response to chemotherapy
The analysis, done in three colon cancer cell lines, is believed to be
the first to profile transcriptome-level changes in response to DNA damage across individual cells

Date:
August 25, 2020
Source:
Michigan Medicine - University of Michigan
Summary:
Single-cell analysis, done in three colon cancer cell lines, is
believed to be the first to profile transcriptome-level changes
in response to DNA damage across individual cells.



FULL STORY ========================================================================== Chemotherapy works by attacking rapidly dividing cells within the
body. But small pockets of cancer cells can withstand its assault,
allowing the cancer eventually to return.


========================================================================== Gaining a better understanding of why some cancer cells survive while
others die is critical for making chemotherapy more effective, says Jun
Hee Lee, Ph.D., a cancer researcher at the University of Michigan Rogel
Cancer Center.

Using a technique called single-cell RNA sequencing, a research team
from U- M was able to show for the first time how individual cells
within a single population of cancer cells respond differently to the
DNA damage caused by chemotherapy. The responses, they found, fall into
three groups: activating genes that control cell death, cell division,
or stress response, according to findings published in Cell Reports.

"Collectively, we observed that cells with different fates actually had completely distinct sets of activated genes and that these different 'transcriptomic landscapes' dictate the fates of cells after DNA
damage from chemotherapy," says Lee, co-senior author of the study
and an associate professor of molecular and integrative physiology at
Michigan Medicine.

While DNA contains the complete instruction manual for the cell,
sequences that are transcribed into RNA tell the story of which genes are switched on or off at a given time -- that is, which sets of individual instructions are being acted upon. The transcriptome is the complete
set of these RNA sequences within a given cell.

Applying single-cell techniques Among scientists, single-cell analysis
is frequently compared to a fruit smoothie, Lee notes. Many types of
studies measure characteristics or responses across a group of cells
-- a mixture of individual players that contribute to a greater whole,
like fruit in a smoothie. This can provide useful information, but can
also obscure differences between and among the individual contributors
-- the cell-level equivalent of the strawberries and blueberries and
bananas in the smoothie. Single-cell techniques allow those individual differences to be teased out.



==========================================================================
The study analyzed more than 10,000 cells from three colon cancer
cell lines.

The cells were exposed to the chemotherapy agent fluorouracil, which is commonly used against colon cancer and other types of cancer. Some of
the observations were replicated with additional techniques and different chemotherapy drugs.

"Previously, the scientific consensus was that DNA damage leads to a
fairly uniform transcriptional response, which leads to different cell
fates in a passive way, based on the given levels of gene expression in
the cell," Lee says. "In contrast, we found that different DNA damage
response genes were often upregulated only in the subset of cells that
all share a particular cell fate." The group is conducting ongoing
research to understand what factors that cause some cells have one fate
and others to have a different fate.

"If we learn that there's a certain sub-population of cells with specific characteristics that allow them to survive chemotherapy when other
cells die, then scientists might look for ways to target those cells specifically," Lee says Making data available to other researchers The
research team, which was co-led by Hyun Min Kang, Ph.D., an associate
professor of biostatistics at the School of Public Health, is also making
their data available online for other researchers.



==========================================================================
"For instance, other scientists can examine how individual genes
are expressed across single cells before and after chemotherapy
treatments. and how the specific gene expression is correlated with the chemotherapy dose, or with the expression of other genes," Kang says. "The online tool can also be used by researchers to test new hypotheses and
generate new data -- and therefore has the potential to accelerate future research on DNA damage responses." This work was supported by grants from
the National Institutes of Health (R01DK102850, R01DK114131, U01HL137182, P30AG024824, P30DK034933, P30DK089503, P30CA046592), the Chan Zuckerberg Initiative, U-M's MCubed Initiative, an Organogenesis Fellowship and an American Association for the Study of Liver Diseases Pilot Research Award.


========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Original written by Ian
Demsky. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Sung Rye Park, Sim Namkoong, Leon Friesen, Chun-Seok Cho, Zac Zezhi
Zhang, Yu-Chih Chen, Euisik Yoon, Chang H. Kim, Hojoong Kwak, Hyun
Min Kang, Jun Hee Lee. Single-Cell Transcriptome Analysis of Colon
Cancer Cell Response to 5-Fluorouracil-Induced DNA Damage. Cell
Reports, 2020; 32 (8): 108077 DOI: 10.1016/j.celrep.2020.108077 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200825115516.htm

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