LSD1+8a is an RNA biomarker of neuroendocrine prostate cancer

Anbarasu Kumaraswamy; Rahul Mannan; Olivia A. Swaim; Eva Rodansky; Xiao-Ming Wang; Aaron Udager; Rohit Mehra; Hui Li; Colm Morrissey; Eva Corey; Michael C. Haffner; Peter S. Nelson; Arul M. Chinnaiyan; Joel A. Yates; Joshi J. Alumkal

Neoplasia: An International Journal for Oncology Research (May 2025)

LSD1+8a is an RNA biomarker of neuroendocrine prostate cancer

Anbarasu Kumaraswamy,
Rahul Mannan,
Olivia A. Swaim,
Eva Rodansky,
Xiao-Ming Wang,
Aaron Udager,
Rohit Mehra,
Hui Li,
Colm Morrissey,
Eva Corey,
Michael C. Haffner,
Peter S. Nelson,
Arul M. Chinnaiyan,
Joel A. Yates,
Joshi J. Alumkal

Affiliations

Anbarasu Kumaraswamy: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
Rahul Mannan: Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
Olivia A. Swaim: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
Eva Rodansky: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
Xiao-Ming Wang: Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
Aaron Udager: Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
Rohit Mehra: Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
Hui Li: RevMAb Biosciences, Burlingame, CA, USA
Colm Morrissey: Department of Urology, University of Washington, Seattle, WA, USA
Eva Corey: Department of Urology, University of Washington, Seattle, WA, USA
Michael C. Haffner: Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
Peter S. Nelson: Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
Arul M. Chinnaiyan: Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, Ann Arbor, MI, USA
Joel A. Yates: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
Joshi J. Alumkal: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Corresponding author at: 7312 Rogel Cancer Center, SPC 5948, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.

Journal volume & issue: Vol. 63
p. 101151

Abstract

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Background: Lysine-specific demethylase 1 (LSD1) is a histone demethylase and regulator of differentiation, including in cancer. A neuronal-specific isoform of LSD1—LSD1+8a—has been shown to play a key role in promoting neuronal differentiation in the developing brain. We previously determined that LSD1+8a transcripts were detected in an aggressive subtype of prostate cancer harboring a neuronal program—neuroendocrine prostate cancer (NEPC)—but not in prostate adenocarcinomas harboring a glandular program. However, the number of samples examined was limited. Methods: Using a large collection of prostate cancer patient cell lines and patient-derived xenografts (PDXs), we measured LSD1+8a using quantitative polymerase chain reaction (qPCR), RNA in situ hybridization (RNA-ISH), and protein detection methods. We then validated our findings using an independent cohort of patient tumor samples. Results: LSD1+8a mRNA expression was detected in every NEPC cell line and PDX examined by qPCR and RNA-ISH but in none of the prostate adenocarcinomas. We validated the RNA-ISH results in patient tumors, confirming that LSD1+8a was expressed in all NEPC tumors but in none of the adenocarcinomas. Finally, we generated a rabbit monoclonal antibody specific to LSD1+8a protein and confirmed its specificity using normal neuronal tissue samples. However, LSD1+8a protein was not detectable in NEPC tumors—likely due to the substantially lower levels of LSD1+8a mRNA in NEPC tumors vs. normal neuronal tissues. Conclusions: Measuring LSD1+8a mRNA is a sensitive and specific method for the diagnosis of NEPC, which is often challenging.

Published in Neoplasia: An International Journal for Oncology Research

ISSN: 1522-8002 (Print); 1476-5586 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: http://www.journals.elsevier.com/neoplasia/

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