Claudette R. Fraire1, Kavita Desai2,3, Indumathy Jagadeeswaran1, Uma A. Obalapuram1, Lindsay K. Mendyka4, Veena Rajaram5, Teja Sebastian1, Yemin Wang6,7, Kenan Onel8, Jeon Lee9, Stephen X. Skapek10 and Kenneth S. Chen1,11 1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 2Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; 3University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA; 4Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA; 5Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 6Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z7, Canada; 7Department of Molecular Oncology, British Columbia Cancer Research Institute, Vancouver, British Columbia V5Z 0B4, Canada; 8Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, USA; 9Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 10Department of Pediatrics, Duke University, Durham, North Carolina 27710, USA; 11Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Corresponding author: kenneth.chenutsouthwestern.edu Abstract

Mutations in the microRNA processing genes DROSHA and DICER1 drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated Drosha or Dicer1 in the developing pineal gland to emulate the pathogenesis of pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. Accordingly, these mice develop pineal tumors marked by loss of microRNAs, particularly the let-7/miR-98-5p family, and derepression of microRNA target genes. Pineal tumors driven by loss of Drosha or Dicer1 mimic tumors driven by Rb1 loss, as they exhibit upregulation of S-phase genes and homeobox transcription factors that regulate pineal development. Blocking proliferation of these tumors facilitates expression of pinealocyte maturation markers, with a concomitant reduction in embryonic markers. Select embryonic markers remain elevated, however, as the microRNAs that normally repress these target genes remain absent. One such microRNA target gene is the oncofetal transcription factor Plagl2, which regulates expression of progrowth genes, and inhibiting their signaling impairs tumor growth. Thus, we demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.

Received November 21, 2024. Accepted March 24, 2025.