Principal Investigator Maureen Lynch and Co-Principal Investigator Yahya Modarres-Sadeghi of our Mechanical and Industrial Engineering Department have received a three-year, $425,000 National Science Foundation award for a project entitled “Mechano-regulation of bone metastatic cancer: linking cell strain to cell function.” Their research is aimed at relieving one of the most deadly problems related to the epidemic of cancer in modern society: cancers metastasizing into the bones. See NSF description of grant.
The main issue addressed by this project, as the two researchers explain, is that the skeleton is the preferred site for metastasis in many cancers, including breast, prostate, lung, and kidney. The spread of metastatic cancer to the skeleton is common, yet incurable. The goal of this project is to define for the first time how the mechanical signals arising from physical activity, which are the primary regulator of bone cell function, affect the bone metastatic cells that are exposed to these same signals.
“After metastasis occurs, patient prognosis dramatically declines due to severe skeletal-related complications, including bone destruction,” say Lynch and Modarres-Sadeghi. “Mechanical signaling, which results from physical activity imparting forces on the skeleton, is inherent to the bone microenvironment and is critical for healthy bone remodeling. Though metastatic cancer cells are exposed to these signals when they arrive in the skeleton, their role in metastasis in unclear.”
There are two reasons for this gap in our knowledge, the researchers say. Firstly, in vitro studies of bone metastatic cancer typically exclude applied mechanical forces. Secondly, the cellular deformations that arise under imposed mechanical forces are unknown.
As the two researchers add about the function of mechanical signaling, “In the context of bone metastasis, we know virtually nothing. Therefore, mechanically-regulated pathways represent a vast collection of untapped potential therapeutic targets.”
The researchers advise that their study will reveal fundamental mechanistic information about biophysical regulation of bone metastatic cancer cells and will facilitate the creation of a mechano-regulatory algorithm that not only links metastatic cancer cell function and cellular deformations, but may also lead to predicting metastatic cancer cell phenotypes in the skeleton given specific mechanical stimuli.
Lynch and Modarres-Sadeghi will focus much of their research on breast cancer because, as they explain, roughly three in four patients with advanced breast cancer develop incurable bone metastases. Once bone metastasis occurs, the lesions put patients at deadly risk for suffering skeletal related events, such as nerve compression, severe bone pain, fracture, and hypercalcemia of malignancy, the last of which is accompanied by the poorest prognosis (median of six weeks survival).
The researchers say that, once ensconced in the bones, metastatic tumor cells interrupt the normal bone remodeling process and initiate bone destruction to release vital growth factors from the bone matrix that literally “feed” the tumor cells. Currently, the standard of care is drugs that merely slow metastatic progression, and do not recover lost bone. The researchers believe that additional factors and cell types are likely promoting bone metastasis, highlighting a lack of fundamental understanding of the mechanisms that underlie bone metastatic tumor initiation and progression.
As Lynch and Modarres-Sadeghi explain, “Our preliminary data show that compression of bone metastatic tumor cells in a 3D bone mimetic scaffold altered their expression of genes that modify bone remodeling, supporting our hypothesis that skeletal mechanical signals are a fundamental regulator of tumor cell behavior. Here, we seek to systematically define the functional relationship between mechanical signals and bone metastatic cell function through development of an integrated in vitro 3D experimental and multi-physics, multi-scale computational platform.”
By combining the expertise of the Lynch lab (Lynch Research Group) in 3D in vitro systems of mechanical loading and cancer cell biology with the expertise of the Modarres-Sadeghi lab (Fluid-Structure Interactions Lab) in fully-coupled fluid-structure analysis, the two researchers believe they are ideally qualified to define the causal link between metastatic breast cancer cell function and cellular deformations.
“The results of this project will transform our fundamental understanding of how tumor cells are regulated in the skeletal microenvironment with considerable potential to improve clinical management of the disease,” say Lynch and Modarres-Sadeghi. “The data collected from these studies will form the foundation for defining the role of mechanical stimulation during bone metastasis.”
This work will be accomplished by pursuing three objectives: 1) Building a tissue-level multi-physics computational model of mechanical loading in a 3D bone mimetic scaffold; 2) determining the cellular strains resulting from interactions between bone metastatic breast cancer cells and fluid flow; and 3) defining a data-driven relationship between cellular strains and bone metastatic breast cancer cell osteolytic phenotype.
As Lynch and Modarres-Sadeghi conclude, “Importantly, our approaches and techniques will not only identify mechanically-regulated pathways involved in mechano-regulation of bone metastasis, but also those most affected, and thus those pathways most likely to result in effective therapeutic targets.” (July 2016)