Connecting biophysical measurements and gene expression to understand tumor heterogeneity

Many tumors comprise a heterogeneous mix of cell types, each of which can play various roles in cancer progression and treatment response and may serve as diagnostic or therapeutic targets. The contributions of different cells can be difficult to uncover using conventional molecular analyses, histology, or immunophenotyping. In a study published in Science Advances the Manalis lab shows they can use their single cell analysis platform to link cells’ biophysical properties—in this case, buoyant mass and stiffness—to gene expression to identify clinically relevant cell types within mantle cell lymphoma cells. 

An aggressive subtype of B-cell non-Hodgkin lymphoma, mantle cell lymphoma serves as an ideal model in which to demonstrate the Manalis group’s approach, representing both a highly heterogenous tumor and a pressing clinical need. Often diagnosed at later stages, it is not currently considered curable. Treatments like chemoimmunotherapy, stem cell transplants, and drugs called BTK inhibitors help manage the disease, which has an average 5-year survival rate of about 50%.

In the Manalis group’s study, conducted in collaboration with the Murakami lab at Dana-Farber Cancer Institute, linked measurements reveal that buoyant mass and stiffness characterize the developmental states of immune cells called B cells, from unspecialized naïve stages to highly specialized plasma cells. These measurements also correlate with cancer-associated expression of B cell receptor signaling genes such as BLK and CD79A. In addition, changes in cell buoyant mass within patient specimens correlate with sensitivity to BTK inhibitors in both mantle cell and chronic lymphocytic leukemia, another B cell malignancy. 

These findings highlight the potential utility of biophysical properties in developing future precision therapeutic strategies for mantle cell lymphoma and other cancers, as well as their value as biomarkers of treatment response. 

With co-author David Weinstock and collaborators in his laboratory at Dana-Farber Cancer Institute, Manalis has previously shown the single cell measurement platform can provide clinically relevant information to help guide cancer treatment decisions, via a Bridge Project collaboration and commercial translation at their startup Travera.

This work has been supported in part by the MIT Center for Precision Cancer Medicine and the Ludwig Center at MIT.