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2D Genetic Map of Prostate Cells Charts Most cancers Progress

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IA examine was revealed on August 10 in mood natureScientists mapped the genetic panorama throughout the human prostate in excessive decision and found how additional or lacking items of chromosomes, referred to as copy quantity modifications, that are considered distinctive to most cancers, are sometimes present in seemingly wholesome tissue.

“This was surprising and completely unexpected,” says examine co-author Alistair Lamb, a urologist within the Nuffield Division of Surgical Sciences on the College of Oxford. We thought all these modifications decided prostate most cancers. However they’re in [tissue] Which is totally benign.”

Far from a regular cell mass, tumors consist of a mixture of malignant, benign, and healthy tissue. Understanding how normal cells become cancerous requires scientists to map genetic changes within this complex ecosystem. In collaboration with gene technology researcher Joakim Lundeberg and colleagues at the KTH Royal Institute of Technology in Sweden, Lamb’s team used a technique called spatial transcription to map copy number changes to specific sites within the prostate.

Unlike methods such as bulk DNA sequencing, where cells are shredded and no information about their physical location is lost, spatial transcription preserves the 3D structure of a sample by genetically tagging RNA molecules with location data before they are sequenced, allowing each sequence to be matched. to its original location within the member.

Graphical depiction of the spatial transcription protocol

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The entire prostate was excised from a cancer patient by prostatectomy, cut horizontally into histological sections and then subdivided into blocks. mRNA was captured from single blocks using barcode spatial probes and sequenced. This allowed the researchers to see if inferred copy number differences in DNA (CNV inference) or gene expression profiles (transcriptome) mapped over areas identified as cancerous under the microscope (consensus pathology).

From Figure 1a temper natureAnd the 608: 360-67, 2022; CC BY 4.0

This involves placing a section of tissue on a glass surface containing a network of dots, each of which anchor short nucleotide strands containing a spatial bar code and a series of thymine residues that bind to mRNA molecules. The tissue sample is permeated just before it is placed on the glass so that the mRNA leaks out of the cells, allowing them to adhere to the mesh, thus locating each molecule within the tissue.

In the study, the researchers wanted to create a map of copy number differences within a prostate surgically removed from an elderly patient, so they grilled tissue cross-sections to obtain transcripts using a grid of 30,000 spots. Each dot, corresponding to a region of just ten cells, picked up about 3,500 molecules of mRNA released from cells near it, allowing the team to determine gene expression. Then, using a computational approach, the team used the RNA they sequenced to predict copy number differences in the cells’ DNA and to identify groups of cells that are genetically identical or clones. They then grouped the clones into a relative hierarchy to chart how the cells’ genetic makeup had changed over time.

Meanwhile, the team visualized healthy tissue under a microscope to outline areas of cancerous and benign tissue based on morphology. Combining imaging data with spatial genetic profiles revealed an astonishing amount of heterogeneity within a single tumor, Lamb says, with low-grade tumor cells (those that almost resemble healthy cells) found between both healthy and highly advanced tumors. cells. As expected, the tumor cells contained copy number differences in oncogenes such as MYC The tumor suppressor gene PTEN. But surprisingly, the same changes occurred in nearby healthy tissue.

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Histological section of prostate tissue showing pathology and genetic clones

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Cells with genetic features of prostate cancer span pathological boundaries: each spot, corresponding to an area of ​​only ten cells, was individually categorized as benign (blue), frontal (green), low-grade (red), or high-grade (red). Bold) prostate cancer (left). The same regions were also grouped based on their genetic profile, with each color representing groups of genetically identical cells (right).

Figures 3c, d temper natureAnd the 608: 360-67, 2022; CC BY 4.0

“What’s cool here is the 2D snapshot. We see the very early events, intermediate events and the tumor has diverged,” says Lundberg. He compares the technique to histological sampling, where a pathologist identifies the tumor under a microscope and dissects it with a laser. It can provide insight into a tumor but ignore the cellular environment around it.”But with spatial transcription, you can capture early events that are blurred when you look under a microscope.”

This kind of whole-organ approach to cancer genetics is something that Elana Fertig, a cancer researcher at Johns Hopkins University who was not involved in the study, is particularly excited about. “I feel it is unbelievable and that is one thing that we have to do more and more. We need to make it possible for we do not miss molecular markers of recurrence that will not be within the dominant lesion,” she says.

To check whether similar patterns occur in other cancers, Lundberg and colleagues repeated the procedure using tissue sections for melanoma, breast cancer and glioblastoma. As before, they found chromosomal changes in both cancer cells and nearby healthy tissue.

These findings suggest that copy number differences occur before, rather than after, benign cells transform into malignant tissue, says Francesca Cicarelli, a cancer geneticist at King’s College London who was not involved in the study. The same observations that seemingly normal cells carry the tumor [copy number variations] You write in an email to the scientist.

This raises the question of what genetic events, if not these copy number differences, drive tumorigenesis. Lamb suggests that DNA changes that were not investigated in the study, such as epigenetic modifications, may play an important role. “There is also a possibility [chemical] Points between cancerous clones and surrounding stromal tissue.

However, capturing early genetic events not visible with a microscope could allow researchers to predict whether an area of ​​benign tissue may lead to a fatal cancer, with important implications for early diagnosis and targeted therapy. “That is very highly effective,” Lundberg says.

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