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Israeli breakthrough: scientists made first 3D-bioprinting of entire active tumor

This novel approach will also enable the development of new medications and the discovery of novel drug targets — at a far faster rate than is currently possible.

The research team(Left to right): Eilam YeiniProf. Satchi-Fainaro and Lena Neufeld.
Credit: Tel Aviv University

Tel Aviv University researchers have achieved a scientific milestone by producing an entire active and alive glioblastoma tumor using a 3D printer.

In order to simulate a real tumor, the three-dimensional bioprinted models are based on samples taken straight from a patient in operating rooms at Tel Aviv Sourasky Medical Center, to the lab.

The 3D-bioprinted tumor is comprised of a complex network of blood vessel-like tubes through which blood cells and medications can flow, replicating the flow of blood in a genuine tumor.

The new technology which was developed by PhD student Lena Neufeld features three-dimensional cancer tissue surrounded by an extracellular matrix that communicates with its surrounding via functional blood arteries.

Microscopic image of the 3D-bioprinted glioblastoma model. The bioprinted blood vessels are covered with endothelial cells (red) and pericytes (cyan). The blood vessels are surrounded with a brain-mimicking tissue composed of gliblastoma cells (blue) and the brain microenvironment cells (green). Different drugs or cells can be perfused through the 3D-bioprinted blood vessels to test their effect on the tumor tissue.

“Glioblastoma is the most fatal central nervous system malignancy, accounting for the majority of brain malignancies,” explains led research Prof. Ronit Satchi-Fainaro, from Faculty of Medicine and Neuroscience, Head of the Cancer Research and Nanomedicine Laboratory and Director of the 3D-BioPrinting for Cancer Research Initiative, at Tel Aviv University.

“We previously found a protein called P-Selectin that is created when glioblastoma cancer cells interact with microglia — brain immune cells,” Prof. Satchi-Fainaro said. “We discovered that this protein causes a failure in the microglia, enabling them to promote rather than assault the lethal cancer cells, so aiding in the progression of the malignancy.
“However, we discovered the protein in tumors excised during surgery but not in glioblastoma cells generated in our laboratory on two-dimensional plastic petri dishes. The reason for this is that cancer, like all tissues, behaves significantly differently on a plastic surface than it does in the human body. Approximately 90% of all experimental medications fail at the clinical stage due to the failure of the laboratory success to be replicated in human “tenants.”

The researchers demonstrating that, unlike cancer cells grown in petri dishes, the 3D-bioprinted model has the potential to be effective for rapid, robust, and reproducible prediction of the most appropriate treatment for a specific patient.

“It is not just the cancer cells,” Prof. Satchi-Fainaro clarifies. “Additionally, it is the cells of the brain’s microenvironment; the astrocytes, microglia, and blood arteries that are coupled to a microfluidic system – specifically, a system that enables the delivery of chemicals such as blood cells and medications to the tumor replica.

“Each model is printed in a bioreactor that we developed in the lab using a hydrogel sampled and replicated from the patient’s extracellular matrix, replicating the tissue itself.

“The brain has unique physical and mechanical qualities in comparison to other organs such as the skin, breast, or bone. Breast tissue is primarily composed of fat, while bone tissue is predominantly composed of calcium; each tissue has unique features that influence the behavior of cancer cells and their response to treatments. It is not optimum to grow all types of cancer on comparable plastic surfaces to simulate the clinical scenario.”

This experiment demonstrated why potentially beneficial treatments rarely make it to the clinic merely because they fail testing in two-dimensional models, and vice versa: why drugs considered a phenomenal success in the laboratory ultimately fail in clinical trials.

“We established that our three-dimensional model is superior for predicting therapy efficacy, target discovery, and drug development.

Illustration.
Credit: Veronica Hughes, PhD of STEAM visuals

“In collaboration with Dr. Asaf Madi’s lab at TAU’s Faculty of Medicine’s Department of Pathology, we performed genetic sequencing on cancer cells grown in the 3D-bioprinted model and compared them to cancer cells grown on 2D plastic and cancer cells isolated from patients.” Prof. Satchi-Fainaro may proceed.

“We found a striking likeness between the 3D-bioprinted tumors and patient-derived glioblastoma cells growing in the presence of brain stromal cells. The cancer cells cultured on plastic evolved significantly over time, eventually losing all resemblance to the cancer cells found in the patient’s brain tumor sample.

“Additional evidence was obtained by determining the tumor’s pace of growth. Glioblastoma is an aggressive disease in part because it is unpredictable: when heterogeneous cancer cells are transplanted separately into model animals, some cancer cells remain latent, while others develop swiftly into an active tumor. This makes sense because persons can die quietly of old age without ever being aware of the presence of such dormant tumors. On the laboratory dish, however, all cancers grow and spread at the same rate. The heterogeneity of our 3D-bioprinted tumor is preserved, and its evolution is comparable to the vast spectrum observed in people or animal models.”

Prof. Satchi-Fainaro believes that this novel approach will also enable the development of new medications and the discovery of novel drug targets — at a far faster rate than is currently possible. Hopefully, in the future, this technology will enable patients to receive tailored medicine.

“If we take a sample of a patient’s tissue and its extracellular matrix, we may 3D-bioprint 100 miniature cancers from it and test numerous medications in various combinations to determine the ideal treatment for this particular tumor.

“Alternatively,” she added, “we can screen a large number of chemicals against a 3D-bioprinted tumor and determine which are the most promising for further development and investment as a possible medicine. The most interesting component, however, is identifying novel druggable target proteins and genes in cancer cells – a difficult effort when the tumor is located inside the brain of a human patient or model animal. Our breakthrough enables unparalleled access to 3D tumors that better match the clinical environment, allowing for optimal investigation.”

The researchers who took part in this research are Eilam Yeini, Yael Shtilerman, Noa Reisman, Sabina Pozzi, Dr. Dikla Ben-Shushan, Dr. Galia Tiram, Dr. Anat Eldar-Boock and Dr. Shiran Farber.  The findings were published in the journal Science Advances today.

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