Visvader: Intertumoral hetergeneity (part 2 of talk): genetic mut model and cell of origin are not mutually exclusive #AACR14
11:55am April 9th 2014 via Hootsuite
Visvader: MaSCs long-lived - could they be prime targets for mutations as br ca progenitors years later? #AACR14
11:54am April 9th 2014 via Hootsuite
Visvader: Lgr5 another mark in alveolar gland - marks bipotent MaSCs. #AACR14
11:53am April 9th 2014 via Hootsuite
Visvader: Now looking at alveolar cells during pregnancy - K5-expressing bi-potent cells active #AACR14
11:52am April 9th 2014 via Hootsuite
Visvader:Even after 52w - mammary gland actively maintained much longer than anticipated. 'Shows the stem cell is long-lived' #AACR14
11:51am April 9th 2014 via Hootsuite
Visvader: FACS: K5 cells are both luminal and basal lineages; both populations expanded. 20w: stem cells maintained duct & tree #AACR14
Visvader: Tet-inducible Keratin5 - basal cell expression; visual of stem cells giving rise to progeny at puberty. 8w - segregation #AACR14
11:48am April 9th 2014 via Hootsuite
Visvader: Colorful data: Elf5-expressing cells contribute to ductal maintenance in adulthood; but by 20w depleted #AACR14
11:47am April 9th 2014 via Hootsuite
Visvader: Efl5 TF: signature of luminal progenitor cells and GFP; only Elf5-GFP have clonogenic activity in vitro #AACR14
11:45am April 9th 2014 via Hootsuite
Visvader: Used 3 color trangenic mice, Dox-inducible: indelible marking of cells and progeny throughout lifespan #AACR14
11:44am April 9th 2014 via Hootsuite
Visvader: Recent work reported Rios et al Nature 2014 http://t.co/yGSg0jy7tO looking at lineage tracing, triple transgen. mice #AACR14
11:43am April 9th 2014 via Hootsuite
Visvader: 3D imaging of mammary gland of keratin fiber prior to puberty: 3D movie, highly elongated #AACR14
11:42am April 9th 2014 via Hootsuite
Visvader: Looking at mammary stem cells - an evolving heirarchy from stem cells, to progenitor cells, to mature cells. ER-PR- #AACR14
11:40am April 9th 2014 via Hootsuite
Jane Visvader, Walter & Eliza Hall Inst, Australia. "The breast epithelial heirarchy and its implications for tumor heterogeneity" #AACR
11:38am April 9th 2014 via Hootsuite
Campbell: Have six types of signatures (C>T at CpG, APOBEC, BRCA, Unk, Unk, APOBEC) Here's Nature 2013 ref: http://t.co/ks8BM3wv45 #AACR1
11:37am April 9th 2014 via Hootsuite
Campbell: Can extract pattern of mutations, know when in time they occur, and a signature when. Early, late, S1 and S2 branches #AACR14
11:34am April 9th 2014 via Hootsuite
Campbell: Another sample: a massive trunk of 16K mutations, but late divergence, no driver mutation in the branch ID'd. #AACR14
11:33am April 9th 2014 via Hootsuite
Campbell: Parallel loss along another branch (parallel evolution), another chromothripsis event etc. #AACR14
11:31am April 9th 2014 via Hootsuite
Campbell: Overlaying particular genes mutated in evol: from CREBBP, PTEN del; to chromothripsis EPHA3 loss; FGFR1 13 copies #AACR14
11:30am April 9th 2014 via Hootsuite
Campbell: Reconstruction of mutational tree - across T1, T2, DCIS: v. complex representation of clonal evolution, tracking muts #AACR14
11:28am April 9th 2014 via Hootsuite
Campbell: Deep into 1 indiv. with multifocal, invasive br ca: 1 focus, four sites; second focus, pure DCIS: parallel evolution #AACR14
11:25am April 9th 2014 via Hootsuite
Campbell: 30/48 had heterogeneity of driver mutations in targeted genes #AACR14
11:23am April 9th 2014 via Hootsuite
Campbell: Not much correlation w/ clinical features (hist. grade, ER/HER2 status, Ki-67, Age). All had 1-12 driver muts/sample... #AACR14
Campbell: Each as pie charts subst/indels; cnv gains/losses. Large chart of driver heterogeneity - no particular patterns ID'd #AACR14
11:22am April 9th 2014 via Hootsuite
Campbell: NGS represents a statistical experiment; their targeted approach is ~400 genes, 276 samples from 46 individuals. #AACR14
11:20am April 9th 2014 via Hootsuite
