Aaron Newman: A Breakthrough Blood Test for Cancer

**Eric Topol** (0:00)
I think we got a quorum. We'll have more, of course, as we get going here.
So I am thrilled to welcome Professor Aaron Newman from Stanford, who published a paper that will probably be looked at as a classic for years to come, where he broke down this tumor microenvironment, also known as TME, to be able to have a blood test, a diagnostic test that can follow the tumor microenvironment in a person's cancer. This has extraordinary implications. So, Aaron, welcome to Ground Truths.

**Aaron Newman** (0:45)
Thanks, Eric, for having me.

**Eric Topol** (0:46)
Yeah. Well, I want to congratulate you. I think this reflects many, many years of work finally harvested in this extraordinary paper, which when this gets fully posted, we'll link to, of course. But I thought what we could do is start with the importance, the significance of this tumor microenvironment. Because with every week that goes by, especially right now or right after the ASCO meetings, this TME gets even more prominent in its importance. So what is TME?

**Aaron Newman** (1:22)
Yeah. So the TME is in many ways the soil in which cancer cells live. And it's a context, it's an environment that includes genetically normal cells of the immune system, as well as stromal cells, which are cells that are structural cells like endothelial cells that produce blood vessels and fibroblasts that produce scaffolding out of collagen, etc. But in a nutshell, it's the genetically normal cells that cancer cells find themselves in. And this soil is incredibly important because it, in many ways, will strongly influence whether a cancer cell will thrive or not. You can think of this as cancer cells are weeds in a garden, and the soil will determine whether the weeds are going to grow or they're going to wither. Whether the cancer cells might spread or metastasize to neighboring lymph nodes or to metastasize in the body in the same way that weeds might spread. But also how they respond to therapy to the extent of that response. And increasing evidence suggests that this tumor microenvironment soil can also strongly determine the propensity for early cancer, like precancerous lesions, to become invasive malignancy. So it is incredibly important.
And not only that, but this relationship between the local environment and the characteristics of, let's say, a weed, or other kinds of plant species, or even any species, it actually has a pretty long history. It can be traced back to over 100 years ago, this Swedish evolutionary botanist in 1922 coined the term ecotype, which actually sounds like a modern term. But it actually is a way to understand how the characteristics or the physical traits of a species depend on its local environment. And when we learned about that, we're like, you know, aha, you know, that's a really great concept and a strong framework for thinking about how cells in any tissue, including in cancer, and in particular, the tumor microenvironment, can change as a function of, you know, their context, where the cells are in space, you know, in a physical location, either inside of the tumor, or on the edge of the tumor, or beyond it. And so we essentially repurposed that concept, and we use it to understand and describe the tumor microenvironment in cancer and its different context dependencies, its relationships to clinical outcomes. It's been an incredibly useful framework for us, and we've been using this to try to understand, are there ecotypes of the tumor microenvironment that are shared across different tumor samples or different cancer types? Do they differ depending on, for example, the cells that are inside of the tumor? You can think about them as maybe the conversations that are happening inside city hall in an urban environment. They're potentially very different than the conversations in PTA meetings in the suburbs, which we can think of as maybe the edge of the tumor. Those will be different from ecotypes or conversations that are further away in what we call the outer stroma.
Maybe in our city analogy, the rural community is talking about agricultural methods and things like that.
The location matters, the neighborhood matters, the cells that they talk to, their social networks, all of these things are encompassed in this concept of a tumor ecotype.

**Eric Topol** (5:01)
Yeah, I love your metaphor of the soil or the cancer, which could try to repress, suppress it or could actually provide more nutrient blood supply and let it flourish. Now, the basic constituents, immune cells, fibroblasts, matrix, I think, the gamut is a bunch of things that are in this stuff.
In a recent paper, we have hundreds if not thousands of these so-called penins, each of us as we get older, in our pancreas, these little precancerous lesions. Just published was the fact that it's the microenvironment that needs some of these to actually develop pancreatic cancer. We keep learning, that was just last week, we keep learning more and more the significance of this TME. Now, in clinical practice today, before we get to your breakthrough work, is the TME assessed in patients with cancer? Because that requires a biopsy, which would be a sampling bias, of course.