Cell fate determination and lineage plasticity in prostate cancer

^{Prostate cancer (PCa) initiation, progression, and therapy resistance involve genetic and epigenetic alterations that lead to aberrant cell lineage specification and plasticity.1–3 The vast majority of primary prostate cancers are pathologically defined as luminal cancer with luminal cell expansion and absence of basal cells. The basal or neuroendocrine PCa is extremely rare in primary or untreated PCa. Adeno-to-neuroendocrine PCa lineage plasticity has been identified in advanced PCa following the targeted therapy of AR inhibition.2 However, the underlying mechanisms of PCa cell fate determination and lineage plasticity are still poorly understood. Therefore, systematically defining the genetic, epigenetic, and microenvironment factors in PCa cell lineage determination and plasticity may reveal the underlying molecular mechanisms and stimulate the development of novel therapeutic strategies to prevent or reverse the current therapy resistance of prostate cancers. This special issue, “Prostate Cell Fate and Diseases”, contains six original articles and five reviews to introduce some recent PCa research progress in the field of prostate cell fate determination and lineage plasticity.}

PCa is one of the most common cancers in men in the world. The normal prostate epithelium consists of luminal cells, basal cells, and rare neuroendocrine cells surrounded by the stromal cell and vasculature.⁴ After surgical or pharmacological castration, the prostate involutes to the regressed state by rapid cellular loss of prostate luminal epithelial cells.⁵ Most primary prostate cancers consist of androgen receptor-positive (AR⁺) luminal cancer cells that are dependent on the activation of the androgen signaling pathway. Androgen deprivation and AR inhibition become the cornerstone of PCa treatment.⁶ During the past decade, adeno-to-neuroendocrine lineage plasticity is recognized as a new mechanism of PCa therapy resistance to the second generation of androgen receptor signaling inhibitors (ARSi) treatment, such as enzalutamide or abiraterone acetate.² The systematic characterization of PCa cell lineage determination and plasticity, such as genetic alterations, master regulators, chromatin modulators and microenvironmental factors, may provide a fundamental understanding of the PCa initiation, progression, and therapy resistance and indicate the potential druggable targets.

The investigation to define the molecular drivers of PCa cell fate determination and lineage plasticity has focused on transcriptional factors and chromatin remodeling family members that promote PCa progression and therapy resistance.² The activation of specific transcription factors, such as N-MYC, SRY-box transcription factor 2 (SOX2), BRN2 and one cut homeobox 2 (ONECUT2), and regulation of chromatin remodeling complexes, such as switch/sucrose nonfermentable (SWI/SNF) complexes, have been identified as the potential regulators of PCa cell lineage plasticity.^7–14 We have identified the essential role of ERG in regulating prostate cell lineage toward a pro-luminal program by orchestrating chromatin interactions.¹⁵ Using single-cell multiomics analyses, we identified forkhead box A2 (FOXA2) orchestrated PCa adeno-to-neuroendocrine lineage transition. Furthermore, KIT signaling pathway was directly regulated by FOXA2 and specifically activated in neuroendocrine PCa (NEPC).¹⁶ This work identified that FOXA2 drives adeno-to-neuroendocrine cell lineage plasticity in PCa and provides a promising pharmacological strategy for NEPC. Here, Wang et al.¹⁷ identified that the deletion of chromodomain-helicase-DNA-binding protein 1 (CHD1) enhanced hypoxia-inducible factor 1α (HIF1α) expression and promoted angiogenesis and metabolic reprogramming in PCa. Takahashi and Takada¹⁸ summarized the roles of chromatin remodelers (SWI/SNF complexes and chromodomain helicase DNA-binding proteins) in the development and progression of PCa.

