2. Academic Validation
  3. Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma

Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma

  • Nat Commun. 2022 Mar 16;13(1):1381. doi: 10.1038/s41467-022-28801-y.
Claudia Capparelli 1 2,  Timothy J Purwin 3,  McKenna Glasheen 3,  Signe Caksa 3,  Manoela Tiago 3,  Nicole Wilski 3,  Danielle Pomante 3,  Sheera Rosenbaum 3,  Mai Q Nguyen 3,  Weijia Cai 3,  Janusz Franco-Barraza 4,  Richard Zheng 5,  Gaurav Kumar 3 6,  Inna Chervoneva 7 8,  Ayako Shimada 7 8,  Vito W Rebecca 9 10,  Adam E Snook 6 8,  Kim Hookim 11,  Xiaowei Xu 12,  Edna Cukierman 4,  Meenhard Herlyn 9,  Andrew E Aplin 13 14
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA. Claudia.Capparelli@Jefferson.edu.
  • 2 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. Claudia.Capparelli@Jefferson.edu.
  • 3 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 4 Cancer Signaling and Epigenetics Program, Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
  • 5 Department of Surgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 6 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 7 Division of Biostatistics, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 8 Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 9 Melanoma Research Center, The Wistar Institute, Philadelphia, PA, 19104, USA.
  • 10 Biochemistry and Molecular Biology Department, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
  • 11 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 12 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 13 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA. Andrew.Aplin@Jefferson.edu.
  • 14 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. Andrew.Aplin@Jefferson.edu.
PMID: 35296667 DOI: 10.1038/s41467-022-28801-y
Abstract

Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRaf and/or MEK inhibitors. We identify the class of cellular inhibitor of Apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRaf/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.

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