Preservation and Expansion of Blastomatous Cells in Stem-like Pleuropulmonary Blastoma Patient-derived Xenograft Affords Therapeutic Targets. Homo sapiens

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, we successfully establish a novel in-vivo model of PPB and uncover anti-NCAM1 as a potential therapeutic strategy for this aggressive malignancy. Overall design: We used Pleuropulmonary blastoma Xns, as well as, fetal and adult lung tissue originally obtained from patients, healthy adults or aborted fetus. This series includes three PPB xenograft samples. All three were derived from the same patient primary PPB sample (D492_PT).