Abstract
Pleuropulmonary blastoma (PPB) is a rare pediatric lung neoplasm that recapitulates developmental pathways of early embryonic lungs. As lung development proceeds with highly regulated mesenchymal-epithelial interactions, a DICER1 mutation in PPB generates a faulty lung differentiation program with resultant biphasic tumors composed of a primitive epithelial and mesenchymal stroma with early progenitor blastomatous cells. Deciphering of PPB progression has been hampered by the difficulty of culturing PPB cells, and specifically progenitor blastomatous cells. Here, we show that in contrast with in-vitro culture, establishment of PPB patient-derived xenograft (PDX) in NOD-SCID mice selects for highly proliferating progenitor blastoma overexpressing critical regulators of lung development and multiple imprinted genes. These stem-like tumors were sequentially interrogated by gene profiling to show a FGF module that is activated alongside Neural cell adhesion molecule 1 (NCAM1). Targeting the progenitor blastoma and these transitions with an anti-NCAM1 immunoconjugate (Lorvotuzumab mertansine) inhibited tumor growth and progression providing new paradigms for PPB therapeutics. Altogether, our novel in-vivo PPB xenograft model allowed us to enrich for highly proliferating stem-like cells and to identify FGFR and NCAM1 as two key players that can serve as therapeutic targets in this poorly understood and aggressive disease.
Highlights
Pleuropulmonary blastoma (PPB) is the most common primary malignancy of the lungs in children[1]
We have shown that serial patient derived xenograft (PDX) propagation in mice significantly enriches for cancer stem cells (CSCs) function and results in a more aggressive phenotype in late passage xenograft (Xn), thereby unveiling responsible pathways and molecules that can serve as new therapeutic targets[10,11,14,15,16,17]
FGFRs can be activated by non FGF ligands such as Neural cell adhesion molecule 1 (NCAM1)
Summary
Pleuropulmonary blastoma (PPB) is the most common primary malignancy of the lungs in children[1]. There is an urgent need to uncover novel therapeutic strategies This embryonal tumor of the lung is characterized by a multistep tumor progression from a less aggressive to a more. The use of patient derived xenograft (PDX) model systems for studying cancer has gained great popularity in Shukrun et al Oncogenesis (2019)8:48 recent years. These in-vivo models provide unique opportunities to uncover and explain important cancerrelated cellular pathways, and have become the reference model for functional validation of discoveries in the field of tumor biology and for preclinical evaluation of anticancer therapy. We have shown that serial PDX propagation in mice significantly enriches for CSC function and results in a more aggressive phenotype in late passage xenograft (Xn), thereby unveiling responsible pathways and molecules that can serve as new therapeutic targets[10,11,14,15,16,17]
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