MERIT Award Recipient: Mina J. Bissell, Ph.D.
Definition of Microenvironment in Breast Cancer
All the cells in an organism have the same genetic material. The Bissell laboratory therefore wanted to learn the basis of organ- and tissue-specificity, i.e. how an organ such as the mammary gland (also referred to as breast in humans) "knows"' to be normal, and what goes wrong when it develops into breast cancer. Dr. Bissell was one of the first to propose and elucidate the important signaling role of the extracellular-matrix (ECM)—the large molecules that are outside the cells and provide many functions for the cells and organs. She also recognized the crucial role of both the microenvironment surrounding each tissue and organ, and the 3-dimensional tissue structures, as factors that determine tissue-specificity in normal differentiation and in cancer.
Together with their collaborators, the Bissell lab has developed unique and versatile 3-dimensional "organotypic" in vitro models for mammary glands from both mice and women that can be used to rapidly distinguish normal and malignant cells. The Bissell lab has shown also that signaling pathways are integrated and "interpreted" by cells differently in 3D vs. 2D in vitro models, and that the 3D models are a much better surrogate for animals than 2D cultures. These models and experimental assays/techniques now are much-appreciated and widely used in basic research as well as in drug testing.
Over the last three decades, through an imaginative blend of cell and molecular biology, the Bissell laboratory has utilized these experimental models to identify the critical components of ECM signaling, including a number of its key receptors that regulate mammary-specific genes. Since the mammary gland (like all tissues and organs) is composed of multiple cell types, and since the Bissell laboratory is interested in understanding not only cell biology but also tissue/organ and cancer biology, they began a long-term collaboration with the laboratory of Dr. Petersen in Denmark, who is an expert in human breast biology. The overall goal of this on-going MERIT Award project is to understand the interactions and the roles of myoepithelial cells (MEPs), which surround the luminal epithelial cells (LEPs) of the mammary gland.
The Bissell/Petersen laboratories have shown that MEPs play a crucial role in keeping the LEPs functional and in proper orientation (polarity) for secretion of milk and other proteins. However, both MEPs and an important ECM molecule, laminin 111 (LN1), are lost as breast cancer progresses. As a result of this MEP and LN1 loss, and the subsequent loss of correct signaling to the LEPs, the LEPs gradually lose their polarity, become disorganized, and become malignant. Dr. Bissell has applied these findings by providing aberrant LEPs with signals that could replace the role of MEPs, and demonstrating that the LEPs can re-acquire proper polarity.
Her laboratory has demonstrated as well that even breast carcinoma cells harboring many genetic alterations can still "revert" to a normal phenotype both in 3D cultures and in vivo when they are manipulated epigenetically to reestablish proper tissue polarity. These key findings could shed light on why tumor cells become dormant and on what could "awaken" them to become malignant again and become metastatic. Collectively, the experimental strategies to be utilized in this research program will address how different cell types of a tissue interact to maintain the integrity of the organ, and how this information could be used for prevention, prognosis and treatment of breast cancer.