Measuring cancer cell state can reveal drug susceptibility

Date:
December 9, 2021
Source:
Massachusetts Institute of Technology
Summary:
Pancreatic cancer cells can exist in, and transition between,
three different cell states, according to new research. These
states respond differently to a variety of cancer drugs, and
altering the tumor microenvironment can drive tumor cells from
one state to another, potentially offering a way to make them more
susceptible to a particular drug.



FULL STORY ==========================================================================
Over the past few decades, scientists have made great strides in
understanding the genetic mutations that can drive cancer. For some types
of cancer, these discoveries have led to the development of drugs that
target specific mutations.


========================================================================== However, there are still many types of cancer for which no such targeted therapies are available. A team of researchers from MIT, Dana Farber
Cancer Institute, and other institutions is now examining whether another
cell trait - - RNA expression patterns -- influences drug responses and
can be used to identify treatments a tumor might be susceptible to.

In a new study of pancreatic cancer cells, the researchers identified
three prototypical RNA-expression states and uncovered differences in
their susceptibility to a variety of cancer drugs. They also discovered
that altering the tumor microenvironment can drive tumor cells from one
state to another, potentially offering a way to make them more susceptible
to a particular drug.

"What we show in this paper is that cancer cell state is plastic in
response to the microenvironment and has a dramatic impact on drug
sensitivity. This opens new frontiers for thinking about drug development
and how to select drugs for individual patients," says Alex Shalek, a
core member of the Institute for Medical Engineering and Science (IMES)
at MIT, an associate professor of chemistry, and an extramural member
of MIT's Koch Institute for Integrative Cancer Research. He is also a
member of the Ragon Institute of MGH, MIT and Harvard and an institute
member of the Broad Institute.

Shalek and Brian Wolpin, an associate professor of medicine at Harvard
Medical School and Dana-Farber Cancer Institute; William Hahn, a
professor of medicine at Harvard Medical School and Dana-Farber; and
Andrew Aguirre, an assistant professor of medicine at Harvard Medical
School and Dana-Farber; are the senior authors of the study, which
appears today in Cell. The paper's lead authors are Srivatsan Raghavan,
an instructor in medicine at Harvard Medical School and Dana-Farber;
Peter Winter, an MIT postdoc; Andrew Navia, an MIT graduate student;
and Hannah Williams, a research fellow in medicine at Harvard Medical
School and Dana-Farber.

Cell states Sequencing a cell's genome can reveal cancer-linked mutations,
but identifying these mutations doesn't always provide information that
can be acted upon to treat a particular tumor. To generate additional data
that could be used to help choose more targeted treatments, Shalek and
other researchers have turned to single-cell RNA-sequencing, which reveals
the genes that are being expressed by each cell at a moment in time.



========================================================================== "There are plenty of situations where the genetics are incredibly
important, where you can develop these very precise drugs that target
mutations or translocations," Navia says. "But in many instances mutations alone don't give you an effective way to target cancer cells relative
to healthy ones." In this study, the researchers analyzed cells from pancreatic ductal adenocarcinoma (PDAC). There are very few targeted
drugs available to treat pancreatic tumors, so most patients receive chemotherapy drugs that may be effective initially but often stop
working as tumors become resistant. Using single-cell RNA-sequencing,
the researchers analyzed about 25 metastatic tumor samples from pancreatic cancer patients.

Previous analyses of pancreatic tumor cell RNA have revealed two broad categories of cell states: basal-like, which is a more aggressive state,
and classical. In the new study, the researchers identified a third state
that appears to be an intermediate between those two. Cancer cells may
pass through this state as they transition from classical to basal-like,
the researchers say.

The researchers also found that the environment in which cancer cells
are grown plays a key role in determining their state. In this study,
they grew matched "organoids," or tiny cancer aggregates from each
patient's biopsy. Such organoids are often used in precision medicine
pipelines to model tumors from individual patients, to help identify
drugs that might be useful for those individuals.

