Most cancers Cell “State of Thoughts” Results Drug Response

In a new study of pancreatic cancer cells, a team of researchers led by scientists from the Dana Farber Cancer Institute identified three prototypical RNA expression states and discovered differences in their susceptibility to various cancer drugs. They also discovered that changing the tumor microenvironment can drive tumor cells from one state to another, potentially offering a way to make them more susceptible to a particular drug.

The results of the new study – recently published in Cell in an article entitled “Microenvironment Drives cell state, plasticity, and drug response in pancreatic cancer” – investigate whether an RNA expression pattern similar to cell characteristics influences the drug response and is used for identification Treatments for a tumor can be susceptible.

“What we show in this article is that the state of cancer cells in response to the microenvironment is plastic and has a dramatic impact on drug sensitivity. This opens new frontiers to thinking about drug development and drug selection for individual patients, ”said Assistant Principal Investigator Alex Shalek, PhD, a core member of the Institute for Medical Engineering and Science (IMES) at MIT and an associate professor. of chemistry and non-university member of the Koch Institute for integrative cancer research at MIT.

Sequencing the genome of a cell can reveal cancer-related mutations, but identifying these mutations does not always provide information that can be addressed to treat a particular tumor. To generate additional data that could help select more targeted treatments, Shalek and other researchers turned to single-cell RNA sequencing, which reveals the genes that are expressed by each cell at any given point in time.

“There are many situations where genetics is incredibly important, where you can develop these very precise drugs that target mutations or translocations,” said study co-author Andrew Navia, a graduate student at MIT. “But in many cases, mutations alone are not an effective way of fighting cancer cells versus healthy cells.”

In this study, the researchers analyzed ductal adenocarcinoma of the pancreas (PDAC) cells. There are very few targeted drugs available to treat pancreatic tumors, so most patients are given chemotherapy drugs that may be effective initially, but often stop working when the tumors become resistant. Using single-cell RNA sequencing, the researchers analyzed about 25 metastatic tumor samples from pancreatic cancer patients.

Previous analyzes of the RNA of pancreatic tumor cells have revealed two broad categories of cell conditions: basal, more aggressive and classic. The researchers identified a third condition in the new study that appears to be an intermediate stage between the two. The researchers say cancer cells can go through this state when they transition from classic to basal.

The researchers also found that the environment in which cancer cells are grown plays a key role in determining their condition. In this study, matching “organoids” or tiny cancerous aggregates were obtained from the biopsy of each patient. Such organoids are often used in precision medicine pipelines to model tumors of individual patients in order to identify drugs that might be useful to those individuals.

When comparing each in vivo single cell profile with the appropriate ex vivo organoid model, the researchers found that the organoids are often in a different RNA state than cancer cells examined directly from the same patient. “We see the same DNA mutations in the original tumor and its model, but when we start looking at what they look like at the RNA level, we find that they are very, very different,” noted Shalek.

That suggests that the condition of a tumor may be influenced by the conditions in which it grows rather than its genetics, he says. The researchers also found that they could induce cancer cells, even long-established cell line models, to switch between different states by changing their growth conditions. Treatment of cells with TGF-beta, for example, drives them into a more aggressive, basal state, while removal of TGF-beta causes the cells to return to the classic state in a dish.

Cells in each of these states depend on different cell signaling pathways for survival. Hence, knowing the cell status is crucial in order to choose the right drug to treat a particular tumor, say the researchers.

“When we started looking at drug sensitivity, it became clear that the same model put into a different state reacts very differently to a drug,” said Navia. “These condition-specific sensitivities become critical when we think about the choice of drugs and the avoidance of resistance. If you don’t know the right state, you can pick the completely wrong link and try to target the wrong paths. For example, if you ignore plasticity, the cancer may only respond temporarily until its cells change state. “

The results suggest that further analysis of the interplay between genetics, cell status, and tumor microenvironment could help researchers develop new drugs that effectively target individual patient’s tumors.

“We’re not erasing decades of understanding cancer as a genetic disease, but we’re certainly saying we need to understand the interface between genetics and state much better,” concluded study co-author Peter Winter, PhD, a postdoctoral fellow at MIT . “The cell condition is absolutely tied to the underlying sensitivity of certain models and thus to patients and certain drugs.”

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