Yale Daily News

Yale researchers design new cancer research model

Yale researchers have designed the first mouse model that successfully mimics the growth of various stages of myeloma cancer in humans, opening a new door for myeloma research.

The researchers, led by School of Medicine professors Richard Flavell and Madhav Dhodapkar, developed a robust in-vivo model to grow and investigate individual myeloma tumors. According to the investigators, this model — which simulates the environment of the human bone marrow in which the cancer develops — is crucial, as it can now be used to screen potential myeloma treatments to develop more effective therapeutic approaches.

The study was published in the journal Nature Medicine on Oct. 10.

“Our results have opened up a plethora of questions needed to be addressed in the field of tumor diversity, biology and development, and our humanized model provides a convenient mode of addressing those questions and elucidating bone marrow niche interactions with individual tumors,” medical school postdoctoral research associate and co-first author Rituparna Das said.

As a malignancy of plasma cells — human cells that produce antibodies, which primarily reside in the bone marrow — myeloma is not easy to study, researchers explained. Myeloma resides in the bone marrow and grows until in a specific environment, Flavell said, adding that growth requirements include nourishing factors such as growth factors, cytokines and other molecules present in the bone marrow. This unique environment, known as a niche in the bone marrow, was first modeled by Flavell’s lab in 2014.

Flavell developed a sophisticated humanized mouse system that was able to replicate the unique niche found in human bone marrow. The system, which used a strain of mouse called MISTRG, contained the five essential cytokines of the bone marrow niche. In a Nature Biotechnology paper published in 2014, Flavell’s lab demonstrated the model’s usefulness in studying hematopoiesis, which refers to the process in which hematopoietic stem cells — undifferentiated human blood cells in the bone marrow — give rise to all types of blood cells.

What differentiates myeloma tumors’ growth microenvironment from the earlier mouse model is the requirement for the key human cytokine interleukin-6. Because myeloma is essentially a tumor of plasma cells, it retains the dependencies of plasma cells, including the cytokine IL-6.

“Researchers for decades have been trying to grow pre-neoplastic myeloma plasma cells in-vitro or in-vivo using mouse models, which remained a challenge. Unlike stem cells, [myeloma] are highly differentiated hematopoietic cells, which do not grow in vitro,” Rakesh Verma, a medical school postdoctoral associate and co-first author of the study, said.

To design an effective in-vivo model with the MISTRG mouse, the researchers incorporated an additional gene that had the ability to introduce human IL-6 into the microenvironment of MISTRG mice..

After introducing the IL-6, the investigators injected the INA-6 cell line with myeloma intrafemorally — into the bones of the mice. The cells grew in the bone of these MISTRG6 mice, but didn’t grow in MISTRG mice or other mouse strains. This supported the researchers’ hypothesis that introducing IL-6 in the model enables the growth of a myeloma tumor dependent on this cytokine.

Dhodapkar’s lab next injected primary tumor samples from human patients into the MISTRG6 mice, and the researchers similarly found a favorable environment in the bone marrow, restricting tumor development at the bone site, as in humans.

“On further growth of tumor, the cells circulated and engrafted other bone marrow sites, clearly reflecting the myeloma biology [in humans],” Das said.

Next, the Yale researchers injected the mice with a further stage of myeloma called plasma-cell leukemias, in which the disease spreads from the bone marrow throughout the whole body, Flavell said. Following this, the tumor spread everywhere.

“In other words, in the system that we studied, we had a very faithful replication in the mice of what you see in human patients,” Flavell said.

Verma also emphasized the importance of the mouse model’s ability to capture not only the cancer’s phenotype, but also the genetic complexity and evolution of the tumor.“This model can help move forward therapeutic platforms, including cellular, small molecular or monoclonal antibodies, from a pre-clinical stage to clinical stage of development,” he said.

More specifically, it can be used to screen myeloma immunotherapies, like CAR-T from Novartis, or small molecular antibody therapies, such as anti-CD38 from Johnson and Johnson, which have had successful preliminary results for myeloma patients.

Finally, the model could potentially assist in designing next-generation combination precision-medicine therapies, Verma said. Rather than waiting and using one line of therapy followed by another, Verma added, “we can bring in multiple targeted approaches in a very personalized way to the patient to get one step closer to the cure for myeloma.”

Correction, Oct. 25: An earlier version of this article misstated Rituparna Das’ role in the paper.