ALK upregulates POSTN and WNT signaling to drive neuroblastoma

Miller Huang; Wanqi Fang; Alvin Farrel; Linwei Li; Antonios Chronopoulos; Nicole Nasholm; Bo Cheng; Tina Zheng; Hiroyuki Yoda; Megumi J Barata; Tania Porras; Matthew L Miller; Qiqi Zhen; Lisa Ghiglieri; Lauren McHenry; Linyu Wang; Shahab Asgharzadeh; JinSeok Park; W Clay Gustafson; Katherine K Matthay; John M Maris; William A Weiss

doi:10.1016/j.celrep.2024.113927

ALK upregulates POSTN and WNT signaling to drive neuroblastoma

Cell Rep. 2024 Mar 26;43(3):113927. doi: 10.1016/j.celrep.2024.113927. Epub 2024 Mar 6.

Authors

Miller Huang¹, Wanqi Fang², Alvin Farrel³, Linwei Li⁴, Antonios Chronopoulos⁴, Nicole Nasholm⁵, Bo Cheng⁴, Tina Zheng⁶, Hiroyuki Yoda⁵, Megumi J Barata⁵, Tania Porras⁴, Matthew L Miller⁵, Qiqi Zhen⁵, Lisa Ghiglieri⁵, Lauren McHenry⁶, Linyu Wang⁵, Shahab Asgharzadeh², JinSeok Park², W Clay Gustafson⁷, Katherine K Matthay⁸, John M Maris⁹, William A Weiss¹⁰

Affiliations

¹ Children's Hospital Los Angeles, Cancer and Blood Disease Institutes, and The Saban Research Institute, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: mhuang@chla.usc.edu.
² Children's Hospital Los Angeles, Cancer and Blood Disease Institutes, and The Saban Research Institute, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴ Children's Hospital Los Angeles, Cancer and Blood Disease Institutes, and The Saban Research Institute, Los Angeles, CA, USA.
⁵ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁶ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁷ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Departments of Pediatrics and Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
⁸ Departments of Pediatrics and Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
⁹ Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Departments of Pediatrics and Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. Electronic address: waweiss@gmail.com.

PMID: 38451815
DOI: 10.1016/j.celrep.2024.113927

Abstract

Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALK^F1174L) cooperate in tumorigenesis, how ALK contributes to tumor formation remains unclear. Here, we used a human stem cell-based model of neuroblastoma. Mis-expression of ALK^F1174L and MYCN resulted in shorter latency compared to MYCN alone. MYCN tumors resembled adrenergic, while ALK/MYCN tumors resembled mesenchymal, neuroblastoma. Transcriptomic analysis revealed enrichment in focal adhesion signaling, particularly the extracellular matrix genes POSTN and FN1 in ALK/MYCN tumors. Patients with ALK-mutant tumors similarly demonstrated elevated levels of POSTN and FN1. Knockdown of POSTN, but not FN1, delayed adhesion and suppressed proliferation of ALK/MYCN tumors. Furthermore, loss of POSTN reduced ALK-dependent activation of WNT signaling. Reciprocally, inhibition of the WNT pathway reduced expression of POSTN and growth of ALK/MYCN tumor cells. Thus, ALK drives neuroblastoma in part through a feedforward loop between POSTN and WNT signaling.

Keywords: ALK; CP: Cancer; MYCN; POSTN; WNT; human pluripotent stem cells; neuroblastoma.

MeSH terms

Anaplastic Lymphoma Kinase / genetics
Cell Adhesion Molecules
Cell Line, Tumor
Humans
N-Myc Proto-Oncogene Protein / genetics
N-Myc Proto-Oncogene Protein / metabolism
Neuroblastoma* / pathology
Receptor Protein-Tyrosine Kinases* / metabolism
Wnt Signaling Pathway

Substances

Anaplastic Lymphoma Kinase
Cell Adhesion Molecules
N-Myc Proto-Oncogene Protein
POSTN protein, human
Receptor Protein-Tyrosine Kinases
ALK protein, human

Abstract

MeSH terms

Substances

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