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▎Editor of WuXi AppTec's content team Breast cancer is one of the most common types of cancer in women, accounting for approximately 23% of the number of cancer cases in women worldwide
.
In general, the 5-year survival rate of breast cancer is relatively high, because many types of breast cancer cells are more sensitive to estrogen or progesterone and can be treated accordingly
.
But for triple-negative breast cancer (TNBC) patients, treatment is more difficult
.
Such breast cancer cells lack receptors for estrogen, progesterone and the growth factor HER2, which means that conventional therapies are not ideal for their treatment
.
And immunotherapy has become the greatest hope for these patients
.
The FDA approved the first immunotherapy atezolizumab for the treatment of TNBC in 2019, which is an anti-PD-L1 monoclonal antibody
.
However, its efficacy is still limited to some patients, and we still need to find other therapeutic targets
.
At present, the research field is focusing on tumor-associated macrophages (TAM), which are cells that exist in the tumor microenvironment and can promote angiogenesis and tumor growth
.
Therefore, finding a signal target that can affect TAM may help kill cancer cells
.
To this end, the team of Professor Liu Xiaole of Harvard Medical School in the United States adopted a library screening method to conduct a carpet search for targets
.
According to the team’s latest research published in Cell, their CRISPR/Cas9 knockout library MusCK can target 4500 mouse genes, which are all related to tumor initiation, development and immune regulation
.
▲Professor Liu Xiaole (picture source: school official website personal homepage) in vitro verification results show that the library can knock out related oncogenes well
.
Next, they introduced the library into the mouse TNBC cell line 4T1, and injected the 4T1 cells infected with the library into the mouse mammary fat pad for tumor formation
.
After 16 days, the researchers collected tumor cells for subsequent analysis
.
The most intuitive result of the experiment is that those mice lacking T cells have the largest tumors, and some mice implanted with 4T1 cells overexpress ovalbumin, which can enhance immune activity, and their tumors have the smallest tumors
.
▲Schematic diagram of the research process (picture source: reference [1]) And by comparing the knockout of sgRNA in the two types of tumors, the researchers found some key genes related to the invasiveness of 4T1 cells
.
For example, the knockout of genes related to the interferon gamma pathway is related to the reduction of tumor size
.
This is consistent with the results of past studies that found that IFNγ can promote tumor invasion
.
During the first screening process, a total of 79 candidate genes were presented to the researchers.
They constructed the library version 2.
0 of these genes and conducted two rounds of screening
.
The second screening process became more refined, and the E3 ubiquitination ligase encoding gene Cop1 in the IFNγ signaling pathway became the focus of attention because it was almost completely knocked out in mice with the smallest tumors
.
Compared with the control group, Cop1 knockout mice not only significantly slowed the progression of their tumors, but their survival period was also prolonged.
Even if they did not receive anti-PD-1 treatment, they could also obtain this advantage
.
▲After Cop1 is knocked out, the number of macrophages that infiltrate the tumor is reduced (picture source: Reference [1]) In addition, the researchers found that down-regulation of Cop1 expression can significantly reduce the chemical substances that attract macrophages in the tumor, which brings The direct result is that the number of macrophages immersed in the tumor is significantly reduced, and the corresponding TC1 tumor volume is also shrinking
.
Specifically, after Cop1 is knocked out, the degree of ubiquitination of the downstream substrate C/ebpδ decreases, which will directly lead to a sharp increase in its expression
.
C/ebpδ can inhibit the transcription of macrophages-related chemokines, thereby reducing the possibility of macrophages entering the tumor
.
This discovery is expected to bring brand-new target drugs to more cancer patients, and bring new hope to patients with breast cancer that is not sensitive to conventional treatment and refractory
.
Reference: [1] Wang X, Tokheim C, Wang B, et al.
In Vivo CRISPR Screens Identify E3 Ligase Cop1 as a Modulator of Macrophage Infiltration and Cancer Immunotherapy Target.
