 Aritra KunduProgram: Chemical Engineering Advisor: Shelly Peyton, PhD. Education: Indian Institute of Technology Delhi Bachelor of Chemical Engineering (2015) |
Research Summary
Engineering A Synthetic 3D Lung
Breast cancer is the leading cause of cancer-related death in women in industrialized countries. Cure rates reach up to 70% for early stage breast cancer patients, by virtue of effective early detection and current advances in adjuvant systemic therapy. However, metastasis to distant sites causes roughly 90% of cancer-related deaths. Breast cancer cells preferentially metastasize to lung, bone, brain, and liver. Earlier it was suspected that a few genetic markers and signaling pathways might be responsible for the tissue tropism of breast cancer metastasis, but they are not well understood. Hence, a novel approach is being taken where instead of the genetic markers the ECM proteins and their role in altering the matrix and thus, the tumor microenvironment are being studied. Breast cancer relapses are most commonly detected in the lung. According to a clinical study, every 3rd woman who developed metastasis was observed to have metastatic relapse in the lungs, while a definitive cure of breast to lung metastasis is yet to be discovered. The current treatments typically only increase the life span of the patients. Therefore, the lung ECM proteins are being studied to understand their role in creating the metastatic niche and harboring the circulating tumor cells. The most commonly identified cells in the lung ECM are fibroblasts, which are primarily responsible for synthesis of ECM proteins such as types I and III collagen, elastin, and fibronectin and ECM remodeling. Besides biochemical properties of the ECM, tissue stiffness is an essential property that maintains the tissue microenvironment. Many important cellular processes such as migration, proliferation, and differentiation are regulated by both the protein composition and the stiffness of the tissue. A study by the Peyton lab measuring the elasticity modulus of lung tissue has produced moduli for multiple methods, such as cavitation rheology (6.1±1.6 kPa), small amplitude oscillatory shear (3.3±0.5 kPa), and micro-indentation (1.4±0.4 kPa). In this study, I will mimic several aspects of the complex 3D microenvironment in the lung using an engineered polyethylene glycol-maleimide (PEG-MAL) 3D hydrogel system, where the concentrations of the peptides and the mechanical properties can be independently tuned. I have developed an algorithm to screen the ECM proteins quantitatively. The primary filters that I have used for screening the proteins are – (1) the proteins need to be integrin binding to facilitate the cells to bind with them using the cell integrins, and (2) the proteins need to be degradable by matrix metalloproteinases (MMPs) to facilitate cell migration by degradation of the ECM. The most integral proteins have been identified and the required peptide sequences (integrin binding and MMP degradable peptides) present in these proteins will be synthesized in collaboration with the Perry group. I will investigate the optimal stiffness of the mimic by preparing them at different conditions, such as varying macromer weight percentage, varying macromer arm length etc. The mechanical characterization of the lung tissue as well as the hydrogels will be done in collaboration with the Crosby lab in the Department of Polymer Science and Engineering. After preparation of the synthetic 3D lung mimic, I will use it to understand how an aggressive (MDA-MB 231) and a non-aggressive (BT-474) metastatic breast cancer cell line alter the lung ECM to create a favorable microenvironment for breast-to-lung metastasis.