Integrative approach to uncover oncogenic mechanisms of DICER1-associated cancers.
Final Report Abstract
DICER1 syndrome predisposes children and young adults to various cancers, many of which are aggressive sarcomas exhibiting shared histological and molecular similarities despite their diverse anatomical origins. While recent studies have advanced our understanding of the genetic underpinnings of these cancers, the underlying developmental biology remains largely unknown. To uncover the cellular origins and developmental hierarchy of DICER1 sarcoma, we studied a lineagetraceable genetically engineered mouse model that allows for precise activation of Dicer1 mutations in Hic1+ mesenchymal stromal cells (MSCs). In this model expression of a compound heterozygous Dicer1 mutation in Hic1+ MSCs was associated with the development of renal sarcomas that closely resemble the human disease, both histomorphologically and genomically. Using single-cell transcriptomic analyses we uncovered Hic1+ MSCs marked by Pdgfra, Dpt, and Mfap4 as putative cells of origin, corresponding to universal fibroblasts of steady-state kidney, localized to the perivascular and subepithelial basal membrane niche. We further show that these fibroblastic progenitors exhibit the capacity to undergo a step wise continuum of rhabdomyoblastic differentiation, including PAX7+ myogenic precursor populations, or transition into high-grade sarcoma. Transcriptomic analyses of patient samples identified analogous cell states in human Dicer1 associated cancers. Our findings suggest that the anatomical predilection for DICER1 sarcomas for subepithelial regions may be linked to the proposed cellular origin within the universal fibroblastic niche associated with the basal membrane. Moreover, these fibroblasts have the potential to undergo rhabdomyoblastic transformation upon Dicer1 disruption, which may be linked to re-expression of embryonic programs and challenges the long-standing dogma that tumors of the rhabdomyosarcoma spectrum develop from a predetermined myogenic lineage. Our study provides a deeper understanding of the cellular contexts driving DICER1-associated sarcomagenesis and opens promising avenues for future mechanistic investigations and therapeutic development for DICER1-associated cancers.
Publications
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Lessons from genomic profiling: towards a molecular‐based classification of ovarian Sertoli–Leydig cell tumour. Histopathology, 84(4), 712-714.
Kommoss, Felix K. F.
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Teratoma‐associated and so‐called pure Wilms tumour of the ovary represent two separate tumour types with distinct molecular features. Histopathology, 84(4), 683-696.
Kommoss, Felix K. F.; Chong, Anne‐Sophie; Apellaniz‐Ruiz, Maria; Turashvili, Gulisa; Park, Kay J.; Hanley, Krisztina; Valera, Elvis Terci; von Deimling, Andreas; Vujanic, Gordan; McCluggage, W. Glenn & Foulkes, William D.
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Exomic and epigenomic analysis of pulmonary blastoma. Lung Cancer, 195, 107916.
Alirezaie, Najmeh; Chong, Anne-Laure; Kommoss, Felix K.F.; Sabbaghian, Nelly; Camacho Valenzuela, Jose; Pelletier, Dylan; Nadaf, Javad; Kolekar, Shailesh B.; Sivapalan, Pradeesh; Evans, Mark G.; Thorner, Paul S.; Fiset, Pierre-Olivier; von Deimling, Andreas & Foulkes, William D.
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Spatial single cell transcriptomic analysis of a novel DICER1 Syndrome GEMM informs the cellular origin and developmental hierarchy of associated sarcomas. openRxiv.
Kommoss, Felix K.F.; Zhang, Joyce; Lynch, Branden J.; Chen, Shary Yuting; Senz, Janine; Moscovitz, Yana; Hill, Lesley Ann; Scott, Wilder; Bush, Jonathan; Chen, Kenneth S.; von Deimling, Andreas; Foulkes, William D.; Morin, Gregg; Underhill, T. Michael; Wang, Yemin & Huntsman, David G.
