The Cancer Custodians

The Cancer Custodians – Issue 102: Hidden Truths – Jioforme

To beat our worst enemy, we must first let it grow.

BY LINA ZELDOVICH

Part of Dennis Plenker’s daily job is growing cancer. And a variety of different ones, too.

Depending on the day and the project, different tumors may burgeon in the petri dishes stocked in the Cold Spring Harbor Laboratory where Plenker works as a research investigator. They might be aggressive breast cancers. They might be glioblastomas, one of the deadliest brain tumors that rob patients of their ability to speak or read as they crowd out normal cells. Or they might be pancreatic cancers, the fast and vicious slayers that can overtake a healthy person within weeks or even days.

These tiny tumor chunks are transparent and bland—they look like little droplets of hair gel that accidentally plopped into a plastic dish and took hold. But their unassuming appearance is deceptive. If they were still in the human bodies they came from, they would be sucking up nutrients, rapidly growing and dodging the immune system defenses. But in Plenker’s hands—or rather in the CSHL’s unique facility—these notorious killers don’t kill anyone. Instead, scientists let them grow to devise the most potent ways to kill them.

PATIENTS IN A DISH: Organoids are three-dimensional, live tissue models grown from patient tumors. They “are essentially patients in a dish,” says Dennis Plenker (center) of Cold Spring Harbor Laboratory. At the CSHL organoid facility, Plenker works with Luce St. Surin (left) and Hardik Patel (right).Bob Giglione / CSHL

These tumor chunks are called organoids. They are three-dimensional assemblages of malignant growths used to study cancer behavior and vulnerability to chemotherapy and the so-called “targeted drugs”—the next generation therapies. Scientists used to study tumors at a single-cell level, but because tumors grow as cell clusters in the body, it proved to be inefficient. The three-dimensional structures make a difference. For example, chemo might destroy the tumor’s outer cell layer, but the inner ones can develop resistance, so where single cells may die, a 3D mass will bounce back. Organoids can provide a window into these little-known mechanisms of drug resistance. They can reveal how normal tissues turn malignant and where the cellular machinery goes off-track to allow that to happen.

As their name suggests, organoids are scientists’ windows into organs, whether healthy or stricken with disease. You need to know your enemy to beat it, Plenker says, and cancer organoids offer that opportunity. Taken from patients currently undergoing cancer treatments, these tumor chunks will reveal their weaknesses so scientists can find the cancers’ Achilles’ heel and devise personalized treatments. “Organoids are essentially patients in a dish,” Plenker says. Only unlike real patients, the organoids can be subjected to all sorts of harsh experiments to zero in on the precise chemo cocktails that destroy them in the best possible way. And they will likely provide a more realistic scenario than drug tests in mice or rats, as animal models aren’t perfect proxies for humans.

These notorious killers don’t kill anyone. Instead, scientists devise the most potent ways to kill them.

The way that cancer proliferates in the body is hard to reproduce in the lab. Stem-cell research made it possible. After scientists spent a decade understanding how various cells multiply and differentiate into other cell types based on molecular cues and nourishment, they were able to make cells grow and fuse into tissues. To stick together like bricks in a nicely laid wall, cells need a biological scaffold that scientists call an extracellular matrix or ECM, which in the body is made from collagen and other materials. Today, the same collagen scaffolds can be mimicked with a gooey substance called Matrigel—and then seeded with specific cells, which take root and begin to multiply.

Some tissue types were easy to grow—Columbia University scientists grew viable bones as early as 2010.1 Others, like kidney cells, were trickier. They would grow into immature tissues incapable of performing their job of cleaning and filtering blood. It took scientists time to realize that these cells wanted more than scaffolding and food—they needed to “feel at home,” or be in their natural habitat. Kidney cells needed the feeling of liquid being washed over them, the Harvard University group found, when they first managed to grow functioning kidney tissue in 2018.2

Cancers have their own growth requirements. In the body, they manage to co-opt the organism’s resources, but keeping them happy in a dish means catering to their dietary preferences. Different cancers need different types of molecular chow—growth factors, hormones, oxygen and pH levels, and other nutrients. Pancreatic adenocarcinoma thrives in low-oxygen conditions with poor nutrients…

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https://nautil.us/issue/102/hidden-truths/the-cancer-custodians

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