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CANCER BIOLOGY PATHWAY Luncheon
January 12, 2017 – 1 – 3 pm – Holden Auditorium
Agenda
Introduction of Cancer Biology Pathway Course Lee Ratner, MD, PhD
Spring 2017 Course Dave Wilson, MD, PhD
Presentations (2nd Year Appointees)
Angela Halstead, PhD – Arora Lab
Elizabeth Ostrander –Challen Lab
Simona Graziano – Gonzalo Lab
Poster session (1st Year Appointees)
Alex Wagner – Griffith Lab
Craig Barcus – Longmore Lab
Fiona Ruiz – Schwarz Lab
Katie Campbell – Griffith Lab
Jennifer Flynn – Wang Lab
Jasmine Sponagel – Rubin Lab
Juo-Chin Yao – Link Lab
Objectives
• To train graduate students and postdoctoral fellows in cancer biology research
• Provide basic scientists training in basic, translational, and clinical cancer research
• Foster interdisciplinarycollaborative undertakings
Program History
• Initiated with institutional funds in 2002 for graduate students
• Program expanded to postdoctoral students with funding of the T32 application in 2006 and full stipends. Successful recompetition in 2011 and ? 2017
• 66 predocs and 22 postdocs thus far
– 2 students in 2014 & 2 postdocs in 2015
– 5 students & 2 postdocs in 2016
– ?1 student + ? 2 postdocs in 2017 and 3 students
• Didactic courses since 1999
• Interdisciplinary - students and fellows participating from many different fields in multiple departments.
Longm
ore
Ste
wart
Mill
s
Weber
H P
iwnic
a-W
orm
s
D P
iwnic
a-W
orm
s
Cooper
Lin
k
Mars
hall
Walter
Bu
Harb
our
Hsie
h
Gonzalo
Bose
Griff
ith
Ratn
er
To
masson
Walter
Weilb
aecher
Aro
ra
Maher
Denard
o
Challe
n
Held
Ley
Milb
randt
Novack
Rubin
Schw
arz
Welc
h
You
Cagan
Wein
traub
Park
s
Anders
on
Cheng
Go
odfe
llow
Batt
achary
a
Virgin
Sle
ckim
an
Mard
is
Num
ber
Tra
inees 9
6
3
0
T32 funded postdoc
T32 funded predoc
SCC funded predoc
Research Mentors
Medic
ine
Cell
Bio
logy
Radio
logy
Path
olo
gy
Genetics
Bio
chem
istr
y
Pedia
tric
s
Radia
tio
n O
nc
Develo
pm
enta
l B
io
Pharm
acolo
gy
Opth
alm
alo
gy
Surg
ery
Num
ber
Tra
inees
Departments
Mole
cula
r C
ell
Bio
Mole
cula
r G
enetics
Bio
chem
istr
y
Develo
pm
enta
l B
io
Com
puta
tio
nal B
io
Imm
unolo
gy
Num
ber
Tra
inees
DBBS Program
T32 funded predoc
SCC funded predoc
40
20
0
30
15
0
T32 funded postdoc
T32 funded predoc
SCC funded predoc
Broad Representation of Molecular Oncology Trainees
Recent Changes in Program• Face-to-face ethics training required for trainees (PERCS)
• Visiting speaker/External advisor
• Research presentations by 2nd yr students & postdocs at
luncheon
• Poster presentations by 1st yr students & postdocs at
luncheon
• IDP Career-development plan
• Grant Writing
• Bioinformatics Bootcamp, Imaging & Drug Discovery
Luncheons
• Career advice speaker at annual luncheon (if time permits)
• Administrative Changes
• Web-Based Surveys
• Training Grant Manual
Cancer Biology AdministrationSiteman Cancer Center
Director:
T Eberlein
Internal Advisory
Committee:
D Link
J Russell
J DiPersio
T Eberlein
V Fraser
D Piston
Extenal Advisory Board:
M Wicha
K Anderson
A Welm
Y Kang
J Campisi
Journal Club
Coursemasters:
D Link
E Sadler
K Lim
H True-Krob
J Cooper
J Miner
S-I Imai
D Ory, J Schaffer
S Elgin, D Chalker
P Schelsinger
N Saccone
O Griffith
Didactic Coursemasters:
