Cell: There are three states of cancer cells!

In the past few decades, scientists have made tremendous progress in understanding the genetic mutations that drive cancer
.

For certain types of cancer, these findings have led to the development of drugs that target specific mutations

In the past few decades, scientists have made tremendous progress in understanding the genetic mutations that drive cancer

In a new study, researchers from research institutions such as the Massachusetts Institute of Technology and the Dana-Farber Cancer Institute studied another cell characteristic— whether RNA expression patterns affect drug response and whether it can be used Identify sensitive treatments for tumors

In this new study on pancreatic cancer cells, these authors identified three typical RNA expression states and discovered differences in their sensitivity to multiple cancer drugs

Alex Shalek, co-corresponding author of the paper and a core member of the MIT Institute of Medical Engineering and Science, said, “What we have shown in this paper is that the state of cancer cells is plastic in response to the microenvironment in which it is located.

Cell state cell state

Sequencing the genome of cancer cells can reveal mutations associated with cancer, but identifying these mutations does not always provide information that actions can be taken to treat specific tumors
.

In order to generate additional data that can be used to help select more targeted treatments, the authors sought the help of single-cell RNA sequencing, which reveals the genes that each cell is expressing at a certain moment

Sequencing the genome of cancer cells can reveal mutations associated with cancer, but identifying these mutations does not always provide information that actions can be taken to treat specific tumors

The co-first author of the paper and a graduate student at MIT, Andrew Navia, said, “There are many cases where genetics is very important, and you can develop these drugs that target mutations or translocations very precisely

The picture is from Cell, 2021, doi:10.

1016/j.

In this new study, the authors analyzed cells from pancreatic ductal adenocarcinoma (PDAC)
.

Currently, there are very few targeted drugs for the treatment of pancreatic tumors.

In this new study, the authors analyzed cells from pancreatic ductal adenocarcinoma (PDAC)

Previous analysis of pancreatic tumor cell RNA revealed two major types of cell states: the basal-like cell state, which is a more aggressive state, and the classical state
.
In this new study, these authors discovered a third state, which seems to be an intermediate state between these two states
.
They say that cancer cells may pass through a third state when they transition from the classic state to the basal-like cell state
.

These authors also found that the growth environment of a cancer cell plays a key role in determining its cell state
.
In this new study, they used the living tissue samples of each patient to cultivate matching "organoids," that is, tiny cancer aggregates
.
Such organoids are often used in precision medicine pipelines to model individual patients’ tumors to help determine drugs that may be useful for these people
.

These authors also found that the growth environment of a cancer cell plays a key role in determining its cell state
.
In this new study, they used the living tissue samples of each patient to cultivate matching "organoids," that is, tiny cancer aggregates
.
Such organoids are often used in precision medicine pipelines to model individual patients’ tumors to help determine drugs that may be useful for these people
.
Precise

When comparing the data of individual single cells with matched in vitro organoid models, these authors found that organoids often exist in different RNA states compared to cancer cells directly derived from the same patient
.
Shalek said, “We saw the same DNA mutations in the original tumor and its model, but when we started to check how they looked at the RNA level, we found that they were very, very different
.
”

When comparing the data of individual single cells with matched in vitro organoid models, these authors found that organoids often exist in different RNA states compared to cancer cells directly derived from the same patient
.
Shalek said, “We saw the same DNA mutations in the original tumor and its model, but when we started to check how they looked at the RNA level, we found that they were very, very different
.
”

He said this suggests that the status of the tumor may be affected by its growth conditions, not just its genetics
.
These authors also found that they can drive cancer cells to switch between different states by changing growth conditions, even in long-established cell line models
.
For example, treating cancer cells with TGF-beta will prompt them to enter a more aggressive basal-like state, while removing TGF-beta in a petri dish will prompt them to return to a classic state
.

He said this suggests that the status of the tumor may be affected by its growth conditions, not just its genetics
.
These authors also found that they can drive cancer cells to switch between different states by changing growth conditions, even in long-established cell line models
.
For example, treating cancer cells with TGF-beta will prompt them to enter a more aggressive basal-like state, while removing TGF-beta in a petri dish will prompt them to return to a classic state
.

The authors say that each type of cancer cell in these states relies on different cell signaling pathways to survive, so understanding the cell state is essential for choosing the right drug to treat a particular tumor
.

The authors say that each type of cancer cell in these states relies on different cell signaling pathways to survive, so understanding the cell state is essential for choosing the right drug to treat a particular tumor
.

Navia said, “When we started to study drug sensitivity, it was obvious that the same model was pushed into different states to respond to drugs very differently
.
When we consider choosing drugs and avoiding resistance, the sensitivity of these specific states It becomes crucial
.
If you don’t know the right state, you may choose the completely wrong compound and try to target the wrong pathway
.
If you don’t think about plasticity, the cancer may only be a temporary response until its cells change state
.
"

Navia said, “When we started to study drug sensitivity, it was obvious that the same model was pushed into different states to respond to drugs very differently
.
When we consider choosing drugs and avoiding resistance, the sensitivity of these specific states It becomes crucial
.
If you don’t know the right state, you may choose the completely wrong compound and try to target the wrong pathway
.
If you don’t think about plasticity, the cancer may only be a temporary response until its cells change state
.
"

Targeted therapy

Targeted therapy Targeted therapy

These findings suggest that further analysis of the interaction between genetics, cell status, and tumor microenvironment may help scientists develop new drugs that effectively target each patient’s tumor
.

These findings suggest that further analysis of the interaction between genetics, cell status, and tumor microenvironment may help scientists develop new drugs that effectively target each patient’s tumor
.

The co-first author of the paper and a postdoctoral researcher at the Massachusetts Institute of Technology Peter Winter said, "We have not erased decades of understanding of cancer as a genetic disease, but we definitely say that we need to better understand genetics and The intersection between cell states
.
Cell state is definitely related to the potential sensitivity of certain models, and therefore to the sensitivity of patients to specific drugs
.
"

The co-first author of the paper and a postdoctoral researcher at the Massachusetts Institute of Technology Peter Winter said, "We have not erased decades of understanding of cancer as a genetic disease, but we definitely say that we need to better understand genetics and The intersection between cell states
.
Cell state is definitely related to the potential sensitivity of certain models, and therefore to the sensitivity of patients to specific drugs
.
"

Cancer cells can be driven from one state to another by changing the signals in their microenvironment.
This discovery raises the possibility of changing the tumor microenvironment through treatment in a predictable way.
Lock the cancer cells in a specific state, and then give a separate drug to target this locked state and improve the therapeutic effect
.

Cancer cells can be driven from one state to another by changing the signals in their microenvironment.
This discovery raises the possibility of changing the tumor microenvironment through treatment in a predictable way.
Lock the cancer cells in a specific state, and then give a separate drug to target this locked state and improve the therapeutic effect
.

These authors are now conducting larger drug screenings to measure how each drug affects different states of pancreatic cancer cells
.
They are also studying other types of cancer to determine whether these cancer cells can also switch between different states in response to changes in their microenvironment
.

These authors are now conducting larger drug screenings to measure how each drug affects different states of pancreatic cancer cells
.
They are also studying other types of cancer to determine whether these cancer cells can also switch between different states in response to changes in their microenvironment
.

Reference:
Srivatsan Raghavan et al.
Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer.
Cell, 2021, doi:10.
1016/j.
cell.
2021.
11.
017.

Reference materials:
Srivatsan Raghavan et al.
Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer.
Cell, 2021, doi:10.
1016/j.
cell.
2021.
11.
017.
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