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

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H P

iwnic

a-W

orm

s

D P

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a-W

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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?

CTSL-mediated degradation of 53BP1 is activated during OIS

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 depletion leads to BRCA1 loss of function and defective HR

Vitamin D ameliorates DNA repair during OIS

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

Acknowledgements

Susana Gonzalo

Ray Kreienkamp

Gonzalo Bedia Diaz

Emily Cybulla

Collaborators

Junran Zhang

Case Western

University

Funding

Siteman Cancer Center pre-doctoral fellowship

National Institutes of Health

DOD Breast Cancer Idea Award

Siteman Cancer Center

Research Fund SLU