with a distinct tumor-host border (termed “nodular”; largely the case in metastatic brain tumors), compared to tumors where cancer cells diffuse into the surrounding tissue (termed “infiltrative”; largely the case in recurrent glioblastoma). We propose that the compressive force exerted by tumors on the normal brain is an important player in the cell death and damage in the surrounding normal tissue, and influence the progression and invasion of the tumor, and eventually the overall survival of the patient. In contrast to the conventional approaches, which focus on the cancer cells, we focus on the mechanisms leading to cell death in the host organ, the eventual cause of death in most cancers.
By focusing on the host organ surrounding the tumor, which is damaged by physical forces from tumors, we will uncover new pathways and targets underlying cancer progression and invasion. This will allow me to design new strategies to overcome the damage in surrounding tissue, and improve patients’ survival.
Developing novel in vitro and in vivo experimental systems to model, stimulate, and quantitatively characterize the biophysical microenvironment of tumors
Just as transgenic mouse models have had an immense impact on dissecting the biological features in cancer research, appropriate experimental and mathematical models that delineate the physical features from biological factors are essential to mechanistically study the role of the tumor’s physical microenvironment. However, the in vivo experimental systems and measurement techniques to model, stimulate, and measure physical abnormalities in tumors are limited or non-existent in many cases. Utilizing my extensive expertise in establishing and analyzing mouse models of cancer, my experience in technology development, and my knowledge of cancer biophysics, Nia Lab proposes the development of multiple technologies to provide appropriate models and tools for cancer researchers at the interface of physical sciences and oncology.
By developing novel technologies, we will provide the essential tools and model systems to mechanistically study the role of physical forces in cancer biology, in both in vitro and in vivo settings. These models and tools are equally applicable in other fields, in which physical forces play a key role, such as morphogenesis, tissue engineering, and health disorders such as fibrosis, concussion, and contusion.