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22May 2020

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Thesis defense Colinda Scheele: stem cell behavior in mammary glands

On May 7, Netherlands Cancer Institute researcher Colinda Scheele received her PhD degree cum laude. She could easily be considered a behavioral biologist, although instead of bonobos or zebra finches, she observed the behavior of generations of stem cells in healthy mammary tissue and mammary tumors in mice - live, in 3D, through a special microscope. One of the things she discovered was that only a small population of tumor cells in the mammary tumor - the cancer stem cells - drives a tumor to be invasive and life-threatening.

Colinda Scheele defended her PhD (online) at Utrecht University under the supervision of NKI researcher and UU professor Jacco van Rheenen. Armed with her cum laude doctoral degree, she can immediately start her own lab as junior group leader at the VIB-KU Leuven Center for Cancer Biology.

Colinda Scheele Nki Promotie


Thesis title: Unmasking in vivo stem cell dynamics in mammary tissue and mammary tumors

This PhD project was funded through a Boehringer Ingelheim PhD Fellowship

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 Stem cells: longer lifespan, more division

Stem cells develop, maintain and repair tissue. That's why they constantly multiply and renew themselves, and have a longer lifespan than regular cells in the body. This process is useful, but not without risks. With every cell division, there is a chance of a DNA mutation. The more a cell divides, the more mutations it passes on, which increases the risk of developing cancer. This is why these stem cells are of great interest to cancer researchers.

Stem cells reveal themselves through their behavior

Unfortunately, stem cells don't look any different from regular cells. For decennia, researchers have been looking for a good 'marker' for stem cells in mammary glands. Until recently, we weren't even sure whether there were stem cells in mammary glands at all, although the way the mammary glands change during puberty, menstrual cycle, and pregnancy made it highly likely that they were. The only thing revealing these stem cells is their behavior.


Color-coded stem cells and their offspring

Using several new techniques, Colinda Scheele followed the behaviors of entire families of mammary gland stem cells in mice, from puberty into adulthood, and from normal to derailed behaviors. She used fluorescent colors to label cells at random. These cells would pass on this color label to the daughter cells during cell division. Her theory was that any regular cell wouldn't divide or live as long, thus disappearing from sight together with its label. All remaining colored cells would be stem cells and their offspring. She continued to follow these stem cells live and in 3D through an advanced microscope.

New stem cell model

She grew familiar with the stem cells and their behaviors, and was now certain that mammary glands do contain stem cells. She then managed to develop a growth model of the mammary gland, which also predicted the development in other branched organs such as kidneys, pancreas, and the prostate. She also observed several previously unknown defining stem cell characteristics, such as their movements and patterns of self-organization.

Clustered inherited mutations

During puberty, the stem cells observed in the mice mostly flock together near the ends of the ducts, where they drive breast development. Once the mice have reached adulthood, the stem cells - now tasked with tissue repair and maintenance - spread out further throughout the mammary gland where each stem cell takes care of a section of the tissue. Each of those stem cells will divide, and so will their daughter cells - ultimately developing into what is known as a clone. There is an inherent risk to this organization pattern: any mutation in the DNA of the original stem cell will transfer to the part of tissue maintained by the cell. An accumulation of these inherited mutations can lead to a tumor - initially benign.


Only a fraction of cancer cells drives tumor expansion

How does such a breast tumor develop into a malignant, invasive, life-threatening tumor? Colinda Scheele applied a similar strategy to mammary tumors in mice. A random selection of cells was labelled with fluorescent colors, which led to the discovery that, similarly to healthy cells, only a small percentage of the labelled cancer cells - the cancer stem cells - were actively dividing, driving the tumor growth. The majority of tumor cells do not contribute to tumor expansion.

Treat the cancer stem cell!

This means that tumor growth might be halted when treatment is specifically targeted at the cancer stem cells within the tumor. Colinda Scheele hopes that her findings on stem cells can contribute to new treatments and higher survival rates for women with breast cancer. Maybe her research could one day even lead to the earlier detection of malignant, invasive tumors. Because, as she states in her summary, prevention is more important than a cure.

 

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