StemCell Therapy

Beronja and Ying dont think their approach has solved every problem for one, mice are still not humans. Also, most breast cancer-causing mutations are acquired later in life, whereas their approach introduces potential cancer-causing mutations while mice are still embryos. However, breast tumors in their model take about the same length of time to develop as those that develop in models where mutations are introduced to adult mice, Beronja said.

Ying screened 520 breast cancer-associated mutations from the TCGA for their effects on tumor development. Most have been found in fewer than 5% of breast cancer patients, and most are in genes of unknown function. He tested them in the context of a known cancer-driving mutation in the gene PIK3CA, the most commonly mutated gene in breast cancer. This would tell him whether these rare mutations commonly found in cancer cells that also have altered PIK3CA are riding its coattails or acting as co-captains.

While many of the mutations had no effect, 17 accelerated tumor growth and development. Whats more, Ying found that several of them shifted the tumors from a less-aggressive luminal subtype to a HER2-positive subtype.

That's something that was previously unknown, Ying said.

Though PIK3CA mutations were thought to dictate a luminal type of breast tumor, mutations in this gene are found in all four breast cancer subtypes, suggesting that other mutations influence tumor type when paired with altered PIK3CA. Their new approach might provide a platform for researchers to understand how, Ying said.

He chose one mutation in a gene called Tsc22d1 to explore more deeply. Tsc22d1 is deleted in about 2% of patients whose mutations are logged in TCGA. This mutation was one of those that Ying had found to enhance PIK3CA-driven tumor development and shift tumors to a HER2-like molecular subtype. His experiments shed light on the function of Tsc22d1, showing that in its unmutated form it acts to suppress PIK3CA-driven tumor growth.

The approach has potential far beyond screening cancer mutations, the scientists said. When Ying was developing his approach, he used his barcodes to trace mammary tissue development and discover that each mouse mammary gland arises from about 120 progenitor cells.

This question that Zhe ended up addressing which is, how many early stem cells give rise to an adult tissue? that's not known for any tissue in a mouse system or a human system, Beronja said. Its my favorite part of the study.

Yings approach could be used to answer similar questions for other tissues, such as skin or the cells lining the mouth, or perhaps to investigate questions surrounding the loss of stem cells as we age, Beronja said. A deeper understanding of these processes could be the first step toward correcting problems in tissue development or slowing the aging process.

Ying hopes that the functional information gleaned from his approach could support precision oncology by identifying future treatment targets.

Such information could directly affect treatment strategy, he said. I think this is the most direct way of translating those results from large genomic projects [like TCGA] into treatment, or at least identifying potential targets.

He and Beronja aim to apply their new strategy to develop mouse models of breast cancer that currently dont exist. One they want to create is a model in which metastasis, or cancer spread, occurs spontaneously and is driven by patient-derived mutations. Another is a spontaneous model of the most aggressive type of breast cancer, triple-negative, or basal-like, which currently lacks any options for targeted treatment. (In contrast, targeted treatments are on the market to treat people with each of the other three types of breast cancer.)

Most cancer-associated mutations are found in genes of unknown function. Beronja thinks his and Yings approach could solve this knowledge gap.

If our little lab is capable to test 520 [mutations] and identify 17 new drivers of tumorgenicity [tumor growth] and fully validate one of them if we can do it, there's really no excuse for the unknown category among the mutations, he said.

This work was funded by the National Institutes of Health, the National Cancer Institute, a Safeway Early Career Award in Cancer Research, and a Thomsen Family Fellowship.

Visit link:
A breast tumor might have thousands of mutations. Which are important? - Fred Hutch News Service

This entry was posted on February 13, 2020 at 12:45 pm and is filed under Stem Cell Negative. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed. |