Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - SUMCASTEC (Semiconductor-based Ultrawideband Micromanipulation of CAncer STEm Cells)

Teaser

Glioblastoma multiforme (GBM) and medulloblastoma (MB) are highly heterogeneous and particularly aggressive brain tumors. Despite typically treatments (i.e surgery, chemotherapy and radiation therapy), both cancers usually recur. More recent molecular classifications of GBM...

Summary

Glioblastoma multiforme (GBM) and medulloblastoma (MB) are highly heterogeneous and particularly aggressive brain tumors. Despite typically treatments (i.e surgery, chemotherapy and radiation therapy), both cancers usually recur. More recent molecular classifications of GBM and MB have highlighted the heterogeneity that exists within pathological subtypes pointing out the role of different developmental signaling pathways in cancer pathogenesis. Due to this heterogeneity, standard therapies provide poor positive outcomes. However, based on cancer similarities, all different types of tumors start from a relatively small fraction of tumor cells, termed Cancer Stem Cells (CSCs) that have the ability to proliferate and maintain tumor growth.
All other cells of the bulk tumor are characterized by limited proliferative capacity and a more specified lineage potential. CSC populations are also termed tumor-initiating cells, because maintains two key properties: self-renewal and differentiation. Self-renewal is defined as the ability of a parental cell to generate an identical daughter cell and a second cell of the same or different phenotype, whereas through the process of differentiation a CSC is able to give rise to the heterogeneous cell lineages that constitute the original tumor. After this initial phase of tumor growth the CSCs become quiescent. The quiescence state is the survival strategy of cancer cells responsible for the later recurrence and relapses. Therefore, new and alternative treatment approaches are necessary to reduce not only long-term toxicity of radiotherapy or chemotherapeutic agents, but also to find a newer targeted therapeutic strategy for example targeting specifically CSCs. The goal of SUMCASTEC is to isolate selectively target quiescent malignant CSCs and subsequently induce a differentiation process to sensitize them to radio- chemotherapy treatments
SUMCASTEC explores radically new approach for cancer stem cells (CSCs) real time isolation and neutralization. A novel micro-optofluidic lab-on-chip (LOC) platform will be developed through a joint and iterative efforts by biologists, clinicians and engineers. For the first time, a single LOC will be able to deliver ultra-wide broadband radiation to compare cell spectral signatures, image subcellular features, and hence modulate CSCs microenvironment conditions with unprecedent space and time resolution. It will be driven to isolate CSCs from heterogeneous differentiated and stem cell populations, and force CSCs differentiation, ultimately inducing sensitivity to anticancer treatments. Extensive in vitro and in vivo testing along with biophysical modelling will validate the approach and establish the proof -of-principle within the project life-time, while laying the ground work for further development of future electrosurgical tools that will be capable CSCs neutralization in tissue.
The targeted scientific breakthrough in SUMCASTEC is the world’s first micro-optofluidic lab-on-chip platform enabling successively Cancer Stem Cells isolation (CSCs) via electromagnetic sensing and cell spectral signature identification, nanoscale imaging of targeted cells and their selective neutralization via electromagnetic radiations.

Within the duration of the project, we will target three main objectives

A. A novel Micro-optofluidic Lab-on-Chip platform build up with
– Full integration of microfluidic channels and reservoirs, broadband high frequency sources and detectors, and nanoscale imaging modules into a CMOS environment
– EM stimulus tuned both in continuous wave format for low power sensing/stimulation, and in pulsed format with MV/m amplitude, ns-width, and KHz-repetition range, for membrane permeabilization and potential control
– Optical imaging with a 20 nm & 1ms resolution
B. Fast isolation, nanoscale imaging and selective neutralization
– Detection, separation and mapping of intracellular properties and processes of CSCs
– Real time CSC isolat

Work performed

After two years, the performed work matches well the initial work plan, and no major deviation has occurred
Hence, the 1st workpackage is closed and two others one are currently running dealing with development of technology and tools for experiments and in vitro biological trials and looking for sensing, exposure and imagining optimal conditions. The WP4 just starts
The technology and the associated fabrication process for implanting fully packaged microfluidic chips on CMOS stack have been developed and after a intense optimization is ready to be used
The main design of the different LOC modules has been performed, some final optimizations are still under way but the first prototypes fabricated showed expected electrical test results et let us confident
Some Out-of-Chip as well On-Chip EM sources have been prototyping and have been already delivered to partner to be successfully used for biological experiments. Others are still under developement and will be finalized soon
The cell selection (MB and GBM cell lines & primary cultures) and biological characterization of produced CSCs enriched cell culture have been performed as well the optimization and the standardization of grown condition
On–Chip Sensing and Out-of Chip Exposure experiment campaigns have been done showing really promising results
Search of optimal conditions to expose cells with series of µseconds or nseconds pulseshave been done using macro containers and showed remarkable effects on targeted cells. Biological investigations are on-going to understand implied mechanisms

Final results

Up to now, no available technology pursues isolation, induced differentiation and selective neutralization of CSCs by using non-ionizing EM radiation. So, Sumcastec research offers an additional option for cancer treatment remotely controlled by engineered systems based on EM technology.
The technological impact of this project is high, given the expected development and implementation of innovative technologies and devices that will provide the realization of the micro-optofluidic LOC using a CMOS technology. The integration of microfluidics and optical components for CSCs isolation, discrimination, neutralization in vitro and in vivo, provides a basis for a new cancer therapeutic strategy. At now, the technology presented is completely new and no industrial reality has yet developed products for the clinic, therefore it could be of interest for patents and collaboration with companies.
Given the high social impact of tumor diseases, SUMCASTEC will substantially contribute to the sustainability of healthcare systems (cost reduction). Once the proof-of-principle of the LOC platform is effectively achieved, it will be possible in a long-term scenario to develop radically new and high potential electrosurgical tools useful for the treatment of several solid cancers.
Finally, the scientific impact of the project is very interesting, representing an advancement in the methodology of integration between physics-engineering and chemical-biological disciplines supporting the multidisciplinary nature of research for a more efficient development of future therapeutic treatments.

Website & more info

More info: http://www.sumcastec.eu.