Genomic analysis of benign prostatic hyperplasia implicates cellular re-landscaping in disease pathogenesis
Abstract/Contents
- Abstract
- Benign prostatic hyperplasia (BPH) entails growth in the central regions of the prostate gland and is common among older men. BPH obstructs urinary outflow, resulting in voiding symptoms and bladder and kidney damage for which current treatments, that target prostate physiology, are only partially effective. A better understanding of BPH may suggest new treatment strategies that target its pathophysiology. Here, we used next-generation sequencing to gain insight into BPH. By RNAseq, we uncovered transcriptional heterogeneity among BPH cases, where a 65- gene BPH stromal signature correlated with symptom severity. Compared to normal prostate, stromal signaling molecules including BMP5 and CXCL13 were enriched in BPH tissues, while estrogen regulated pathways were depleted. Addition of BMP5 to prostatic myofibroblast cells in culture altered their expression profile towards a BPH profile that included the BPH stromal signature. Our RNAseq analysis also suggested an altered cellular milieu in BPH, which we verified by immunohistochemistry and single-cell RNAseq. In particular, BPH tissues exhibited enrichment of myofibroblast subsets, with concurrent depletion of neuroendocrine cells and an estrogen receptor (ESR1)- positive fibroblast cell type residing near epithelium. Finally, by whole exome sequencing, we uncovered somatic single nucleotide variants (SNVs) in BPH, of uncertain significance in pathogenesis, that were indicative of clonal cell expansions consistent with cellular relandscaping. Thus, our genomic characterization of BPH has identified a clinically-relevant stromal signature and new candidate disease pathways (including a likely role for BMP5 signaling), and reveals BPH to be not merely a hyperplasia, but rather a fundamental re-landscaping of cell types.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Middleton, Lance |
|---|---|
| Degree supervisor | Pollack, Jonathan D |
| Thesis advisor | Pollack, Jonathan D |
| Thesis advisor | Brooks, James |
| Thesis advisor | Lipsick, Joseph Steven, 1955- |
| Thesis advisor | West, Robert |
| Degree committee member | Brooks, James |
| Degree committee member | Lipsick, Joseph Steven, 1955- |
| Degree committee member | West, Robert |
| Associated with | Stanford University, Cancer Biology Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Lance Middleton. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Lance Wade Middleton
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