Bioengineered Models Could Improve Understanding of Bone Cancer, Metastases

Lor Randall, MD, FACS

Tissue-engineered platforms could pave the way for a deeper understanding of cancer arising in or metastasizing to the bone and ultimately lead to targeted therapeutic developments, according to a review published in the Journal of Biomechanics.

In the paper, researchers noted that biomaterials can replicate cancer behavior by creating 3-dimensional (3D) systems designed to explore neoplasm behavior, screen chemotherapies, and develop novel therapeutic delivery approaches.

The research is a clear sign that bioengineering will be a significant partner with more conventional scientific disciplines that have driven cancer discovery in the future, explained R. Lor Randall, MD, FACS, one of the authors on the paper.

"Bioengineering has come to the clinical table,” said Randall, the David Linn Endowed Chair for Orthopedic Surgery, as well as professor and chair of the Department of Orthopedic Surgery at University of California Davis Comprehensive Cancer Center. “It's a message that it is not just pharmacy, biochemistry, and molecular biology, but also bioengineering that is going to help us really take the next steps in treatments for patients with cancer, as we look to create these platforms to really tease out the mechanisms that go across all of those disciplines."

In an interview with OncLive, Randall, discussed the rationale and motivation behind this intriguing approach and how it could significantly impact the understanding of how cancer arises in or metastasizes to bone. 

OncLive: What was the rationale to begin this type of research?

Randall: One of the concepts is that there are models [needed] to understand cancer progression, and particularly bone is a very complicated organ system. Like any living structure, people think of bones simplistically because it's sort of a solid thing, right? However, it's actually a very sophisticated organ system; it's hematopoietic, it's structural, it's your calcium deposits for all sorts of things. It's a living organ and a living tissue.

Therefore, as it relates to cancer, there are obviously primary bone cancers that arise, such as osteosarcoma, chondrosarcoma, and Ewing sarcoma, and then there are other cancers that go to bone, such as breast cancer, prostate cancer, lung cancer, and those are much more prevalent and complicated. However, in both of those [cancers], whether it goes to the bone or is something that arises from the bone, the bone microenvironment is very complicated. 

Historically, research has been strictly in vitro, or in very, very sophisticated models like knockin mice, genetically engineered mice, murine mice, or some other complex organ system. However, the problem arises when you're looking at the details of the organ system—in this case, bone, but it could be the liver, or anything being able to study at a cellular and molecular level—that you can't necessarily do with the complexity of a genetically engineered mouse. 

Therefore, bioengineers have created these "biofactories" that allow you to create actual artificial microenvironments that contain all of the necessary ingredients of the organ system, and then use cells within that to understand how those cells work in that microenvironment in terms of tumor progression.

For example, what we're trying to do at University of California Davis is look at the very first steps of cancer metastasis. Therefore, we know that cancer in osteosarcoma arises within the bone and then evolves or progresses to develop metastasis that go on to the lung. What we're trying to do is create this bioengineered bone marrow that allows us to introduce our osteosarcoma cells, and then subject them to certain stressors, such as oxygen tension, dial in some macrophages and a variety of other microenvironmental factors to see how these cells progress in their ability to migrate and therefore potentially metastasize. Therefore, these bioengineered substrates are really becoming ubiquitous in benchwork, in cancer biology. 

Is this research strictly preclinical or has any in-human testing been conducted?

This is all preclinical right now. However, clinicians and medical oncologists will have an interest in this, [and should] become aware of this: the way by which we're going to be studying cancer is not necessarily strictly in vitro or necessarily in murine mouse models where they're pretty complicated, but in these hybrid-engineered tissues. [Here], we can really look at how the cancer progresses. These new platforms will help us really recreate the environments we want to understand anoxia and the immune landscape that is happening in human tissues far better than what we can do with mice or in a petri dish.

How does this research compare with what has been done in patient-derived xenografts (PDX)?

PDX is a great technology. When you want to look at it a drug response, PDX is a very good way by which to do that. However, it has its own limits in terms of understanding the pathways by which these tumors either develop in their native tissues like in bone, or if they metastasize to the bone. How we can better target them?

Therefore, if we take a breast metastasis out of the bone, for example, and put it into a mouse, and treat the mouse with certain drugs, it doesn't necessarily tell us what's going to happen in the bone per se, because now that tumor is no longer in the bone. These are just more sophisticated ways to understand the tumor in its microenvironment that you don't have in the PDX nor in vitro.

It's synthetic of sorts, but the goal is to have a very fastidious understanding of the microenvironment and of how that tumor is going. This is completely theoretical on my part, but you could potentially introduce tumor cells from the patient into one of these discs, which are small little discs of the engineered bone marrow, and then subject them to different drugs and see how they respond.

This is a perfect example of precision medicine and how this is moving into the future of oncology treatment. How do you foresee practice changing?

It is eye opening to me because my background has been in molecular biology. This is taking it to this level of scaffolds, of engineered environment, by which you either introduce the cancer cell or the genetically altered cancer cell, and then the therapies. These synthetic platforms are just incredible, and they are 3D, which is important to point out.

One of the things we want to learn is how either a cell metastasizes into this area, or how a cell originates in this area and metastasizes out. That is a physical phenomenon, right? It's not a passive phenomenon. Looking at those early steps of immigration or emigration from that environment, you really need to have a very good look at the microenvironment itself. There will be computer 3D printing of these, and you can ultimately mass produce them.

What are the immediate next steps for this research?

We are using these engineered bone marrows to look at the initial steps in osteosarcoma, to better elucidate what it is and where it becomes something more than the local control issue and becomes something that is going to spread elsewhere. Next steps also will be to start collaborating to look at the lung microenvironment, where most of these osteosarcomas spread to, because we want to figure out what's happening when it leaves the house, so to speak, but then we also want to know what's happening when it arrives in the new station. Both ends of that will need to be explored more.

Reference

1. Thai VL, Griffin KH, Thorpe SW, et al. Tissue engineered platforms for studying primary and metastatic neoplasm behavior in bone. J Biomechanics. 2021;115(110189). Published online January 22, 2021. doi:10.1016/j.jbiomech.2020.110189