Cell 2021.
DOI:10.
1016/j.
cell.
2021.
09.
006
.
In general, the 5-year survival rate of breast cancer is relatively high, because many types of breast cancer cells are more sensitive to estrogen or progesterone and can be treated accordingly
.
But for triple-negative breast cancer (TNBC) patients, treatment is more difficult
.
Such breast cancer cells lack receptors for estrogen, progesterone and the growth factor HER2, which means that conventional therapies are not ideal for their treatment
.
And immunotherapy has become the greatest hope for these patients
.
The FDA approved the first immunotherapy atezolizumab for the treatment of TNBC in 2019, which is an anti-PD-L1 monoclonal antibody
.
However, its efficacy is still limited to some patients, and we still need to find other therapeutic targets
.
At present, the research field is focusing on tumor-associated macrophages (TAM), which are cells that exist in the tumor microenvironment and can promote angiogenesis and tumor growth
.
Therefore, finding a signal target that can affect TAM may help kill cancer cells
.
To this end, the team of Professor Liu Xiaole of Harvard Medical School in the United States adopted a library screening method to conduct a carpet search for targets
.
According to the team’s latest research published in Cell, their CRISPR/Cas9 knockout library MusCK can target 4500 mouse genes, which are all related to tumor initiation, development and immune regulation
.
▲Professor Liu Xiaole (picture source: school official website personal homepage) in vitro verification results show that the library can knock out related oncogenes well
.
Next, they introduced the library into the mouse TNBC cell line 4T1, and injected the 4T1 cells infected with the library into the mouse mammary fat pad for tumor formation
.
After 16 days, the researchers collected tumor cells for subsequent analysis
.
The most intuitive result of the experiment is that those mice lacking T cells have the largest tumors, and some mice implanted with 4T1 cells overexpress ovalbumin, which can enhance immune activity, and their tumors have the smallest tumors
.
▲Schematic diagram of the research process (picture source: reference [1]) And by comparing the knockout of sgRNA in the two types of tumors, the researchers found some key genes related to the invasiveness of 4T1 cells
.
For example, the knockout of genes related to the interferon gamma pathway is related to the reduction of tumor size
.
This is consistent with the results of past studies that found that IFNγ can promote tumor invasion
.
During the first screening process, a total of 79 candidate genes were presented to the researchers.
They constructed the library version 2.
0 of these genes and conducted two rounds of screening
.
The second screening process became more refined, and the E3 ubiquitination ligase encoding gene Cop1 in the IFNγ signaling pathway became the focus of attention because it was almost completely knocked out in mice with the smallest tumors
.
Compared with the control group, Cop1 knockout mice not only significantly slowed the progression of their tumors, but their survival period was also prolonged.
Even if they did not receive anti-PD-1 treatment, they could also obtain this advantage
.
▲After Cop1 is knocked out, the number of macrophages that infiltrate the tumor is reduced (picture source: Reference [1]) In addition, the researchers found that down-regulation of Cop1 expression can significantly reduce the chemical substances that attract macrophages in the tumor, which brings The direct result is that the number of macrophages immersed in the tumor is significantly reduced, and the corresponding TC1 tumor volume is also shrinking
.
Specifically, after Cop1 is knocked out, the degree of ubiquitination of the downstream substrate C/ebpδ decreases, which will directly lead to a sharp increase in its expression
.
C/ebpδ can inhibit the transcription of macrophages-related chemokines, thereby reducing the possibility of macrophages entering the tumor
.
This discovery is expected to bring brand-new target drugs to more cancer patients, and bring new hope to patients with breast cancer that is not sensitive to conventional treatment and refractory
.
Reference: [1] Wang X, Tokheim C, Wang B, et al.
In Vivo CRISPR Screens Identify E3 Ligase Cop1 as a Modulator of Macrophage Infiltration and Cancer Immunotherapy Target.
Cell 2021.
DOI:10.
1016/j.
cell.
2021.
09.
006
