Congress Abstracts - Society for Developmental Biology

stem cell‐like characteristics. However, given the complexities of tissue architecture in a tumor, identification of the developmental
lineages of these transformed cells often remains a daunting task. Taking advantage of the simplicity of tissue architecture in the fly
model, we have investigated the cellular determinants of neoplasia following loss of highly conserved tumor suppressors such as Lgl
or Scribble (Scrib). Our findings provide a broad framework for carcinogenesis wherein the transcription factors and signalling
pathways linked to primitive cell states in an organ primodium provide the cooperative drives required for neoplasia in lgl or scrib
mutant clones. Conversely, those transcription factor and signalling pathways specifying terminal cell fates induce rapid elimination of
oncogenically targeted cells. Switch-to-a-primitive-cell-state, therefore, is a critical driver of carcinogenesis. These findings from the
fruit fly model offer novel insights to cancer mechanisms and also provide novel therapeutic opportunities.
Program/Abstract # 414
FGF signaling pathways required for lung development are essential mediators of the pathogenesis of pleuropulmonary
blastoma and adenocarcinoma
Ornitz, David M; Yin, Yongjun (Washington University in St. Louis, USA); Hill, D. Ashley (Children’s National Medical Center,
USA); Betsuyaku, Tomoko (Keio University School of Medicine, Japan)
Mice lacking Fibroblast Growth Factor (FGF) 9 have pulmonary hypoplasia and die at birth due to respiratory failure. Investigation of
the underlying mechanisms identified an early embryonic feed-forward signaling interaction between mesenchymal FGF and β-
catenin-dependent Wnt signaling that is essential for lung mesenchymal growth and differentiation. To further probe the function of
FGF9, we have developed an inducible mouse model in which FGF9 can be expressed in lung epithelium. We find that expression of
FGF9 in embryos induces lung mesenchymal hyperplasia whereas expression in adults causes the rapid proliferation of progenitor-like
cells in distal airway epithelium. Embryonic induction of FGF9 closely models the histopathology of Pleuropulmonary Blastoma
(PPB), a syndromic lung cancer that is associated with heritable mutations in Dicer1. Genetic modeling identified FGF9 as an
essential mediator of the pathogenesis of PPB. In contrast to embryos, induction of FGF9 in the adult resulted in the rapid formation of
adenocarcinoma. This is relevant to human disease in that amplification of FGFR1 occurs in 22 percent of squamous cell lung cancer,
and mutations in FGFR3 have been identified in non-small cell lung cancer. FGF ligands, including FGF9 are also expressed in a
large proportion of lung cancers and activation of FGF signaling is one mechanism of escape from anti-EGFR therapies. Genetic
modeling in the adult lung identified FGF receptor 3 (FGFR3) as the obligate FGFR mediating the FGF9 oncogenic signal. These data
identify the FGF9-FGFR3 pathway as a primary oncogenic signal and suggest that this pathway could be exploited for therapeutic
applications in some forms of human lung adenocarcinoma.
Program/Abstract # 415
3-O-sulfated heparan sulfate expands the Kit+ epithelial progenitor pool via FGFR2b-dependent proliferation.
Patel, Vaishali; Lombaert, Isabelle (NIH, USA); Xu, Yongmei; Liu, Jian (University of North Carolina, USA); Hoffman, Matthew
(NIH, USA)
During organogenesis a rapid expansion of the epithelial progenitor pool is required for growth and morphogenesis. Kit and Fgfr2b
signaling maintain and expand the progenitor pool in branching epithelial organs. Elucidating the cellular mechanisms that induce
rapid expansion of epithelial progenitors is crucial to understand organogenesis and to expand progenitors for regeneration. Since
heparan sulfate (HS) is required for Fgfr2b function we hypothesized that specific HS synthesized by Kit+ progenitors may control
their expansion. Kit+ epithelial cells were isolated from fetal salivary glands and the HS biosynthetic enzymes were analyzed.
Surprisingly, the enzymes that generate 3-O-sulfated heparan sulfate (3-O-HS) were specifically and highly expressed in Kit+
progenitors and Fgfr2b-signaling rapidly increases their expression. Using recombinant enzymes to specifically modify HS we show
that 3-O-HS increases Fgfr2b signaling and the number of Kit+ progenitors. Alternatively, reducing Kit signaling decreases 3-Osulfotransferase
expression and organogenesis. Thus 3-O sulfated HS increases Fgfr2b and Kit signaling that feeds back to increase
HS biosynthesis providing a rapid response mechanism to modify HS structures and control progenitor proliferation in response to a
growth factor. The identification of specific HS structures that control localized progenitor cell proliferation will be useful to expand
progenitor cells for use in regenerative therapy.
Program/Abstract # 416
An AP2/ERF transcription factor important for new organ development
Duran Medina, Yolanda; Marsch-Martinez, Nayelli (Cinvestav -IPN Unidad Irapuato, Mexico)
Plant organ production is indeterminate, organs are continuously formed in a highly controlled manner. Organ development depends
on the meristematic activity. Leaves, stems and axillary meristems are produced from shoot apical meristem (SAM). The function of
the SAM is to maintain itself as a source of cells and to generate daughter cells that are displaced towards the meristem periphery,
where they acquire specific differentiation pathways. The maintenance of the SAM requires a precise coordination of growth and
differentiation. Hormones have an important role in this balance, but it is apparent that additional signals influence hormone signalling
to control meristem function and leaf initiation. Many genes are also involved in organ development. An AP2/ERF transcription factor
of Arabidopsis is expressed in restricted regions in organ primordia and young organs. The overexpression of this gene promotes the
development of small size organs, due to a reduction in cell size and cell number. This gene plays a role in cell differentiation
reflected through ectopic callus formation in roots. According to global gene expression analysis using the overexpression mutant,
some its effects may be due to hormonal signaling alteration. The overexpression phenotype and global expression data suggest that
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