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Moreover, our rapid autopsy cohort included 34 patients, each with 2—3 metastatic sites characterized through RNA-Seq. This provided an opportunity to query the intertumoral phenotypic heterogeneity within patients. Of the 34 patients with 2—3 analyzed metastases, 5 patients However, this may underestimate the extent of heterogeneity, as 2—3 metastases generally represent a fraction of the total tumor burden.
In addition, there can be intratumoral phenotypic heterogeneity that is not readily assessed through bulk RNA sequencing Supplemental Figure 2. To discover novel gene expression profiles for each of the mCRPC phenotypes, we cross-compared the patient metastases RNA-Seq data from the defined phenotypic cohorts i. This analysis generated a comprehensive list of unique and shared upregulated differentially expressed genes vs.
The relationships between different mCRPC phenotypes have not been clearly established though prior studies suggest that SCNPC is often derived from an AR-positive precursor, or share a common progenitor 18 , Thus, we investigated these relationships by studying the phenotypic progression of an individual with mCRPC and a complicated treatment history. He was treated with leuprolide and bicalutamide but ensuing CT and bone scans revealed numerous metastases in liver, lung, and bone. He subsequently received 2 cycles of capecitabine and gemcitabine with eventual PSA progression prior to death Supplemental Figure 4.
We therefore questioned whether the DNPC phenotype is a transition stage. Indeed, serial passaging in intact mice of LuCaP Disease progression is a continuum in mCRPC specimens.
Black arrows point to clusters of cells with SYP positivity. Results are expressed as log 2 FPKM or as enrichment scores and are colored according to scale. The amphicrine phenotype and relationship with REST expression. Thus, to establish the existence of AMPC cells in our clinical specimens i. ACTB was used as a loading control. Short, second film exposure; long, 5-minute film exposure.
Results are expressed as log 2 FPKM and colored according to scale. The upper band represents the REST4 splice variant. Additionally, the REST transcript has multiple splice variants that produce truncated proteins Next, we examined alternative splicing of the REST transcript. Log 2 mean-centered ratios of genes are depicted and colored according to scale. D Venn diagram describing the interrelationships of all upregulated genes vs. A subtype of mCRPC exhibits features of squamous cell carcinoma.
To determine if the squamous pearls occurred spontaneously during LuCaP Squamous pearl cells from LuCaP Transcriptome analysis determined that genes were upregulated and 29 genes were downregulated in LuCaP DNPC can convert to a squamous phenotype. Black arrows point to squamous pearl structures. Interestingly, patient had an adenocarcinoma phenotype in the initial prostate biopsy and was subsequently treated with diethylstilbesterol DES for 13 months prior to cystoprostatectomy.
At the time of cystoprostatectomy, histology and IHC revealed adenocarcinoma with focal basaloid and squamous differentiation in several sections of the prostate as well as a left axillary lymph node that was consistent with squamous carcinoma.
The other 2 patients with KRT6-positive metastases, patients and , had primary prostate cancers with no evidence of squamous differentiation, and subsequent hormone therapy led to the appearance of squamous mCRPC. Although DES and hormone therapies have been linked to the development of squamous cancer in the prostate with subsequent squamous metastases 32 — 36 , this report provides evidence for hormone therapy—mediated conversion of ARPC to squamous DNPC at metastatic sites.
These results indicate that squamous cell conversion is not a rare occurrence in end-stage disease and should be considered an emerging phenotype following resistance to AR-directed therapy. Transcript signatures define the molecular phenotypes of mCRPC. The variability in expression of any single marker, both at the biological level and technical level makes tumor classification by immunohistochemistry challenging.
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Transcript panels for tumor classification have been explored as predictive and prognostic biomarkers for treatment decision-making 45 , Thus, removing the squamous genes from the analysis showed a more effective clustering of the tumors into their respective phenotypes Supplemental Figure 8C.
The clinical phenotyping of mCRPC has been limited to morphologic and immunohistochemical analyses. The classifications prompted a call for further elucidation of underlying mCRPC biology and more accurate nomenclature that limits confusion between research and medical fields At the transcriptome level, expression signatures for classifying SCNPC have been demonstrated 51 , but an encompassing signature that appreciates the spectrum of mCRPC phenotypes has not been identified.
Observations made through our rapid autopsy program support a treatment-induced shift in mCRPC phenotypes with ARI therapies increasing the number of AR-null and AR-low metastases at end-stage disease 5. Moreover, Beltran et al. Of note, the genomic landscapes of intrapatient CRPC metastases are relatively similar 4. Thus, our analysis indicating that intertumoral phenotypic heterogeneity is not a rare occurrence argues that epigenetic, posttranscriptional, posttranslational, and microenvironment events can contribute to phenotypic diversity in mCRPC.
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Taken together, our data add further clinical support for the proposed mCRPC disease continuum and demonstrates that treatment-induced selective pressures can change the phenotypic and molecular landscapes of mCRPC. Schematic of the mCRPC disease continuum. The proposed mechanisms, molecular drivers, and cellular differentiation states following AR pathway inhibition therapy. For example, prostate and lung epithelial cells can be reprogrammed to small cell NE cancers through induction of the same transcription factor pathways As new in original [vg] box.
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