3D extracellular matrix microenvironment in bioengineered tissue models of primary pediatric and adult brain tumors

Authors: SOOD, DISHA - Tufts University; TANG-SCHOMER, MIN - The Jackson Laboratory; POULI, DIMITRA - Tufts University; MIZZONI, CRAIG - Tufts University; RAIA, NICOLE - Tufts University; TAI, ALBERT - Tufts University; ARKUN, KNARIK - Tufts Medical Center; WU, JULIAN - Tufts Medical Center; BLACK III, LAUREN - Tufts University; SCHEFFLER, BJORN - University Of Florida; GEORGAKOUDI, IRENE - Tufts University; STEINDLER, DENNIS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KAPLAN, DAVID - Tufts University

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/11/2019
Publication Date: 10/4/2019
Citation: Sood, D., Tang-Schomer, M., Pouli, D., Mizzoni, C., Raia, N., Tai, A., Arkun, K., Wu, J., Black Iii, L.D., Scheffler, B., Georgakoudi, I., Steindler, D.A., Kaplan, D.L. 2019. 3D extracellular matrix microenvironment in bioengineered tissue models of primary pediatric and adult brain tumors. Nature Communications. 10:4529.

Interpretive Summary: With our discoveries of the cancer stem cell from gliomas, and roles for extracellular matrix (ECM) during normal brain development and gliomagenesis, we studied here ECM composition and its dynamic alterations involved in malignant brain tumors. Cell-cell and cell-ECM signaling has long been understudied in human brain tumor cell differentiation, affecting the successful screening of emerging therapeutics. We established in this study a tunable 3D bioengineered brain tissue model platform using native brain-derived ECM components and live imaging to systematically evaluate individual patient-derived brain tumor responses. In this new culture system, analysis of RNA for the transcriptome and metabolic imaging distinguished sub-populations within a tumor type that presented different metabolic activities and drug sensitivities. Other brain cancer-related biomarkers, e.g. related to aberrant lipogenesis, have implications for future screening of new cell and molecular therapies based on a sensitive bioassay described here that affords accurate analysis of a patient's brain tumor grown in 3D and accurately reflecting disease and response to therapies.

Technical Abstract: The brain has a unique extracellular matrix (ECM) composition, and its dynamic alterations are involved in malignant brain tumors. Yet the reciprocal matrix-cell signaling has long been overlooked in the human brain due to lack of access, which has hampered studies of brain ECM roles in tumor cell differentiation, migration and drug sensitivity. We established a tunable 3D bioengineered brain tissue model platform by integrating microenvironmental biomimicry of native brain-derived ECMs and live imaging to systematically evaluate patient-derived brain tumor responses. Using pediatric ependymoma and adult glioblastoma (GBM) as examples, the 3D brain-mimetic ECM microenvironment with a balance of cell-cell and cell-matrix interactions supported distinctive phenotypes, which are associated with tumor type-specific and ECM-dependent patterns in the tumor cells' transcriptomic and release profiles. Label-free metabolic imaging of the composite model structure distinguished sub-populations within a tumor type that presented different metabolic activities and drug sensitivities. Finally, the 3D bioengineered system captured the presence of extracellular lipid-containing droplets as a potential biomarker for aberrant lipogenesis with implications in GBM's drug response. Together, the versatile bioengineered 3D tumor tissue system sets the stage for mechanistic studies deciphering the role of microenvironment in brain tumor progression and drug response.