SLC22A3/OCT3 drives serotonin-mediated stemness in pancreatic cancer

  • Cell Rep. 2026 Jun 23;45(6):117387. doi: 10.1016/j.celrep.2026.117387.
Nivedeta Krishna Kumar  1 ,  Venkatesh Varadharaj  1 ,  Neelanjana Gayen  1 ,  Annant Bir Kaur  1 ,  Kirtana Arikath  1 ,  Ashu Shah  1 ,  Poompozhil Mathivanan  1 ,  Palanisamy Nallasamy  1 ,  Zahraa Wajih Alsafwani  1 ,  Bhuvaneshwari Seshadri  1 ,  Pratima Raut  1 ,  Sanchita Rauth  1 ,  Jimmie Persinger  2 ,  Sandipan Brahma  3 ,  Micah Schott  4 ,  Rebecca E Oberley-Deegan  4 ,  Geoffrey A Talmon  5 ,  Jesse L Cox  5 ,  Surinder K Batra  6 ,  Moorthy P Ponnusamy  7
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
  • 2. Department of Genetics Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
  • 3. Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA; Department of Genetics Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
  • 4. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA.
  • 5. Department of Pathology, Microbiology & Immunology, University of Nebraska Medical Center, Omaha, NE, USA.
  • 6. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA. Electronic address: [email protected].
  • 7. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA. Electronic address: [email protected].
PMID: 42250222 DOI: 10.1016/j.celrep.2026.117387
Abstract

Pancreatic Cancer (PC) is a highly aggressive malignancy, with Cancer Stem Cells (CSCs) playing a critical role in metastasis, therapy resistance, and recurrence, thereby presenting significant treatment challenges. Emerging evidence suggests that normal embryonic and adult progenitor stem cells share common gene signatures with CSCs. However, the early pluripotency-associated factors and stemness programs that become aberrantly reactivated during oncogenic transformation remain poorly defined. Here, we identify SLC22A3/OCT3 (Solute Carrier Family 22 Member 3) as a reactivated embryonic-associated signature that regulates PC stemness. SLC22A3 is markedly upregulated in CSC-enriched populations, and its silencing in PC cells grown in both 2D cultures and 3D Organoid models significantly reduces key stemness features. Moreover, serotonin (5-HT) transport, mediated by SLC22A3, enhances overall stemness via downstream histone modifications, linking serotonin signaling to CSC regulation. Collectively, these findings establish SLC22A3 as a regulator of serotonin-driven stemness and a potential therapeutic target in PC.

Keywords
CP: cancer; CP: stem cell research; SLC22A3/OCT3; histone serotonylation; pancreatic cancer stem cells; self-renewal; serotonin signaling; serotonin transporter.
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