Tumor Genetics Blog

By: Päivi Pihlajamaa and Alison Ollikainen

Why do cancer cells grow faster than normal cells? What are the mechanisms that drive tumor growth? Is there any way to slow them down? Päivi Pihlajamaa, a senior researcher in the Medical Systems Biology research group sheds some light on these questions by talking about her current research on what makes cancer cells grow faster than the normal cells and the role of aberrant transcriptional pathways which promote tumor growth.

Can you introduce yourself?

I am an experimental scientist. My background is a Masters degree in Translational Health Biosciences with a major in Drug Development (University of Turku) and a PhD from the Faculty of Medicine (University of Helsinki). I have been working since 2014 as a post-doctoral researcher and currently as a senior researcher at the University of Helsinki.

Where do you work?

I work at the Faculty of Medicine of University of Helsinki in the Medical Systems Biology Research Group led by Professor Jussi Taipale, which is part of the Finnish Center of Excellence in Tumor Genetics Research. I also worked one year at the University of Cambridge, UK, where Jussi Taipale has another research group.

What are you studying?

I have always been drawn to basic biomedical research and I have been studying different aspects of transcription factors and gene regulation in my PhD and post-doctoral projects. Currently, my main goal is to study what makes cancer cells grow faster than the normal cells.

Transcription factors are proteins that bind to the DNA and determine which genes are expressed in each cell. Do they regulate how fast a tumor will grow?

Transcription factors control many different functions in cells, but some of them, like MYC, regulate cell growth. In normal healthy tissue, cell growth and proliferation (how rapidly cells reproduce) are tightly controlled, but during the formation of tumors, cells escape these control mechanisms and begin to grow uncontrollably. MYC is known to be overactive in more than half of human cancers, so studying how it promotes cell proliferation is important.

So, in normal tissues, there are a “certain amount” of healthy cells, but in tumors there are too many cells that are growing too fast?

Yes, in tumors the control mechanisms fail, so cells proliferate continuously, resulting in too many cells. In my work, I am interested in how aberrant transcriptional pathways promote tumor growth and I’m studying what are the exact regulatory events by which transcription factors such as MYC make cells grow faster.  

How do you study regulation of cell growth?

I am using modern experimental methods in mammalian cell culture systems such as CRISPR/Cas9-based precision genome editing and genome-wide screens to study the functional relationship between transcription factor binding, gene expression, and cell proliferation.

In simple terms, in the beginning of the experiments, I make small mutations in the genome of the cells, which are meant to disrupt transcription factor binding sites, for example, a small change to mutate the MYC binding site. Then I follow how the mutations affect cell growth.

How many mutations do you make in the cells?

We can study few mutations only or even tens of thousands in one experiment. However, I aim at making only one mutation per cell, so then it is easy to analyze their effects from the data.

How do you know “where” to put the mutation?

Based on the earlier results from our group and many others, we can predict which might be the important downstream target genes that MYC regulates. Then I design the mutation in a way that it should prevent MYC from binding to that site.

Does this mimic what might happen in a living person who might harbor this mutation and see how that affects the amount of cells that grow?

Yes and no. In theory, similar mutations might occur in human tumors, but usually it is the master regulator MYC that is out of control, regulating downstream genes that in turn enable cells grow faster. So rather than mimicking the mutations that occur in human tumors, the more important idea here is to use the mutations as an experimental tool to prove a point: if a particular gene or DNA element is important for cell growth, mutating it will make cells grow slower.

What’s the lab work like and how long does an experiment like this take?

After introducing the mutations to the DNA of the cells, I culture the cells for a defined time period, for example one week or three weeks. Then I study the final population of cells to identify which mutations affected cell proliferation. For this, I process their DNA for next-generation sequencing, and then I analyze the sequence information to see what mutations are there. Often these experiments involve culturing hundreds of millions of cells and handling dozens of large culture dishes.

What kind of cells are you using, where do they come from? Can you do the same experiment on cells from other types of tissue?

MYC is overactive in many different human cancers, so new findings from this work might ultimately help patients with various cancers. In these experiments, I am using cells derived from human colon cancer and leukemia, but other cell and tissue types could be used as well. 

What could this work mean for the treatment of cancer?

Since MYC is the master regulator of cell proliferation, it would be an ideal target for cancer therapeutics. But MYC itself is not easy to target with drugs. That’s why we try to identify which of its downstream target genes contribute to faster growth rate in cancer by using this experimental strategy to mutate its binding sites. The goal is to identify some gene or pathway that could be inhibited by cancer drugs.