3D photograph illustrating diving cancer cells during mitosis
Credit: Christoph Burgstedt/Getty Images

Using a spatial transcriptomic strategy to evaluate tens of thousands of normal and malignant tissue sites across whole organs, researchers have gained new insights into the early evolution of cancer. Interestingly, the researchers identified areas of supposedly healthy tissue that already had many of the genetic characteristics of cancer.

“Defining the transition from benign to malignant tissue is fundamental to improving early diagnosis of cancer,” wrote the authors in a report of the work, which was published in Nature. “Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution.”

The study was led by Alastair Lamb, PhD, of Oxford’s Nuffield Department of Surgical Sciences, and Joakim Lundeberg, PhD, of KTH Royal Institute of Technology, and was funded by Cancer Research UK.

The team used a spatial transcriptomics strategy to infer copy number variations (CNVs) in >120,000 regions of benign and malignant tissues across multiple organs. CNVs are specific segments of DNA that are duplicated or deleted in different cells.

“[When CNVs] occur in cells, these are also passed on reliably to daughter cells when they divide,” explained Lamb. “So [CNVs] are a useful marker for defining ‘clones’—groups of cells with a common genetic heritage.”

Furthermore, the gain or loss of a DNA segment can lead to enhanced or reduced expression of genes encoded in that segment. “If [a CNV encodes] a tumor suppressor protein and gene copies are lost leading to less of it being produced, that can lead to cancer,” explained Lamb.

“The power in studying CNVs is surveying the entire genome for gains and losses of genomic regions,” added Lundeberg. “We did this at a massive scale since we analyzed thousands of areas within a single tissue section.”

Focusing on the prostate, the research team identified clonal patterns in cancerous and noncancerous regions of the organ. “Specifically, we performed an in-depth spatial analysis of the prostate organ that generated an unprecedented atlas of up to 50,000 tissue domains in a single patient and 120,000 tissue domains across ten patients,” they wrote.

“[Our] approach revealed some surprising results,” said Lamb in a press statement. “For example, we have found that many of the copy number events we previously thought to be linked specifically to cancer are actually already present in benign tissue.”

They corroborated their analysis with two breast cancer samples, some skin, a lymph node, and some brain tissue. “We [show] that, in some tumour types, particularly in prostate, glioma and breast cancers, CNV analysis identifies distinct clonal patterns within tumours,” they wrote.

“We propose that CNVs can precede tumorigenesis [and] are insufficient to deliver immediate phenotypic transformation,” they continued. “These [altered benign] cells may represent an intermediate state between benign and malignant cells.”

The team has a few plans to advance the work. “Our immediate next step is to identify the clonal composition of small numbers of cells that have spread to the lymph nodes, the first point of spread in men with prostate cancer, and identify which clone those cells arose from in the prostate,” said Lamb. “We know that the only prostate cancer cells that really matter are those that have the capacity to spread.”

They also plan to explore the whole ecosystem of the prostate gland. “There is great interest in understanding the ecosystem over time—achieving a spatiotemporal map of prostate disease,” said Lundeberg.

“Technically we would also like to add additional spatial modalities to our analysis, such as epigenomics and proteomics,” he said. This will help them elucidate the very early molecular events in healthy cells harboring CNV signatures of cancer.

The team’s findings may also have implications for early disease detection and treatment. “If our work is successful in identifying features of ‘lethal clones’ by focusing on initial sites of spread, then this would allow us, in other patients, to use these features to identify early on whether certain prostate cancer clones are present that definitely need urgent treatment, or whether others may not need treating at all and those men can avoid the many side effects of treatment,” said Lamb.

“Importantly, we do not see this as replacing our current histopathology-based decision making,” said Lamb. “In prostate cancer, the Gleason grading system has served us very well for many decades. Instead, we want to add a key layer of spatial molecular detail to fill the big gaps left by using histopathology alone. This way, we hope, the right patients will get the right treatment at the right time!”

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