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INSTITUTE ACTIVITIES

Pre-clinical mouse model development

The tumor bank supports the scientific activity of multiple groups developing pre-clinical cancer models. Patient derived xenografts (PDX) are models of cancer where the tissue or cells from a patient's tumor are implanted into an immunodeficient or humanized mouse. Facilities at the Weizmann-Brazil Tumor Bank are used by Institute researchers to create specialized PDX animal models for their cancer-related experiments. This in-house development of PDX models offers a significant savings over the costs of purchasing study-specific animal models from commercial biotech firms. Here are two examples of recent projects that were heavily dependent of the use of PDX models:

A project led by Prof. Yosef Yarden and related to non-small cell lung cancers (NSCLCs) used the Tumor Bank’s PDX facility and resources, as well as cell-derived xenografts, to examine mutations that can lead to the emergence of drug resistance in patients who initially responded well to treatment. This research, the continuation of a project published in 2021 in Embo Molecular Medicine, suggest that a large fraction of lung cancer patients whose tumors express EGFR mutations might benefit from the addition of an EGFR monoclonal antibodies like cetuximab, which was shown to be effective in preventing tumor relapses in PDX models

A study, led by Dr. Efrat Shema of the Department of Immunology and Regenerative Biology and published in Molecular Cell, describes the analysis of two epigenetically distinct subpopulations of a lethal glioma called Diffuse Intrinsic Pontine Glioma, or DIPG. DIPG is an aggressive brain tumor that occurs in an area of the brainstem (the lowest, stem-like part of the brain) called the pons, which controls many of the body’s most vital function such as breathing, blood pressure, and heart rate. Because of its location in the brain and how rapidly it progresses, DIPG is a “high-grade” malignant brain tumor. Using cytometry by time-of-flight (CyTOF) to analyze a wide panel of histone modifications in primary tumor-derived lines or mice tumors, Dr. Shema and her team established new concepts for the analysis of epigenetic heterogeneity in cancer that could be applied to future improved treatments.

The tumor bank model collection

The tumor bank is in the process of establishing a large repository of human and mouse cell lines for the use of the Weizmann cancer research community. The cell lines are collected from various labs in Weizmann, validated (by DNA fingerprinting), quality assured (by mycoplasma test and growth validation), and characterized (by RNA sequencing). The generated resource will allow labs to easily share cell lines and collaborate on different projects.

In addition, the tumor bank will host a collection of well-characterized mouse tumors, stored frozen and as paraffin blocks (FFPE). This will be accompanied by a comprehensive database recording tumor characteristics, H&E staining, growth rate curve, and RNA sequencing results. Together with the cell line repository, we hope to generate a Weizmann-based powerful resource to empower the Weizmann cancer research community.

Animal models

The Weizmann-Brazil Tumor Bank allows scientists to establish models in which tumors, freshly obtained from patients in the operating room after biopsy or tumor resection, are implanted directly under the skin of genetically engineered animal models in a procedure known as patient-derived xenografts (PDX).

These tumors, which resemble to the greatest possible extent the original tumor growing within the human patient, can then be transferred from the first animal model to additional specimens, eventually propagating the tumors into a large colony - all bearing the same human tumor. This colony provides the researchers with a unique opportunity to perform a large variety of experimental manipulations, in parallel on identical replicas of the original tumor. These manipulations enable the identification of critical genes whose targeting can stop tumor growth or even kill the tumor.

The work of Prof. Yardena Samuels, head of the Weizmann-Brazil Tumor Bank, has already yielded four new PDX mouse strains, and it is hoped that this synergy between the two facilities will generate more use of PDX mice for basic cancer research.

Picture (left): Preparation of a tumor sample extracted from a PDX mouse, prior to implantation into additional animal models.

Examining real cancer samples

The Weizmann-Brazil Tumor Bank receives tissues from biopsied tumors or tumors removed from patients through the cooperation of various medical centers. The images below are examples of human melanoma tissue samples received from Hadassah Medical Center in Jerusalem.

Generally, the samples received are divided into small pieces; some are implanted into immunodeficient mice, and the rest are stored for future use.

Most of the stored samples are kept in the “biobank”, i.e., a -80°C freezer, while a small amount is preserved in formaldehyde, and then processed into paraffin blocks. The scientists cut the blocks into thin slices (6 μm) in order to allow histologic examination of tissue morphology, genes, vessels, etc. 

The sample shown above is from a metastatic melanoma tumor, also known as stage IV melanoma (when cancer cells have spread to other organs). It portrays the tumor cells variability in size, shape, and staining (pleomorphism), as well as the presence of melanocytes (scale bar indicated).