A new method could elucidate the identity and activity of cells in an entire organ or tumor at unprecedented resolution, according to a study co-led by researchers at Weill Cornell Medicine, NewYork-Presbyterian and the New York Genome Center.
The method was launched on January 2 in natural biotechnology, Record patterns of gene activity and the presence of key proteins in cells in tissue samples while retaining information about the precise location of cells. This enables the creation of complex, data-rich “maps” of organs, including diseased organs and tumors, which could be broadly useful in basic and clinical research.
“This technology is exciting because it allows us to map the spatial organization of tissue, including cell types, cellular activity and cell-cell interactions, in an unprecedented way,” said Associate Professor Dan Landau, Ph.D., co-senior author of the study. MD in Hematology and Medical Oncology, member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, and core faculty member at the New York Genome Center.
Another co-senior author is Dr. Marlon Stoeckius of 10x Genomics, a California-based biotechnology company that makes laboratory equipment used to analyze cells in tissue samples. The three co-first authors are Dr. Nir Ben-Chetrit, Xiang Niu and Ariel Swett, who were respectively postdoctoral fellows, graduate students and research technicians in Landau’s lab during the study.
The new method is part of a broader effort by scientists and engineers to develop better ways to “see” how organs and tissues work at the microscopic scale. Researchers have made significant progress in recent years, especially in techniques for analyzing gene activity and other layers of information in individual cells or small populations of cells. However, these techniques often require lysing the tissue and separating the cells from their neighbors, so information about the original location of the heterotypic cells within the tissue is lost. The new method also captures this spatial information at high resolution.
The approach, called spatial protein and transcriptome sequencing (SPOTS), is based in part on existing 10x Genomics technology. It uses glass slides suitable for imaging tissue samples with common microscope-based pathology methods, but also coated with thousands of specialized probe molecules. Each probe molecule contains a molecular “barcode” that indicates its two-dimensional position on the slide. When a thinly sliced tissue sample is placed on a glass slide and made permeable to its cells, probe molecules on the slide grab the messenger RNA (mRNA) of neighboring cells, which are essentially transcriptions of active genes Book. The method involves the use of designer antibodies that bind to the protein of interest in the tissue and also bind to specific probe molecules. Using rapid, automated techniques, researchers can identify captured mRNAs and selected proteins and map them precisely to their original locations throughout a tissue sample. The generated maps can be considered individually, or compared with standard pathology imaging of the sample.
The team demonstrated SPOTS on normal mouse spleen tissue, revealing the organ’s complex functional architecture, including clusters of different cell types, their functional states, and how these states vary with cell location.
To highlight the potential of SPOTS in cancer research, the researchers also used it to map the cellular organization of mouse mammary tumors. The resulting map depicts immune cells called macrophages in two distinct states, represented by protein markers — one state is active and anti-tumor, and the other is immunosuppressive and forms a barrier that protects tumors.
“We can see that these two macrophage subpopulations reside in different regions of the tumor and interact with different cells — differences in the microenvironment may drive their different activity states,” said Dr. Landau, also in New York City. Oncologist – Presbyterian/Weill Cornell Medical Center.
These details of a tumor’s immune environment—details that are often unresolved due to the sparseness of immune cells within tumors—may help explain why some patients respond to immune-boosting therapy and others do not, and could inform future immune responses, he added. Therapy design.
This initial version of SPOTS has a spatial resolution such that each “pixel” of the resulting dataset sums gene activity information for at least a few cells. Dr. Landau said, however, that researchers hope to narrow this resolution down to individual cells soon, while adding other layers of key cellular information.
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