[ScienceDaily] Studying the state of cancer cells can know the drug’s sensitivity

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Over the past few decades, scientists have made great strides in understanding the genetic mutations that can lead to cancer. For several types of cancer, these findings have contributed to the development of drugs that target specific mutations.

However, there are still many types of cancer that do not have a targeted treatment. A team of researchers from MIT, the Dana Farber Cancer Institute and others are now examining whether another cellular feature — RNA expression patterns — affects drug response and can be used to determine treatments for acquired tumors.

In a new study of pancreatic cancer cells, researchers identified three prototypical RNA expression states and discovered differences in their susceptibility to a variety of cancer drugs. They also found that changing the tumor microenvironment can push tumor cells from one state to another, potentially finding a way to make them more sensitive to a particular drug.

“What we write in this paper is that the cancer cell state is a plastic state in response to a response in the microenvironment and has a significant impact on drug sensitivity,” says Alex Shalek. ” He is a core member of the Institute of Medical Sciences and Engineering (IMES) at MIT, an associate professor of chemistry, and an off-campus member of MIT’s Koch Institute for Integrative Cancer Research and a member of the Board of Directors. Fellow of the Ragon Institutes of MGH, MIT and Harvard and a fellow of the Broad Institute.

Shalek and Brian Wolpin, associate professor of medicine at Harvard Medical School and the Dana-Farber Cancer Institute; William Hahn, professor of medicine at Harvard Medical School and Dana-Farber; and Andrew Aguirre, an assistant professor of medicine at Harvard Medical School and Dana-Farber; are the lead authors of the study, published today in Cell. The paper’s lead authors are Srivatsan Raghavan, a medical instructor at Harvard Medical School and Dana-Farber; Peter Winter, a postdoctoral fellow at MIT; Andrew Navia, an MIT graduate; and Hannah Williams, a medical researcher at Harvard Medical School and Dana-Farber.

Cell state

Sequencing a cell’s genome can reveal mutations associated with cancer, but identifying these mutations does not always provide information that can lead to a treatment for a tumor. Specifically. To generate additional data that can be used to help select more targeted treatments, Shalek and other researchers turned to single-cell RNA sequencing, which shows the genes being expressed by each cell at a time.

“There are a lot of situations where genetics is absolutely critical, where you can develop drugs that target mutations or translocations,” says Navia. “But in many cases, the mutation alone doesn’t give you an effective way to target cancer cells relative to healthy cells.”

In this study, the researchers analyzed cells from pancreatic adenocarcinoma (PDAC). There are very few targeted drugs available to treat pancreatic tumours, so most patients receive chemotherapy drugs that can be effective initially but often lose their effectiveness as the tumor begins to resist. medicine. Using single-cell RNA sequencing, the researchers analyzed about 25 metastatic tumor samples from pancreatic cancer patients.

Previous analyzes of pancreatic tumor cell RNA have revealed two major cellular states: a basal-like state, which is more active, and a state classic. In the new study, the researchers identified a third state that appears to be intermediate between the two. Cancer cells can go through this state as they transition from the classical state to the basal one, the researchers say.

The researchers also found that the environment in which cancer cells grow plays an important role in determining their state. In this study, they grew matched “organoids,” or small cancerous masses combined from each patient’s biopsies. Such organoids are often used in precision drug pathways to create tumor models from individual patients, to help identify drugs that work in those people.

When comparing each single-cell structure in vivo with the appropriate ex vivo organoid model, the researchers found that the organoids often exist in a different RNA state than the cancer cells examined directly from the same one patient. “We saw the same DNA mutations in the original tumor and its model, but when we started examining what they looked like at the RNA level, we found that they were very different,” says Shalek. too different”.

“It shows that the state of a tumor can be influenced by the conditions of its development rather than just inherited from it,” he said. The researchers also found that they can prompt cancer cells, even long-standing cell line models, to switch between different states by altering their growing conditions. For example, treating cells with TGF-beta pushes them to a more basal-like, more active state, while TGF-beta takes the cells back to their classical state in a lab dish.

“Cells in each of those states depend on different cell signaling pathways to survive, so recognition of the cellular state is crucial for type selection,” the researchers said. the right drug to treat a particular tumor.”

“When we started looking at drug sensitivities, we found it very clear that the same model pushed into a different state would respond very differently to a drug,” says Navia. “This state-of-the-art sensitization becomes important when we think about drug selection and avoiding drug resistance. If you don’t know the right state, you can choose the wrong compound altogether and try to aim for the wrong path. If you don’t consider plasticity, the cancer may respond only temporarily until its cells change state. ”

Target therapy

The findings suggest that further analysis of the interplay of genetics, cellular state, and tumor microenvironment could help researchers develop new drugs that can effectively target tumor of each patient.

“We’re not erasing decades of understanding cancer as an inherited disease, but we’re certainly saying we need to better understand the intersection between genetics and state,” Winter said. “Cellular status is purely related to the baseline sensitivity of certain samples, and thus to specific patients and drugs.”

The discovery that cancer cells can be manipulated from one state to another by modifying signals in their microenvironment increases their ability to lock cancer cells into one state. specificity can be predicted by treating changes in the tumor microenvironment, and then delivering a specific drug that targets that lock state and improves treatment efficacy.

Together with their colleagues at Dana-Farber, the MIT team is now running much larger samples of the drug to measure how each drug affects pancreatic cancer cells in different states. They are also studying other types of cancer to determine if those cancer cells can switch between different states in response to changes in their microenvironment.

The study was funded in part by the National Institutes of Health, the Koch Institute, and the Dana-Farber/Harvard Cancer Center Bridge Project, the Ludwig Center for Molecular Cancer at MIT, the Beckman Young Research Program, the Fellowship. Sloan in Chemistry, and the Pew-Stewart Scholars Program in Cancer Research.

Information sources:

Materials provided by Massachusetts Institute of Technology. The original was written by Anne Trafton. Note: Content may have been modified in presentation and length.

References:

  1. Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer

Srivatsan Raghavan, Peter S. Winter, Andrew W. Navia, Hannah L. Williams, Alan DenAdel, Kristen E. Lowder, Jennyfer Galvez-Reyes, Radha L. Kalekar, Nolawit Mulugeta, Kevin S. Kapner, Manisha S. Raghavan, Ashir A. Borah, Nuo Liu, Sara A. Väyrynen, Andressa Dias Costa, Raymond WS Ng, Junning Wang, Emma K. Hill, Dorisanne Y. Ragon, Lauren K. Brais, Alex M. Jaeger, Liam F. Spurr, Yvonne Y Li, Andrew D. Cherniack, Matthew A. Booker, Elizabeth F. Cohen, Michael Y. Tolstorukov, Isaac Wakiro, Asaf Rotem, Bruce E. Johnson, James M. McFarland, Ewa T. Sicinska, Tyler E. Jacks, Ryan J. Sullivan, Geoffrey I. Shapiro, Thomas E. Clancy, Kimberly Perez, Douglas A. Rubinson, Kimmie Ng, James M. Cleary, Lorin Crawford, Scott R. Manalis, Jonathan A. Nowak, Brian M. Wolpin, William C Hahn, Andrew J. Aguirre, Alex K. Shalek. Cell, 2021; 184 (25): 6119

DOI: https://www.cell.com/cell/fulltext/S0092-8674(21)01332-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867421013325%3Fshowall%3Dtrue

The article is translated and edited by ykhoa. org – please do not reup without permission!

Source: ScienceDaily

Link: https://www.sciencedaily.com/releases/2021/12/211209124228.htm

Author: Roxie Duong

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