L Ratner – Adult Oncology
D Wilson – Pediatric Oncology
Other Training:
Bioinformatics Bootcamp,
P Payne
Grant Writing,
G Colditz,
K Dodson
Imaging Luncheons
J Fitzpatrick
Drug Discovery
Luncheons
R Dolle
M Kinch
Program Director:
L Ratner
Co-Director:
G Longmore
Steering Committee:
S Stewart
T Ley
Administrative Staff:
K Kharasch
C Lyons
Washington University School
of Medicine Dean: D
Perlmutter
Division of Biology &
Biomedical Sciences Director:
J Russell
Training Program Research
Mentors
Training Program Clinical
Mentors:
L Ratner, S Waqar
J Schwarz, J Michalski
M Powell, P Thaker
D Novack
B Siegel, F Dehdashti
J DiPersio, R Vij
J Moley, W Fields
Trainees:
1 T32 Predoc
4 T32 Postdocs
6 SCC Predocs
Trainee Schedules Average # of hrs/wk
Fall Semester,
Year 1
Imaging Workshops
Journal Club
Clinical Mentoring Program
Other Lectures
Laboratory Research
(8 hrs total)
1
1 (4 hrs once per mo)
1-2
36
Spring Semester,
Year 1
Grant Writing Workshop
Bioinformatics Bootcamp
Molecular Basis of Cancer Course (even years)
Other Lectures
Laboratory Research
(4 hrs total)
20 hrs on one week
1.5
1-2
36
Fall Semester,
Year 2
Drug Discovery Workshops
Journal Club
Clinical Mentoring Program
Other Lectures
Laboratory Research
(5 hrs total)
1
1 (4 hrs once per mo)
1-2
36
Spring Semester,
Year 2
Special Emphasis Pathway in Cancer Biology (odd years)
Other Lectures
Laboratory Research
1.5
1-2
36
PreDoc Applicants Admitted in 2015SimonaGraziano Gonzalo
SLU Biochem 3rd yr VitD, 53BP1, PARP, & Breast Ca
Elizabeth Ostrander Challen Medicine MolCellBio3rd yr DNMT3a, Tet2, & AML
PreDoc Applicants Admitted in 2016Jasmine Sponagel Rubin Pediatrics MolCellBio2nd yr
mTOR Pathway in Sexual Differences in Glioblastoma
Katie Campbell Griffith Medicine MolCellBio3rd yrLandscape of HPV-Neg Oral Cancer
Jennifer Flynn Wang Genetics ComSysBio3rd yrTransposable Elements in Epigenomic Dysregulation
Jun-Chin Yao(Robin) Link Medicine MolCellBio3rd yr Stromal CXCL12 in MDS
Fiona Ruiz Schwarz Rad Onc MolCellBio3rd yrCervical Cancer Genomics in Radiosensitivity
Cancer Biology Pre-Doc Trainees
Cancer Biology Post-Doc Trainees
PostDoc Applicants Admitted in 2015
Angela Halstead Arora Medicine PPAR, RXRA, & bladder cancer
PostDoc Applicants Admitted in 2016
Alex Wagner Griffith Genetics Genome Interpretation Explorer
Craig Barcus Longmore Medicine DDR2 in Breast Cancer Metastasis
PostDoc Applicants Admitted in 2017
Bethany Prudner vanTine/Held MedicineOxidative Phosphorylation in Ras-MediatedSarcoma
Journal Clubs & Coursemasters Participating In Molecular Oncology Training
Program
Experimental Hematopoiesis Journal Club Link
Cancer Biology Journal Club Lim
Hematology & Oncology Journal Club Sadler
Student-Run Cell Biology Journal Club True-Krob
Cytoskeleton Discussion Group Cooper
Cell Biology of Extracellular Matrix Miner
Molecular Mechanism of Aging Imai
RNA Biology Ory/Schaffer
Chromatin, Epigenetics, Nuclear Organization Elgin,Chalker
Structural Biology Schlesinger
Human Genetics Saccone
Cancer Informatics Griffith
Clinical Mentoring Session Clinical Mentors
Medical Oncology Lee Ratner MD PhD
Saima Waqar MD
Radiation Oncology Julie Schwarz MD PhD
Jeff Michalski MD MBA
Stem Cell Transplantation John DiPersio MD PhD
Ravi Vij MD
