High performance diagnostic platforms for uncovering micro-/nano-environmental heterogeneity within aggressive cancer cells

Abstract

1 High performance diagnostic platforms for uncovering micro/nanoenvironmental heterogeneity within aggressive cancer cells M. Veiseh, A. Ramkumar, F. Linn, J. Lu Mandana.Veiseh@parc.com, Abhishek.Ramkumar@parc.com, Felicia.Linn@parc.com, JengPing.Lu@parc.com Palo Alto Research Center (PARC, a Xerox Company), Electronic Materials and Devices, 3333 Coyote Hill Road| Palo Alto, CA 94304 USA Abstract Background: Metastatic cancer progression follows complex and heterogeneous molecular and structural changes in tissue architecture and function at multiple scales. While there is extensive literature describing how the transformation from health to malignancy alters the architecture of cells and their microenvironment, little is known about the role of heterogeneous cellular nanoenvironments in tumor aggression. This is partly due to infancy of the nano-scale architectural profiling strategies within proper three dimensional (3D) contexts and the increased detectable heterogeneity by high spatiotemporal resolution approaches. We are exploring spatiotemporal characteristics and physicochemical identities of solid breast cancer cells and their micro/nanoenvironments in relation to tumor aggression. Methods: High-performance live cell sensing, bio-microelectromechanical systems (Bio-MEMS) with tunable physicochemical properties for high resolution imaging, and multi-scale imaging (fluorescent, scanning electron and optical microscopy), and tumor microenvironmental probes are being used to monitor human cancer cells of different subtypes (e.g. basal vs. luminal breast cancers) under two and three dimensional (2D, 3D) culture conditions. Cancer cells grown in optically-compatible 2D or 3D MEMS (plain or patterned) are assessed for morphology, 3D structure, physicochemical signatures, nano-topography of cell surface and adjacent environments, tumor microenvironmental probe uptake, and growth. Results and conclusions: Breast cancer cells grown on optically thin gold substrates revealed distinct 3D phenotypic characteristics (including different forms and sizes of nano-scale surface domains and tendrils), and growth according to aggression state. Same cells (grown under 2D or 3D culture conditions) responded to distinct structural and chemical environments induced by opaque silicon-based MEMS. Cells formed stable adhesions and structures on both plain and patterned MEMS within 4 days, and exhibited distinct surface topologies, 3D structures, and growth over time. The spatiotemporal characteristics and functions differed in different tumor subtypes and within cell subpopulations of the same subtype. This study may enable development of new diagnostic platforms for identification of aggressive subpopulations within cancer cells. Such platforms may uncover a previously undetected composition or a new mode of action for metastatic cells and their nanoenvironments. With the long-term goal of deciphering and targeting nano-scale metastatic events within malignant breast and brain cancers, our work may impact both early cancer detection and prevention. Keywords: Cell-based sensing, Heterogeneity, Bio-MEMS, Imaging, Tumor microenvironment, 3D cultures, Cancer, Metastasis.