Plenary talk: Peter Campbell, Wellcome Trust. "Subclonal diversitivication in primary breast cancer" #AACR14
11:19am April 9th 2014 via Hootsuite
Stegmaier: Along with genetic features, shRNA and chemical screens, a map of mutant to wild-type spectrum of AML vulnerability #AACR14
10:50am April 9th 2014 via Hootsuite
Stegmaier: 'Cancer Vulnerability Map' - take ped ca cell lines, systematically conduct screens with pooled, barcoded cell lines #AACR14
10:49am April 9th 2014 via Hootsuite
Stegmaier: Future direction developing CRISPR tech for effect of GSK-3 inhibitors within in vivo models #AACR14
10:48am April 9th 2014 via Hootsuite
Stegmaier: Summary - can ID new targets using combination of chemical and genetic screens; pan-inh GSK-3 stabilizes b-catenin tho #AACR14
10:47am April 9th 2014 via Hootsuite
Stegmaier: 2 lead compounds are being further developed; BRD-1652 hits both alpha and beta isoforms of GSK-3; shown active in AML #AACR14
10:42am April 9th 2014 via Hootsuite
Stegmaier: Looked for new GSK-3 inhibitors - 320K compounds from MLPCN collection removed similar existing inh. structures #AACR14
10:41am April 9th 2014 via Hootsuite
Stegmaier:Second story: GSK-3alpha. Sometimes it's better to go back and mine older data. Looking at GSK-3 inhibitors #AACR14
10:32am April 9th 2014 via Hootsuite
Stegmaier: Looking at upstream activators of SYK / downstream effectors; select for FLT3-ITD positive AML #AACR14
10:30am April 9th 2014 via Hootsuite
Stegmaier: FLT3 activation correlates with SYC activation; SYK + FLT3 interact ref Puissant Cancer Cell 2014 http://t.co/37YmnWgeT8 #AACR14
10:24am April 9th 2014 via Hootsuite
Stegmaier: SYK identified; showed induction of myeloid differentiation; tested SYK inhibitors worked in multiple mouse models #AACR14
10:19am April 9th 2014 via Hootsuite
Stegmaier: Using Gefitinib, used proteomics (MS) to ID candidates; also used shRNA against kinases and look to match gene exp sig #AACR14
10:17am April 9th 2014 via Hootsuite
Stegmaier: Used Gefitinib from their initial screen; found AML + lung ca reports where Erlotinib caused compl. remission #AACR14
10:15am April 9th 2014 via Hootsuite
Stegmaier: Poly A plate, RT, hyb, capture on LMNX beads and read. Originally used Affy for gene exp 2004 pub http://t.co/7Ghl1uZSXJ #AACR14
10:14am April 9th 2014 via Hootsuite
Stegmaier: Using 500 genes in 384-well plates called GE-HTS 'Ligated mediated amplification' Peck 2006 pub http://t.co/DLZJRXeBD9 #AACR14
10:12am April 9th 2014 via Hootsuite
Stegmaier: ID of state switches, or aberrant TF's; look at AML vs differentiated myelonoid cells; use gene sig's, ID marker genes #AACR14
10:11am April 9th 2014 via Hootsuite
Stegmaier:Trad small molecule discovery is phenotype-based; last 10y, using targets, example BRAF V600E (vemurafenib) #AACR14
Stegmaier: Can target chromatin regulators, like DOT1L for MLL Bernt et al Cancer Cell 2012 pub http://t.co/Z5btF49jER #AACR14
10:10am April 9th 2014 via Hootsuite
Stegmaier: Ped cure rates for AML ~55%; showed Circos plot from this Patel 2012 NEJM pub. http://t.co/DcdqFZVMJj #AACR14
10:07am April 9th 2014 via Hootsuite
Stegmaier: ID of target - in many cases are intractable or unknown; using chemical screening, shRNA screens for AML #AACR14
10:06am April 9th 2014 via Hootsuite
Stegmaier: Ewings in children: large lists of toxicities, infertility, and medications; about 70% cure rate #AACR14
10:04am April 9th 2014 via Hootsuite
Stegmaier: Focus is on pediatric oncology: leukemia, Ewing Sarcoma, neruoblastoma; uses chemical, functional genomics and proteomics #AACR14
10:03am April 9th 2014 via Hootsuite
First up: Kimberly Stegmaier, Dana-Farber "Integrating "Omic" Approaches to Identify New Therapeutic Approaches for Cancer" #AACR14
10:02am April 9th 2014 via Hootsuite
“Dale, you run on inspiration.” “Yes, that, and coffee too.” #AACR14
9:58am April 9th 2014 via Hootsuite
RT @johnomics: Biscuit phylogeny in Cambridge Zoology tea room proving highly controversial http://t.co/0M0PZp2NO3
9:20am April 9th 2014 via Hootsuite
