Poster Discussion 2 - Biology

Genome

Transcriptome

Proteome

Metastasome

Genome

• 39267: HDAC inhibitor/multidrug resistant cell lines– PCI-24781 induces acetylation, inhibits growth,

enhances chemosensitivity

• 39309: EXT/osteochondromas– Biallelic inactivation of either EXT1 or EXT2 is less than

expected for classic tumor suppressor model

• 39356: DNA demethylation/synovial sarc– VPA and Zebularine (Zeb) are synergistic for

suppression of growth of synovial sarcoma SYO-1 cells

Genome

• 39393: CNV (SNP)/osteosarcoma– Recurrent amplification: 1p36, 12q13-15, 17p11.2,

20p12– Recurrent deletion: 1q31, 6q16, 8q24.13, 10q23,

17p13– New targets to look for contribution to tumorigenesis

• 39448*: Sleeping Beauty/osteosarcoma - forward genetic screen for new genomic loci

Osteosarcoma Development and Metastasis Gene Discovery

Conditional sleeping beauty

osteosarcoma

New loci that when interrupted by transposon (common insertion sites CIS) activates oncogene or inactivates tumor suppressor to contribute to osteosarcoma formation or metastasis.

New gene

p53R270H/+

B Moriartity and D Largaespada

Osteoblast precursor (Osx)-Crerecombinase

T2/onc concatomer

Non-directedScreen forNew Pathways

Transcriptome• 39218: DAXX mRNA/CASP8/p38 MAPK/sarcoma

– 82 primary sarcomas, SW1353 chondrosarcoma line– FAS-mediated apoptosis via FADD/CASP8 or

DAXX/ASK1– EGF-related association between CASP8 and DAXX may

involve p38 MAPK pathway

• 39338: GGAA/EWS-FLI regulation– NR0B1 (high in ES) promoter with ggaa repeats– Transcription by EWS/FLI requires dual binding of FLI

• 39473: miRNA profiles/imatinib-treated GIST– GIST cell lines treated with imatinib– 10x upregulation of 23 microRNA– Check out a number of them from chromosome 14q32.31

• 39354*: miRNA profiles/liposarcoma

Identification of differentially expressed microRNAs in liposarcoma subtypes

12 liposarcomas14 well-differenttiated17 de-differentiated 9 myxoid 5 round cell 4 pleiomorphic

Lipomas, fat - 7/10

microRNAsHierarchal clustering

Myxoid

Round cellDe-differentiated

DifferentialExpressionmiRNAs

Discriminatory miRNAsunsupervised - 585supervised - 62

Which ones? - talk with Caroline

Caroline Gits et al

Cell Biology

• 38426: PRP-1/chondrosarcoma– PRP-1 isolated from neurosecretory cells of the

hypothalamus; associated with myc expression leading to antiproliferation

– Specific therapeutic window

• 39388: Anti-CD99 antibody/Ewings– CD99 membrane glycocylated protein that when

stimulated leads to reactivation of p53 pathway– Effective in sarcomas that have intact TP53

Metastasome

• 39270: expression profiles/osteosarcoma– 63 primary osteosarcoma patients (+/- mets)– Patterns predictive of metastatic tumors– RhoA pathway may be best discriminator

• 39312: EMMPRIN/osteosarcoma

Emmprin expression is associated with metastatic phenotype in osteosarcoma

- 16 osteosarcoma cell lines versus normal osteoblast - RT-PCR- IHC in 52 prechemotherapy patient biopsies- siRNA knockdown of Emmprin in HOS and SaOS-2- Gelatin zymography, VEGF ELISA, Matrigel invasion assay (HOS)- Co-culture SaOS-2 with osteoblast (hFOB) and fibroblast (MRC-5)

MMPs VEGF

(Cancer cells and stroma)

EMMPRIN - Extracellular matrix metalloproteinase inducer

EMMPRIN

H Han et al.

Knock down EMMPRIN?

Emmprin expression is associated with metastatic phenotype in osteosarcoma

- 16 osteosarcoma cell lines versus normal osteoblast - RT-PCR- IHC in 52 prechemotherapy patient biopsies- siRNA knockdown of Emmprin in HOS and SaOS-2- Gelatin zymography, VEGF ELISA, Matrigel invasion assay (HOS)- Co-culture SaOS-2 with osteoblast (hFOB) and fibroblast (MRC-5)

MMPs VEGF

(Cancer cells and stroma)

EMMPRIN - Extracellular matrix metalloproteinase inducer

EMMPRIN

H Han et al.

Knock down EMMPRIN?

Make things better!