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Early Detection of cancer onset based on sensing field cancerization at the organ level

Periodic Reporting for period 2 - SENSITIVE (Early Detection of cancer onset based on sensing field cancerization at the organ level)

Reporting period: 2019-11-01 to 2022-10-31

Cancer remains a major cause of death worldwide. Tumors of the gastrointestinal (GI) tract account for over 20% of newly diagnosed cases, while some of the GI tract tumors are quite deadly. As with most cancer types, prevention and early diagnosis crucial for the clinical outcome. Imaging techniques are either not sensitive enough or too expensive to be used as a routine approach for early diagnosis.
Early stages of cancer are characterized by tissue changes which cannot be easily detected by current means of body scan and imaging. These changes are being referred to as “field cancerization” and imply that a whole region in a tissue/organ can be prone to develop cancer and/or that a tissue segment larger than the tumor itself is affected, leading to tumor reappearance (recurrence) at a later stage. The SENSITIVE project is trying to address exactly this issue: to develop imaging methodologies and modalities that could allow the detection of such tumor-prone regions and allow early detection of cancer and/or assessment of tumor margins during operation.
The SENSITIVE consortium managed to generate hardware and software which allows the ex vivo and in vivo Raman and scattering measurements in mouse and human tissue, respectively. These modules allowed us to discriminate healthy from diseased tissue, and identify unique spectra for these. Combined with the molecular analysis, which matches the optical measurements, provided not only a deeper understanding of the disease development and progression, but also very promising diagnostic methodologies which could have a great impact in the clinic.
WP1: A hybrid Scattering/Raman microscope was developed and characterized, and an imaging protocol was designed to enable coregistered measurements with the existing at HMGU OA/SHG/THG microscope. In specifics, RiverD developed a Raman module, optimized for tissue Raman microscopy in the red and near-infrared region of The spectrally resolved depolarization spectra module was developed by UC3M. the electromagnetic spectrum. The control and data pre-processing software was programmed in MATLAB and C#, using a .NET framework, while a software developer kit (SDK) was created by RiverD and RAYFOS for the software of the hybrid microscope.In collaboration with RiverD, UC3M designed the coupling interface of the scattering module for straightforward coupling to the hybrid microscope. A LabVIEW based software was also developed. The integration of these two modalities into a new hybrid microscope was implemented by HMGU in close collaboration with RiverD, UC3M, and RAYFOS. The microscope was successfully is WP3.

WP2: Experiments were performed towards the development of mouse models in one hand, and establishing procedures for obtaining human tissues and actual collection of the first biopsies. Two different mouse models for esophageal and colorectal carcinoma have been developed. A small scale breeding program is running at HMGU. This was necessitated by the need for measurements on fresh material. The esophageal model which is going to be measured relies on the overexpression of the IL2 cytokine which is known to lead to inflammation, hyperplasia and eventually metaplasia and cancer. The colorectal model relies on the tissue specific knockout of the tumor suppressor protein APC in the small and large intestine of mice. With respect to human samples, protocols for taking biopsies from patients have been established. Ethical approval for patient work has been obtained from the independent review board (IRB) of the UMCG. First biopsies (n = 32) have already been acquired from patients with Barrett’s esophagus and Lynch syndrome in the first 2 weeks since we are running, and more patients are scheduled.

WP3: The optical measurements with the Scattering/Raman and the hybrid SHG/OA/2PEF microscopes on mouse and human tissue samples were performed by HMGU. Unique pattern fields were extracted and used in correlation studies with the molecular data which were generated in WP4. Squamocolumnar junction, forestomach and stomach from over 30 control and experimental mice were measured. For the intestine, tumor and nontumor mucosa from APC knockout mice were measured. As controls, we used healthy mucosa from controlo miced. Fixed esophageal and colorectal biopsies from Barrett's and Lynch synderomw patients were meaused alongside controls.

WP4: The molecular profile of all biopsies in WP3 were molecularlyh characterized with RNA-seq using the Illumina platform at BRFAA. RNA-seq data were processed and deregulated cell processes were identified. Interestingly, the molecular profiles and optical measurement seem to correlate significantly. Moreover, tissue adjacent to the tumor, albeit histologically normal, seems to share similarities with both the tumor and the control mouse counterpart.

WP5. Two clinical trials were performed on Barrett's and Lynch syndrome patients. A total of 30 patients have been measured so far with very promising results.
The SENSITIVE consortium put together for the first time a hybrid Scattering/Raman microscope which was used to measure mouse and human tumors ex vivo. By combining scattering and Raman mesurements we were able to discriminate tumor tissue and tumor-adjacent from healthy tissues. The molecular profiling perfomed matched the Ramam signatures uidentified in mouse models of esophageal and colon cancer. In addition, a scattering/Raman endoscope was developed and used for the first time in 2 clinical trials in humans.