Gynecologic Oncology Premal Thaker MD
Matthew Powell MD
Surgical Oncology Jeffrey Moley MD
Ryan Fields MD
Oncologic Surgical Pathology D Novack MD
Oncologic Radiology &
Nuclear Medicine
Barry Siegel MD
Farrokh Dehdashti MD
Clinical and Translational Mentoring Program
SPECIAL EMPHASIS PATHWAY IN CANCER BIOLOGY L41 5196 BIOL
This course is designed to present pre- and postdoctoral trainees with an organized educational format to explore major
contemporary topics in cancer biology. The elective will provide an integrated view of cancer research including basic science,
translational science, and clinical investigation. Approximately 60 minutes will be devoted to a didactic presentation by a faculty
member with interaction by the participants. The remaining 30 minutes will be used to discuss a pivotal research paper from this
field, preselected by the faculty member. Outside reading (30-60 min/week) will be required. 2 units.
Tuesdays 12:00p-1:30p January 10 through April 25, 2017
Location: 7th floor conference room of the Southwest Tower
Schedule
1.17.17 David DeNardo, PhD Tumor microenvironment: mediator of disease progression & resistance
1.24.17 Grant Challen, PhD Epigenetics in cancer pathogenesis
1.31.17 Joshua Rubin, MD, PhD Sexual dimorphism in cancer pathogenesis
2.07.17 Laura Schuettpelz, MD Toll signaling in normal and pathological hematopoiesis
2.14.17 Chris Sturgeon, PhD iPSC models for the study of development and cancer
2.21.17 Todd Druley, MD, PhD Germline variants and cancer
2.28.17 Karen Gauvain, MD Novel interventions for management of brain tumors
3.07.17 Jason Mills, MD, PhD Pathogenesis of gastric metaplasia and cancer
3.14.17 Spring Break No Class
3.21.17 Jeff Bednarski, MD, PhD DNA repair and oncogenesis
3.28.17 Jeff Magee, MD, PhD Leukemogenesis
4.04.17 Brian van Tine, MD, PhD Novel approaches to sarcoma therapy
4.11.17 Gavin Dunn, MD, PhD Modeling glioblastoma multiforme
4.18.17 Student Invited Speaker
4.25.17 Student Invited Speaker
Siteman Cancer Center
Cancer Biology Pathway program 2017
Simona GrazianoDpt of Biochemistry and Mol Biology, Saint Louis University School of Medicine
Jan 10th, 2017
Oncogenic Ras-induced senescence
Irradiation of Ras-expressing cells during the mitotic phase results in senescence bypass
and cellular transformation
Why are these cells proficient in engaging the DDR but deficient in repairing
DNA damage? What are the factors contributing to DNA repair deficiencies?
Senescent fibroblasts
b-gal, SAHF, SASP, SAPD, SADS
Primary
fibroblastsRasV12 Replication
Stress/DDR
DNA damage
accumulation
Malignant transformation
Secondary hits
(mutations)
Day 2 Day 4 Day 6
DNA repair factors and OIS
NHEJ
NHEJ machinery recruitment
53B
P1
53B
P1
53BP1
HR
RAD51RAD51
Homology search & strand invasion
BRCA1
RasV12
VDR
VDR
VD
Primary
fibroblastsRasV12 Senescent fibroblasts
b-gal, SAHF, SASP, SAPD, SADS
Day 6
Malignant transformation
Secondary hits
(mutations)
Hallmarks of OIS
Primary
fibroblastsRasV12 Senescent fibroblasts
b-gal, SAHF, SASP, SAPD, SADS
Day 6
Malignant transformation
Secondary hits
(mutations)
Ras senescent cells are deficient in BRCA1, 53BP1 and VDR
Through which regulatory mechanisms 53BP1 and BRCA1 are modulated
during Oncogene-induced senescence?
