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Semiconductor-based Ultrawideband Micromanipulation of CAncer STEm Cells

Periodic Reporting for period 2 - SUMCASTEC (Semiconductor-based Ultrawideband Micromanipulation of CAncer STEm Cells)

Reporting period: 2019-01-01 to 2021-02-28

Glioblastoma multiforme and medulloblastoma 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, 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 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 via electromagnetic sensing and cell spectral signature identification, nanoscale imaging of targeted cells and their selective neutralization via electromagnetic radiations.
After 4 years, the performed work during this project matches well with the envisioned program, most of main objectives has been reached and no major deviation has occurred except the impact of the COVID outbreak that occurred during the last more experimental active period.
Actually, the activity regarding the labscale system development led in WP2 has allowed to design and optimize high performances and innovative Lab on Chip sensors, nanoscope microchip and exposure microsystems. Some EM sources have been also conjointly and successfully developed by IHP and CREO to be implemented with on-chip exposure modules as well to be used for macroscale experiment by biologists in their labs. In the frame of WP4, different micro-optofluidic sensing and nanoimaging&exposure LOC platform has been prototyped based on BiCMOS chip. Preliminary electrical and optical tests performed these platforms were successful. Only final biological validation of effective CSCs isolation and neutralization induced by selected EMFs from WP3 activities could not been led until the end.
Concerning WP3 activities isolation, characterization of CSCs and their enrichment from GBM and MB cell lines went well using different approaches. Concerning the primary human GBM cells, we were able to establish a bank from 17 patients. EM signatures have been be satisfactorily characterized and can used to calibrate the main setting parameters of LOC sensing platform.
Regarding the neutralization of CSCs, we note that the effects of pulses are very different according to their nature (nanopulses or micropulses). The nanopulses do not induce a decrease in the CSC population. Conversely, they seem to facilitate dedifferentiation and enrichment in CSCs. The effects induced by micropulses on tumor cells are much more interesting, especially on MB cells, since they are irreversible, unlike those observed on normal astrocytes. The effects observed from the exposure of GBM cells to micropulses are not irreversible unlike those observed on MB cells.
Globally,led in vivo tests demonstrated a selective and effective action of a specific micropulses in delaying significantly the tumor engraftment and inhibiting the tumor growth in both xenograft MB and GBM models. As a combined treatment (micropulses + ionizing radiation) could be very promising for an overall future improvement of brain cancer therapy, we investigated further the possibility of radio-sensitization induced by the micropulses pre-treatment on MB and GBM.
2 Patents have been deposited, at least 86 actions of dissemination though Journal Papers, Conference Papers, Workshop organized and various talks have been performed
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.
Microfluidic CMOS lab-on chip dedicated to Single Cancer cell electomanipulation and analysis