When comparing each in vivo single-cell profile to the matched ex
vivoorganoid model, the researchers found that the organoids often exist
in a different RNA state than cancer cells examined directly from the
same patient. "We see the same DNA mutations in the original tumor and
its model, but when we start to examine what they look like at the RNA
level, we find that they're very, very different," Shalek says.



==========================================================================
That suggests that the state of a tumor can be influenced by the
conditions in which it's grown rather than its genetics alone, he
says. The researchers also found that they could drive cancer cells,
even long-established cell line models, to switch between different
states by changing their growth conditions.

Treating cells with TGF-beta, for example, drives them to a more
aggressive, basal-like state, while taking TGF-beta away leads the cells
to revert to the classical state in a dish.

Cells in each of those states depend on different cell-signaling pathways
to survive, so knowing the cell state is critical to selecting the right
kind of drug to treat a particular tumor, the researchers say.

"When we started looking at drug sensitivity, it became very clear
that the same model pushed into a different state would respond
very differently to a drug," Navia says. "These state-specific
sensitivities become critical as we think about selecting drugs and
avoiding resistance. If you don't know the right state, you could pick
the entirely wrong compound and try to target the wrong pathways. If
you don't consider plasticity, the cancer may only respond temporarily
until its cells change state." Targeted therapy The findings suggest
that further analyzing the interplay of genetics, cell state, and the
tumor microenvironment could help researchers to develop new drugs that
would effectively target individual patients' tumors.

"We're not erasing decades of understanding cancer as a genetic disease,
but we're certainly saying that we need to much better understand
the intersection between genetics and state," Winter says. "Cell state absolutely has ties to the underlying sensitivity of certain models, and therefore patients and to specific drugs." The discovery that cancer
cells can be driven from one state to another by modifying the signals
in their microenvironment raises the possibility of locking cancer cells
into a particular state in a predictable way by therapeutically altering
the tumor microenvironment, and then giving a separate drug to target
that locked state and enhance treatment efficacy.

With their colleagues at Dana-Farber, the MIT team is now running much
larger drug screens to measure how each drug affects pancreatic cancer
cells in different states. They are also studying other types of cancer
to determine if those cancer cells are also able to transition between different states in response to changes in their microenvironment.

The research was funded, in part, by the National Institutes of Health,
the Koch Institute and Dana-Farber/Harvard Cancer Center Bridge Project,
the Ludwig Center for Molecular Oncology at MIT, the Beckman Young
Investigator Program, a Sloan Fellowship in Chemistry, and the Pew-Stewart Scholars Program for Cancer Research.

========================================================================== Story Source: Materials provided by
Massachusetts_Institute_of_Technology. Original written by Anne
Trafton. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Srivatsan Raghavan, Peter S. Winter, Andrew W. Navia, Hannah
L. Williams,
Alan DenAdel, Kristen E. Lowder, Jennyfer Galvez-Reyes, Radha
L. Kalekar, Nolawit Mulugeta, Kevin S. Kapner, Manisha S. Raghavan,
Ashir A. Borah, Nuo Liu, Sara A. Va"yrynen, Andressa Dias Costa,
Raymond W.S. Ng, Junning Wang, Emma K. Hill, Dorisanne Y. Ragon,
Lauren K. Brais, Alex M. Jaeger, Liam F. Spurr, Yvonne Y. Li,
Andrew D. Cherniack, Matthew A. Booker, Elizabeth F. Cohen, Michael
Y. Tolstorukov, Isaac Wakiro, Asaf Rotem, Bruce E. Johnson, James
M. McFarland, Ewa T. Sicinska, Tyler E. Jacks, Ryan J. Sullivan,
Geoffrey I. Shapiro, Thomas E. Clancy, Kimberly Perez, Douglas
A. Rubinson, Kimmie Ng, James M. Cleary, Lorin Crawford, Scott R.

Manalis, Jonathan A. Nowak, Brian M. Wolpin, William C. Hahn,
Andrew J.

Aguirre, Alex K. Shalek. Microenvironment drives cell state,
plasticity, and drug response in pancreatic cancer. Cell, 2021;
184 (25): 6119 DOI: 10.1016/j.cell.2021.11.017 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211209124228.htm

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