Nature: Using spatial genomics to understand how breast cancer cloning evolved

Genome sequencing of cancer shows that different subclones are often embedded in
the same tumor.
Although these are based on the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms behind them are less well understood
.

Recently, an international research team used spatial genomics technology to map different clones
in two patients' breast tumors.
The findings, published Nov.
9 in the journal Nature, provide new insights
into how tumors progress and interact with their surroundings.

For this study, the researchers employed a new method
called base-specific in situ sequencing (BaSISS).
With this method, they were able to quantitatively map the genetic makeup of tumor clones and their spatial structure
.

The research team used this method to analyze eight tissue samples from two patients with multifocal breast cancer from different stages
of cancer progression.
They found that the different clones showed a certain spatial structure in the samples, with specific gene expression patterns, as well as microenvironments and microanatomical niches
.

Co-corresponding author Professor Mats Nilsson from the Life Sciences Laboratory at Stockholm University in Sweden said: "With this innovative technique, we are able to accurately reconstruct the diffusion process
of these clones.
An important conclusion we came to after our study is that the reasons for cancer cell survival and spread are not just genetic changes, but may also be related
to where they are located.
This adds another layer of complexity and opens up potential new ways
to treat the disease.
”

Professor Mats Nilsson is a pioneer in the field of in situ sequencing and his team has developed a variety of in situ sequencing methods that have been commercialized
through Cartana.
In 2020, Cartana was acquired by 10x Genomics, and Mats Nilsson became 10x Genomics' scientific advisor.

The BaSISSIAN process involves cryosectioning freshly frozen tissue blocks, followed by spatial clonal localization and phenotyping
.
After using batch cell sequencing to discover emerging mutations and tumor subclones, they designed specific fluorescent molecular probes to detect where on the slice transcripts were expressed
.
The cloned atlas
are then generated by computer methods.

Nilsson and colleagues applied this approach to eight tissue blocks in two patients, one with ER-positive and HER-negative primary invasive breast cancer and the other with triple-negative invasive breast cancer
.
These tissue samples cover all stages of cancer progression, from ductal carcinoma in situ to invasive cancer and lymph node metastasis
.

The analysis results showed that subclonal growth showed complex patterns
.
For example, the researchers found that subclonals tend to form spatial patterns
associated with their histological progression.
However, there are hundreds of mutations between each subclone that exist in both carcinoma in situ and invasive histological states
.
This suggests that there is also a disconnect
between histology and genetic disease progression.

The researchers also noted an association
between phenotypic or histological state and the genetic state of cells.
For example, clones carrying PTEN mutations showed higher density Ki-67 IHC nuclei staining
compared to wild-type PTEN clones.
However, Ki-67 scores were similar for any clone, whether ductal carcinoma in situ or invasive state, suggesting that although Ki-67 upregulation occurred at a similar time to PTEN mutation timing, it occurred before
the tumor became aggressive.

Moritz Gerstung, co-senior author of the German Cancer Research Centre, said: "What's exciting about this technology is that for the first time we're seeing how the environment affects cancer evolution
.
Our ability to see which cancer clones become more aggressive and which are not, which will help us better understand the key steps in tumor growth and how we can mitigate or prevent disease
.
”

Original search

Lomakin, A.
, Svedlund, J.
, Strell, C.
et al.
Spatial genomics maps the structure, nature and evolution of cancer clones.
Nature (2022).
https://doi.
org/10.
1038/s41586-022-05425-2