Although the contributions of genetic alterations have been identified in prostate cancer lineage plasticity, such as tumor protein p53 (TP53), RB transcriptional corepressor 1 (RB1), and phosphatase and tensin homolog (PTEN) loss,¹⁹ there is mounting evidence also supporting the essential role of epigenetic regulations as a mechanism for PCa lineage plasticity.²⁰ Many drugs have been developed to specifically target epigenetic factors, suggesting the importance of identifying critical epigenetic factors that promote lineage plasticity. Takahashi and Takada¹⁸ summarized the roles of epigenetic enzymes (histone methyltransferases/demethylases) in the progression and drug response in prostate cancer. Zhang and Zeng²¹ summarized how RNA modification N⁶-methyladenosine (m⁶A methylation) dysregulation promotes PCa progression and treatment.

Tumor microenvironment factors may also influence cancer cell lineage plasticity through abnormal oxygen delivery and metabolism in malignant tissues.² Takahashi and Takada¹⁸ summarized the roles of noncanonical Wingless-type MMTV integration site family (WNT) signaling pathways, mainly that involving Wingless-type MMTV integration site family, member 5a (WNT5A), in PCa progression and metastasis. Advanced prostate cancer showed resistance to immune checkpoint blockade therapy. To understand how prostate cancer cell-intrinsic mechanisms promote immune evasion, Zhu et al.²² reviewed the roles of the genetic alterations, androgen receptor signaling, cancer cell plasticity, and oncogenic pathways in shaping the immunosuppressive microenvironment of prostate cancer. Du et al.²³ revealed that programmed cell death 1 (PD-1) inhibitor plus anti-vascular endothelial growth factor (VEGF) agent could benefit the metastatic castration-resistant prostate cancer (mCRPC) patients with a retrospective real-world study of 25 mCRPC patients. Zhu et al.²⁴ reviewed that disruption of the circadian clock influenced PCa initiation and development through regulating multiple pathways, including the cell cycle, epithelial-mesenchymal transition (EMT), tumor immunity, and the endocrine system.

Metabolism reprogramming is now recognized as a new hallmark of tumors and another mechanism of cancer cell lineage plasticity.²⁵ Glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. Here, Zhao et al.²⁶ summarized the role of glutamine metabolism alterations in therapeutic resistance and disease progression of PCa and suggested novel therapeutic strategies. Wang et al.¹⁷ identified that deletion of CHD1 enhanced HIF1α expression and promoted angiogenesis and metabolic reprogramming in PCa.

A systematic study of potential mechanisms driving cell lineage determination and plasticity and identifying novel biomarkers is imperative for the early diagnosis and therapy of PCa. Mitogen-activated protein kinase (MAPK) pathways play vital roles in prostate cancer progression. Huang et al.²⁷ showed that the upregulation of MAPK signal scaffold protein, mitogen-activated protein kinase-8-interacting protein 2 (MAPK8IP2), was significantly associated with worse overall survival outcomes and progression-free intervals. Zhu et al.²⁸ identified an autophagy-related gene prognostic index (ARGPI) correlated with biochemical recurrence, metastasis, and chemoresistance in patients with prostate cancer undergoing radical radiotherapy or prostatectomy. Prostate Imaging Reporting and Data System (PI-RADS) scoring system has shown good ability to interpret and report prostate magnetic resonance imaging (MRI) results, but there are still false positives. Wang et al.²⁹ summarized the causes of “false positive MRI diagnosis” and identified that overestimation of PI-RADS and ambiguous images was an important cause of false positives. Feng et al.³⁰ investigated the role of senescence in PCa undergoing radical prostatectomy (RP) or radical radiotherapy (RT). They identified 12 senescence-related genes related to the clinical features of PCa patients undergoing RP or RT.

As highlighted in this special issue, genetic alterations, epigenetic events, master regulators, chromatin modulators, and microenvironmental factors play important roles in PCa cell lineage determination and plasticity. Remarkably, each of these factors has the potential impact on the drug sensitivity and patients’ survival. A systematic characterization of the role of genetic, epigenetic, and microenvironmental factors, through the integrated profiling of patient tissues with complete series of tumor evolution, combining experimental modeling both in vitro and in vivo, will be needed to define the molecular mechanism and drivers of the PCa cell lineage determination and plasticity and develop a potential pharmacological strategy that reverses the cell lineage plasticity of PCa.

COMPETING INTERESTS

The author declares no competing interests.