Mechanisms by which FOXA2 drives prostate tumor cell plasticity and activation of the KIT signaling

On November 3, Cancer Cell published online a research paper entitled "FOXA2 lineage plasticity drives and KIT pathway activation in neuroendocrine prostate cancer" by Gao Dong's research group at the Center for Excellent Innovation in Molecular Cell Science, Chinese Academy of Sciences. This study reveals the key role of FOXA2 in regulating the transition of prostate adenocarcinoma to neuroendocrine carcinoma lineage and the activation of KIT signaling pathway, and finds 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 in Europe and the United States. Early prostate cancer is an adenocarcinoma with luminal lineage characteristics, and its tumor cell survival is highly dependent on androgen receptor (AR) signaling pathway, so androgen deprivation therapy (ADT) based on targeting AR is a common treatment for patients with early prostate cancer. Although most patients respond at the beginning of treatment, a significant number of patients develop drug resistance with prolonged treatment and further develop 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 transcriptional factor-regulated cell lineage plasticity have received close attention from the scientific community. Also, in studies of prostate cancer, lineage transition in adenocarcinoma-neuroendocrine carcinoma has been implicated as an important factor in the development of induced resistance. Therefore, it is urgent to identify regulators that directly drive this lineage transition, as well as to develop potential drugs that can be used directly in clinical treatment.

To find key regulators driving the transition of prostate cancer lineages, the researchers specifically knocked out the Pten; Trp53; Rb1 gene in luminal cells using the Tmprss2CreERT2/+; Ptenflox/flox; Trp53flox/flox; Rb1flox/flox; ChgaLSL-tdTomato/+ mouse models, while monitoring the expression of Chga, a signature gene of neuroendocrine cells, in real time using tdTomato signaling in luminal cell-initiating adenocarcinoma cells to construct a mouse model of prostate adenocarcinoma to neuroendocrine carcinoma lineage transition. The researchers then performed single-cell multi-omics sequencing of mouse prostate tumor samples at different stages of progression from prostate adenocarcinoma to the neuroendocrine carcinoma lineage and finally obtained 10,7201 high-quality single-cell multi-omics data; after analysis of cell heterogeneity, transcriptional regulation, and microenvironment, FOXA2 was identified as an important transcriptional regulator of prostate adenocarcinoma-neuroendocrine carcinoma lineage transition; multiple published human prostate tumor databases, single-cell sequencing results, and tissue samples from cancer patients were further analyzed to confirm the important role of FOXA2 in neuroendocrine prostate cancer. By knocking down FOXA2 expression in neuroendocrine tumor cells, the researchers successfully achieved partial reversal of neuroendocrine prostate cancer to adenocarcinoma, verifying the role of FOXA2 in regulating the transition of prostate adenocarcinoma to the neuroendocrine carcinoma lineage.

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

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

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