Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer
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Abstract
Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes of a range of human NECs and show convergence to the activation of a common epigenetic program. With a particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), we analyze cell lines, patient-derived xenograft (PDX) models and human clinical samples to show the existence of two distinct NEPC subtypes based on the expression of the neuronal transcription factors ASCL1 and NEUROD1. While in cell lines and PDX models these subtypes are mutually exclusive, single-cell analysis of human clinical samples exhibits a more complex tumor structure with subtypes coexisting as separate sub-populations within the same tumor. These tumor sub-populations differ genetically and epigenetically contributing to intra- and inter-tumoral heterogeneity in human metastases. Overall, our results provide a deeper understanding of the shared clinicopathological characteristics shown by NECs. Furthermore, the intratumoral heterogeneity of human NEPCs suggests the requirement of simultaneous targeting of coexisting tumor populations as a therapeutic strategy.
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/6545798.
This manuscript provides a deep understanding of clinicopathological characteristics shown by NECs and suggests the requirement of simultaneous targeting of coexisting tumor populations as a therapeutic strategy.
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/4581189.
In this study, Cejas et al. attempt to address the similarities and differences between a variety of neuroendocrine carcinomas (NECs) which originate from diverse tissues such as the lung, prostate and skin. In particular, they focus on the chromatin landscapes of these tumours with an aim to translate these findings into having therapeutic benefit for patients.
The authors focus on the NEC subtypes small-cell lung carcinoma (SCLC), neuroendocrine prostate cancer (NEPC) and Merkel Cell Carcinoma (MCC). To explore the epigenomic regulation of these NECs, the authors used a number of techniques including scRNA-seq, ATACseq and whole exome sequencing.
Throughout this study there is a …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/4581189.
In this study, Cejas et al. attempt to address the similarities and differences between a variety of neuroendocrine carcinomas (NECs) which originate from diverse tissues such as the lung, prostate and skin. In particular, they focus on the chromatin landscapes of these tumours with an aim to translate these findings into having therapeutic benefit for patients.
The authors focus on the NEC subtypes small-cell lung carcinoma (SCLC), neuroendocrine prostate cancer (NEPC) and Merkel Cell Carcinoma (MCC). To explore the epigenomic regulation of these NECs, the authors used a number of techniques including scRNA-seq, ATACseq and whole exome sequencing.
Throughout this study there is a focus on the NEC subtype NEPC, which makes the study extremely relevant and important for many reasons. NEPC is a lethal form of prostate cancer which mainly originates following anti-androgen treatment in prostate cancer patients. There are currently no effective therapeutic strategies available for NEPC and therefore the need to develop new and innovative strategies to combat this disease is particularly pressing.
This was a very well put together paper, and it highlights some crucial epigenomic features of the NECs which may have real benefits for future treatment options for NEPC, which may target primary tumours as well as metastatic lesions. This paper has highlighted a number of interesting pathways which may be pursued further in order to expand on the scope of the project and identify targets which may be clinically relevant.
A particularly striking result was the change of transcription factor (TF) dominance which arose through the passaging of NEC cells in vitro, from ASCL1 dominance towards NEUROD1 dominance. In addition, it was interesting that the patient derived xenograft (PDX) models showed mutual exclusivity for TF expression, whilst the clinical samples often showed dual expression of factors. As the TFs induce a number of similar NE programming in the cells (i.e. inducing INSM1 etc) I was curious whether there was any redundancy in the TF expression? Or whether one might be more dominant? Is it possible to say which was switched on at a given point?
The extent of similarities between the various NE tumour types despite having wildly different anatomical sites/cells of origin was fascinating. The ability to differentiate and identify NEPC subtypes based on TF expression was also a novel result as these subtype groupings had previously been observed in SCLC but not yet described in prostate tumours.
For multiple pathologies, the use of animal models to recapitulate human disease is extremely useful, and critical to study the effect of novel therapeutic strategies. In this study however they highlighted the different epigenomic states of the PDX animal/in vivo models compared to the clinical samples. These results really emphasise the need to use multiple model systems and representative in vivo, as well as in vitro, systems to study disease in order to accurately study disease.
In future studies, I would be curious to see the transcriptional analysis of lung metastatic sites in NEPC patients to see how they differed from the primary site, and whether there were any similarities/differences between the metastatic lesions and the de novo SCLC tumours.
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