Dr. Martin H. Hager – Instructor in Surgery Harvard Medical School

The metastatic cascade

Tumor cell invasion mechanisms

MAT

EMT

Mesenchymal cell movement

Tumor cell invasion mechanisms

MAT

EMT

Amoeboid cell movement

Identification of significant focal copy number alterations

Beroukhim et al. Nat. 463, 18 Feb 2010

DIAPH3 loss is associated with metastatic prostate cancer

Breast Carcinoma

Prostate Carcinoma

Hepatocellular Carcinoma Chr13

DIAPH3 loss is associated with metastatic prostate cancer

DIA

PH

3 lo

g2

cop

y n

um

ber

un

its

-0.5

0.1

0

-0.1

-0.2

-0.3

-0.4 n=181 n=37

Primary Site

Met

DIA

PH

3 lo

g2

cop

y n

um

ber

un

its

-0.5

0.2

0.1

0

-0.1

-0.2

-0.3

-0.4

Gleason Score

6 8 7 9

n=53 n=12 n=102 n=12 n=36

Met

DIAPH3 loss is associated with metastatic prostate cancer

An unidentified region of HD matches the DIAPH3 gene locus

An unidentified region of HD matches the DIAPH3 gene locus

DRF3 forms a complex with EGFR

DRF3 regulates EGFR trafficking

DRF3 regulates EGFR signaling

DRF3 regulates proliferation and epithelial morphogenesis

Loss of DRF3 cooperates with RAS to promote cell invasion

Loss of DRF3 cooperates with RAS to promote cell invasion

HMEC HRASV12 Control shRNA HMEC HRASV12 DRF3 shRNA

Loss of DRF3 cooperates with RAS to promote cell invasion

Loss of DRF3 promotes an amoeboid phenotype

Loss of DRF3 promotes invasion and metastasis

Supported by:

In collaboration with:

Michael J. Eck, M.D., Ph.D.

David S. Pellman, M.D.

James E. Bradner, M.D.

Richard O. Hynes, Ph.D.

Henry H. Higgs, Ph.D.

Joan S. Brugge, Ph.D.

Jose M. Silva, Ph.D.

William C. Hahn, M.D., Ph.D.

Sizhen Gao, M.D.

Ghassan Mouneimne, Ph.D.

Robert A. Weinberg, Ph.D.

Gregory Hannon, Ph.D.

Ilona N. Holcomb, Ph.D.

William B. Isaacs, Ph.D.

Wennuan Liu, Ph.D.

Acknowledgements:

Michael R. Freeman, Ph.D.

the Freeman lab

Please see poster P24-39 tomorrow, 4:00-5:30 PM (P24 - Genetics and Molecular Biology II)