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Harnessing urinary extracellular vesicles microRNA by acoustic trapping as potential biomarkers for prostate cancer

Ku, Anson LU (2020) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Prostate cancer (PCa) is an interesting study case of clinical management of uncertainty. PCa is the most diagnosed but only the second-leading cause of non-cutaneous cancer-related mortalities among men in developed countries. To put simply, the life-time risk of PCa diagnosis and mortality is approximately 11% and 3% respectively; a ~3.6-fold difference. The large number of PCa incidence is attributed to the routine use of a serum biomarker known as prostate-specific antigen (PSA) produced by the prostatic lumen epithelium. PSA is a highly sensitive biomarker for detecting general prostate perturbations such as prostatitis, benign prostate hyperplasia (BPH) and PCa but it cannot easily distinguish them at low serum concentration. To... (More)
Prostate cancer (PCa) is an interesting study case of clinical management of uncertainty. PCa is the most diagnosed but only the second-leading cause of non-cutaneous cancer-related mortalities among men in developed countries. To put simply, the life-time risk of PCa diagnosis and mortality is approximately 11% and 3% respectively; a ~3.6-fold difference. The large number of PCa incidence is attributed to the routine use of a serum biomarker known as prostate-specific antigen (PSA) produced by the prostatic lumen epithelium. PSA is a highly sensitive biomarker for detecting general prostate perturbations such as prostatitis, benign prostate hyperplasia (BPH) and PCa but it cannot easily distinguish them at low serum concentration. To confirm PCa diagnosis, prostate tissue biopsy is still required today. Thus, the screening strategy today creates a large pool of men that will go through PSA testing, prostate biopsy and, possibly, treatments that may not die as a result of the disease. In-addition to the unnecessary interventions, the economic and psychological toll of PCa diagnosis and treatment is burdensome to individuals. There is no doubt that PSA testing can save lives but PCa screening today can benefit from additional biomarkers in multiple areas. First would be to distinguish men likely to harbor clinically significant PCa and therefore require biopsies versus those that do not. Second, those that will likely progress to high grade or malignant disease thus requiring clinical intervention versus those that do not.
Our goal in this work is to address the need for new biomarkers through “liquid biopsy” that can supplement PSA to discern patients with and without high grade PCa and therefore requiring tissue biopsies. We begin by describing our efforts to develop a novel technology termed “acoustic trapping” to enrich extracellular vesicles (EVs), a new source of biomarkers that have tremendous potential in clinical management of PCa. In paper 1, we assessed the performance of the acoustic trap then demonstrated that EVs from cell-conditioned media, plasma and urine can be enriched. Next, in paper 2, we developed an optimized pipeline for urinary EVs enrichment and next-generation sequencing of small RNA. In paper 3, we interrogated the microRNA (miRNA) profiles of EVs from 207 clinical urine samples from patients with biopsy-positive or biopsy-negative PCa. Lastly, in paper 4, we describe our efforts to understand the role of hypoxia and androgen signaling on EVs secretion from PCa cells.
In all, this work contributes to PCa research by paving a new way to isolate and sequence the miRNA content from urinary EVs. This will provide a method for the routine use of EVs via liquid biopsy to better stratify patients in the hopes of reducing unnecessary tissue-biopsies and over-treatment of PCa.
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author
supervisor
opponent
  • professor Falcón-Pérez, Juan M., Derio, Spain
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2020:22
pages
98 pages
publisher
Lund University, Faculty of Medicine
defense location
Hörsalen Medicon Village, Scheleevägen 2, Byggnad 302, Lund
defense date
2020-02-28 09:00:00
ISSN
1652-8220
ISBN
9789176198827
language
English
LU publication?
yes
id
02ca3461-4264-4823-b405-915ec8292593
date added to LUP
2020-02-06 15:40:16
date last changed
2020-06-16 15:28:52
@phdthesis{02ca3461-4264-4823-b405-915ec8292593,
  abstract     = {Prostate cancer (PCa) is an interesting study case of clinical management of uncertainty. PCa is the most diagnosed but only the second-leading cause of non-cutaneous cancer-related mortalities among men in developed countries. To put simply, the life-time risk of PCa diagnosis and mortality is approximately 11% and 3% respectively; a ~3.6-fold difference. The large number of PCa incidence is attributed to the routine use of a serum biomarker known as prostate-specific antigen (PSA) produced by the prostatic lumen epithelium. PSA is a highly sensitive biomarker for detecting general prostate perturbations such as prostatitis, benign prostate hyperplasia (BPH) and PCa but it cannot easily distinguish them at low serum concentration. To confirm PCa diagnosis, prostate tissue biopsy is still required today. Thus, the screening strategy today creates a large pool of men that will go through PSA testing, prostate biopsy and, possibly, treatments that may not die as a result of the disease. In-addition to the unnecessary interventions, the economic and psychological toll of PCa diagnosis and treatment is burdensome to individuals. There is no doubt that PSA testing can save lives but PCa screening today can benefit from additional biomarkers in multiple areas. First would be to distinguish men likely to harbor clinically significant PCa and therefore require biopsies versus those that do not. Second, those that will likely progress to high grade or malignant disease thus requiring clinical intervention versus those that do not. <br/>Our goal in this work is to address the need for new biomarkers through “liquid biopsy” that can supplement PSA to discern patients with and without high grade PCa and therefore requiring tissue biopsies. We begin by describing our efforts to develop a novel technology termed “acoustic trapping” to enrich extracellular vesicles (EVs), a new source of biomarkers that have tremendous potential in clinical management of PCa. In paper 1, we assessed the performance of the acoustic trap then demonstrated that EVs from cell-conditioned media, plasma and urine can be enriched. Next, in paper 2, we developed an optimized pipeline for urinary EVs enrichment and next-generation sequencing of small RNA. In paper 3, we interrogated the microRNA (miRNA) profiles of EVs from 207 clinical urine samples from patients with biopsy-positive or biopsy-negative PCa. Lastly, in paper 4, we describe our efforts to understand the role of hypoxia and androgen signaling on EVs secretion from PCa cells.<br/>In all, this work contributes to PCa research by paving a new way to isolate and sequence the miRNA content from urinary EVs. This will provide a method for the routine use of EVs via liquid biopsy to better stratify patients in the hopes of reducing unnecessary tissue-biopsies and over-treatment of PCa.<br/>},
  author       = {Ku, Anson},
  isbn         = {9789176198827},
  issn         = {1652-8220},
  language     = {eng},
  number       = {2020:22},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Harnessing urinary extracellular vesicles microRNA by acoustic trapping as potential biomarkers for prostate cancer},
  url          = {https://lup.lub.lu.se/search/ws/files/75905525/KAPPA_Final.pdf},
  year         = {2020},
}