New model reveals how genomic instability occurs in histologically benign tissue

Understanding which cells give rise to which areas of cancer can improve our understanding of how a tumor grew and grew, including how it changed genetically over time. This was made possible by a new technique called spatial transcriptomics, which allows scientists to see what genetic changes are occurring without breaking down the tissue they are examining. This adds a new dimension that researchers have now used to reveal which cells have mutated and where in an organ’s ecosystem.

Current techniques for studying the genetics of cells in tumors involve taking a sample from the cancerous area and analyzing the DNA of those cells. The problem is that many cancers, like prostate cancer, are three-dimensional, which means that a single sample would only give a small glimpse of the tumor.

In a new study published in Nature and funded by Cancer Research UK, the researchers used spatial transcriptomics to create a cross-sectional map of an entire prostate, including areas of healthy and cancerous cells. By grouping the cells according to a similar genetic identity, they were surprised to see areas of supposedly healthy tissue that already had many of the genetic hallmarks of cancer. This finding was surprising because of both the genetic variability within the tissue and the large number of cells that would be considered healthy, but contained mutations usually identified with cancer cells.

Prostate tissue is three-dimensional, and like most organs susceptible to cancer, we still have a lot to learn about the cellular changes that cause cancer and where it comes from. One thing we’re pretty sure of is that it starts with genetic mutations.”

Alastair Lamb, Nuffield Department of Surgical Sciences, University of Oxford

“We’ve never had this level of resolution available before, and this new approach has revealed surprising results. For example, we found that many copy number events that we previously thought were specifically related to cancer are actually already present in benign tissue. This has great implications for diagnosis and also potentially for deciding which elements of a cancer need to be treated.”

Professor Joakim Lundeberg from the KTH Royal Institute of Technology, said: “Mapping thousands of tissue regions in a single experiment is an unprecedented approach to deconvolve tumor heterogeneity and their microenvironment. This high-resolution view impacts how we approach complex ecosystems such as cancer. The ability to identify early events is particularly exciting going forward.”

Additionally, the researchers analyzed more than 150,000 regions in three prostates, two breast, skin, lymph node and brain tissue cancers, and developed an algorithm to track clusters of cells with similar genetic changes – clones – in their precise location. This approach allowed them to zoom in from visible tissues to microscopic multicellular structures and to the genes themselves, while keeping a handle on the overall tissue landscape.


Journal reference:

Erickson, A. et al. (2022) Spatially resolved clonal copy number alterations in benign and malignant tissue. Nature.

Irene B. Bowles