Gao Dong's group discovered the mechanism by which FOXA2 drives prostate tumor cell plasticity and KIT signaling pathway activation

On November 3, the international academic journal Cancer Cell published online a research paper
entitled "FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer" by the Gao Dong Research Group of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences 。 This research work revealed the key role of FOXA2 in regulating the lineage transition from prostate adenocarcinoma to neuroendocrine carcinoma and the activation of KIT signaling pathway, and found that KIT inhibitors have clinical application prospects
in the treatment of neuroendocrine prostate cancer.

Prostate cancer is the male malignant tumor with the first incidence and the second mortality rate in Europe and the United States, and the incidence of prostate cancer in men in China is also on the rise rapidly
.
Early prostate cancer is an adenocarcinoma with luminal cell lineage characteristics, and the survival of tumor cells is highly dependent on the androgen receptor (AR) signaling pathway, so androgen deprivation therapy (ADT) based on targeted AR is a common treatment
for patients with early prostate cancer 。 Although most patients respond at the beginning of treatment, as treatment prolongs, a significant proportion develop drug resistance and progress to castration-resistant prostate cancer
.
Among them, neuroendocrine prostate cancer is one of the most malignant castration-resistant prostate cancers
.
However, there is currently no effective treatment
for neuroendocrine prostate cancer.
In many related studies over the past few years, tumor progression and treatment resistance caused by the plasticity of cell lineages regulated by transcription factors have received close attention
from the scientific community.
Also in prostate cancer research, the lineage shift of adenocarcinoma-neuroendocrine carcinoma is also considered to be an important factor
in inducing drug resistance.
Therefore, it is urgent to identify the regulators that directly drive this lineage shift and to develop potential drugs that can be directly used in clinical treatment
.

To find the key regulators driving the lineage transition of prostate cancer, the researchers used Tmprss2^CreERT2/+; Pten^flox/flox; Trp53^flox/flox; Rb1^flox/flox; The Chga^{LSL-tdTomato/+} mouse model specifically knocks out Pten in luminal cells; Trp53; Rb1 gene, while using tdTomato signal to monitor the expression of Chga, the characteristic gene Chga of neuroendocrine cells in real time, was used in adenocarcinoma cells to monitor the expression of the characteristic gene Chga in lumenal cells, and a mouse model
of the transition from prostate adenocarcinoma to neuroendocrine carcinoma lineage was constructed 。 Subsequently, the researchers carried out single-cell multi-omics sequencing of mouse prostate tumor samples with different stages of prostate adenocarcinoma to neuroendocrine carcinoma lineage transition, and finally obtained 107201 high-quality single-cell multi-omics data.
After analyzing cell heterogeneity, transcriptional regulation and microenvironment, FOXA2 was identified as an important transcriptional regulator of prostate adenocarcinoma-neuroendocrine carcinoma lineage transition.
Further analysis of multiple published human prostate tumor databases, single-cell sequencing results, and tissue samples from tumor patients confirmed the important role
of FOXA2 in neuroendocrine prostate cancer.
By knocking down the expression of FOXA2 in neuroendocrine tumor cells, the researchers successfully achieved a partial reversal of neuroendocrine prostate cancer to adenocarcinoma, and verified the role of FOXA2 in regulating the lineage transition of
prostate adenocarcinoma to neuroendocrine carcinoma.

More importantly, in order to further search for therapeutic targets for neuroendocrine prostate cancer, the researchers found that FOXA2 can directly regulate the KIT signaling pathway to specifically activate
it in neuroendocrine prostate tumor cells through chromatin co-immunoprecipitation (ChIP-seq) analysis of the tumor microenvironment and FOXA2.
Through genetically engineered mice and human organoid culture, it was determined that KIT signaling pathways regulate the growth
of neuroendocrine prostate tumors.
The use of KIT-targeted shRNA and a variety of clinical-grade drugs, such as imatinib, can effectively inhibit the growth
of neuroendocrine prostate tumors in humans and mice in vivo and in vitro.

This work explores the molecular mechanism of FOXA2 in mediating the lineage transition of prostate adenocarcinoma and neuroendocrine carcinoma, and identifies the KIT signaling pathway as a key target for the treatment of neuroendocrine prostate cancer
.
In addition, this work emphasizes the importance of transcription factors in studying cell lineage plasticity, which provides a theoretical basis
for the treatment of drug-resistant tumors caused by cell plasticity.

Researcher Gao Dong of the Center of Excellence in Molecular Cell Excellence is the corresponding author of the paper, postdoctoral fellow Li Fei is the co-corresponding author, doctoral student Han Ming, postdoctoral fellow Li Fei, and doctoral student Zhang Yehan are the co-first authors
.
The research was strongly supported
by Professor Huang Hai of Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Professor Zheng Junke of Shanghai Jiao Tong University and Professor Bai Fan of Peking University.
The work was supported
by the Chinese Academy of Sciences, the National Natural Science Foundation of China, the Ministry of Science and Technology and the Shanghai Municipal Science and Technology Commission.
This work is supported
by the Center of Excellence for Molecular Cells Genome Tagging Program, the Animal Experiment Technology Platform, the Cell Biology Technology Platform, and the Chemical Biology Technology Platform.

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