VDR depletion causes DNA damage and premature senescence
VDR
0.0
0.5
1.0
1.5
qR
T-P
CR
Re
lativ
e e
xpre
ssio
n shscrshVDR(1)shVDR(2)
A
D E
BRCA
1
B
BRCA1
RAD51
VDR
p21
Cyclin A
Vinculin
sh
scr
sh
VD
R
53BP1
CTSL
γH2AX
C
DAPI γH2AX
shscr
shVDR
shsc
r
shVDR
0
10
20
30
% g
H2
AX
Positi
ve
Ce
lls
Pro
po
rtio
n o
f ce
lls (
%)
shscr shVDR
% P
ositi
ve
Ce
lls
SA-β-Gal
shsc
r
shVD
R(1
)shVD
R(2
)
0
20
40
60
shsc
r
shVD
R(1
)
shVD
R(2
)0
50
100
Cell cycle profile
Sub G1
G0/G1
SG2/M
Figure 4
* **
*
*
*
*
p=0.04p=0.001
p=1.8e-05
p=4.58e-05
VDR
0.0
0.5
1.0
1.5
qR
T-P
CR
Re
lativ
e e
xpre
ssio
n shscrshVDR(1)shVDR(2)
A
D EBR
CA1
B
BRCA1
RAD51
VDR
p21
Cyclin A
Vinculin
sh
scr
sh
VD
R
53BP1
CTSL
γH2AX
C
DAPI γH2AX
shscr
shVDR
shsc
r
shVDR
0
10
20
30
% g
H2
AX
Positi
ve
Ce
lls
Pro
po
rtio
n o
f ce
lls (
%)
shscr shVDR
% P
ositi
ve
Ce
lls
SA-β-Gal
shsc
r
shVD
R(1
)shVD
R(2
)
0
20
40
60
shsc
r
shVD
R(1
)
shVD
R(2
)0
50
100
Cell cycle profile
Sub G1
G0/G1
SG2/M
Figure 4
* **
*
*
*
*
p=0.04p=0.001
p=1.8e-05
p=4.58e-05
VDR
0.0
0.5
1.0
1.5
qR
T-P
CR
Re
lativ
e e
xpre
ssio
n shscrshVDR(1)shVDR(2)
A
D E
BRCA
1
B
BRCA1
RAD51
VDR
p21
Cyclin A
Vinculin
sh
scr
sh
VD
R
53BP1
CTSL
γH2AX
C
DAPI γH2AX
shscr
shVDR
shsc
r
shVDR
0
10
20
30
% g
H2
AX
Positi
ve
Ce
lls
Pro
po
rtio
n o
f ce
lls (
%)
shscr shVDR
% P
ositi
ve
Ce
lls
SA-β-Gal
shsc
r
shVD
R(1
)shVD
R(2
)
0
20
40
60
shsc
r
shVD
R(1
)
shVD
R(2
)0
50
100
Cell cycle profile
Sub G1
G0/G1
SG2/M
Figure 4
* **
*
*
*
*
p=0.04p=0.001
p=1.8e-05
p=4.58e-05
VDR VDR
X
BRCA1 BRCA1
X
CTSL53BP1
BRCA1 BRCA1
VDR
VDRVD
VDR
VD
53BP1
Vitamin D(1,25D)
Tumor cellsTNBC and BRCA1-mutated
Grotsky et al., JCB 2013
Growth-arrested cells
Croke et al., Cell Cycle 2013
Lamin A/C lossProgerin expression
Gonzalez-Suarez et al., EMBO J 2009 & 2011Kreienkamp et al., Oncotarget 2016
Senescent fibroblasts
b-gal, SAHF, SASP, SAPD, SADS
Primary
fibroblastsRasV12 Replication
Stress/DDR
DNA damage
accumulation
Malignant transformation
Secondary hits
(mutations)
Day 2 Day 4 Day 6
Graziano et al., Oncogene 2016