Pathology as Integrative Pathology as Integrative Research BiologyResearch Biology

Robert D. Cardiff, M.D., Ph.D.And

Jose J. Galvez, M.D.Center for Comparative Medicine

University of California, Davis

GEMS = Genetically Engineered Mice

PERLS = Computer Languages

PATHOLOGYPATHOLOGYPATHOLOGYPATHOLOGY

CONTEXT

INTEGRATION

INTEGRATION INTEGRATION of of

STRUCTURE AND FUNCTIONSTRUCTURE AND FUNCTION

PATHOLOGYPATHOLOGY

Interpretation of morphologic alterations requires knowledge of and integration of structure, function, natural history, etiology and clinical context.

Armed with this information, pathology provides integrative biology. Without this information, histopathology is useless.

VALIDATION: Pathology’s VALIDATION: Pathology’s New ChallengeNew Challenge

VERIFICATION: Yes, that is a tumorof the mammary gland.

VALIDATION: …a malignant neoplasm of the mammarygland (adenocarcinoma, mammary gland) initiated by the Her2/neu gene with a solid, lobular pattern and cells with oval, uniform nuclei and relatively abundant cytoplasm. The tumor resembles lobular carcinoma of the human breast because it….

Model Validation is the process of delineating the attributes (characteristics) of an experimental system that accurately matchthe attributes (characteristics) of human disease.

Validation is a process that accurately matches words (terminology) and/or pictures (images).

Validation requires comparison words or images that define the characteristics of mouse and human tumors.

PERLSPERLSof the Information Ageof the Information Age

The characteristics are documented by images obtained using technical protocols and described using terminology.

The MMHCC Steering Committee has asked the MMHCC Pathologists to provide all four.

PERLSPERLS

PERLSPERLS

• Controlled vocabulary. What do YOU mean? (Diagnostic Terminology)

• Description Logic: How do YOU describe it? (Characteristics)

• Objects: How will YOU represent it? (Images)

• Machine Languages: Will MY computer understand and integrate it? Will THEIR computers retrieve and use it? (Protocols)

• Integration: Pathology will integrate structure and function. BUT, Pathologists will need to learn and use computer languages.

MOUSE MODELS OFMOUSE MODELS OFHUMAN BREAST CANCERHUMAN BREAST CANCER

• Genetically Engineered Mice (GEM) have unique tumor phenotypes

• GEM integrate Structure and Function.• The in-vivo biological test for oncogenicity of

potential oncogenes (surrogate for human disease)

GEMSGEMS

GEM MAMMARY TUMOR GEM MAMMARY TUMOR MORPHOLOGYMORPHOLOGY

GEM mammary tumors are unique.

• Resemble “SPONTANEOUS” mammary tumors: fgf-3, notch-3, wnt-1,wnt-10b

• Mimic HUMAN BREAST CANCER: c-erbB2, src, myc, SV40 Tag, IGFr-2, others

• Unique GENE-SPECIFIC “SIGNATURE” PHENOTYPE: c-erbB2, myc, ras, IGF-2, SV40 Tag, ret-1, others

• Unique PATHWAY PATHOLOGY: wnt-1 vs erbB

The genes and structure of breast cancersare repeated.

Lobular

NST

Tubular

Cribriform

PATTERNS OF HUMAN BREAST CANCER

•Lobular Carcinoma ---E-Cadherin •Medullary Carcinoma-BrCa1•Comedo Carcinoma--- Her-2 (erbB2)•Others

HUMAN CANCER

The genes and structure of breast cancersare repeated.

Breast Cancer Associated with c-erbB2

HUMAN MOUSE

HUMANMOUSEGEMSGEMS

PERLSPERLS

• Controlled vocabulary. What do YOU mean? (Diagnostic Terminology)

• Description Logic: How do YOU describe it? (Characteristics)

• Objects: How will YOU represent it? (Images)

• Machine Languages: Will MY computer understand and integrate it? Will THEIR computers retrieve and use it? (Protocols)

• Integration: Pathology will integrate structure and function. BUT, Pathologists will need to learn and use computer languages.

GEM MAMMARY TUMORSGEM MAMMARY TUMORSthatthat

• Mimic HUMAN BREAST CANCER: c-erbB2, src, myc, SV40 Tag, IGFr-2, others

Lobular Carcinoma

A B

IS A OR B HUMAN?

The whole slide?

GEMSGEMS

• Controlled vocabulary. What do YOU mean? (Diagnostic Terminology)

• Description Logic: How do YOU describe it? (Characteristics)

• Objects: How will YOU represent it? (Images)

• Machine Languages: Will MY computer understand and integrate it? Will THEIR computers retrieve and use it? (Protocols)

• Integration: Pathology will integrate structure and function. BUT, Pathologists will need to learn and use computer languages.

GEMGEM MAMMARY TUMOR MAMMARY TUMOR MORPHOLOGYMORPHOLOGY

GEM mammary tumors are unique.

• Resemble “SPONTANEOUS” mammary tumors: fgf-3, notch-3, wnt-1,wnt-10b

• Mimic HUMAN BREAST CANCER: c-erbB2, src, myc, SV40 Tag, IGFr-2, others

• Unique GENE-SPECIFIC “SIGNATURE” PHENOTYPE: c-erbB2, myc, ras, IGF-2, SV40 Tag, ret-1, others

• Unique PATHWAY PATHOLOGY: wnt-1 vs erbB

GEMGEM MAMMARY TUMORS MAMMARY TUMORSUnique GENE-SPECIFIC “SIGNATURE” PHENOTYPE:

c-erbB2, myc, ras, IGF-2, SV40 Tag, ret-1, others

RAS MYC NEUSTRUCTURE and FUNCTION

PERLSPERLS

• Controlled vocabulary. What do YOU mean? (Diagnostic Terminology)

• Description Logic: How do YOU describe it? (Characteristics)

• Objects: How will YOU represent it? (Images)

• Machine Languages: Will MY computer understand and integrate it? Will THEIR computers retrieve and use it? (Protocols)

• Integration: Pathology will integrate structure and function. BUT, Pathologists will need to learn and use computer languages.

WNT PATHWAYERBB PATHWAY

ERBB2

ANTI-SMOOTH MUSCLE ACTIN

WNT1

• Myoepithelium •Branching Ductules • Acinar or Solid • Keratinization• Stroma• Expansile

PATHWAY PATHOLOGY

PERLSPERLS

• Controlled vocabulary. What do YOU mean? (Diagnostic Terminology)

• Description Logic: How do YOU describe it? (Characteristics)

• Objects: How will YOU represent it? (Images)

• Machine Languages: Will MY computer understand and integrate it? Will THEIR computers retrieve and use it? (Protocols)

• Integration: Pathology will integrate structure and function. BUT, Pathologists will need to learn and use computer languages.

PATHWAY PATHOLOGY

H and E

WNT PATHWAYDevelopmental

Anti-CK8

• Myoepithelium •Branching Ductules • Acinar or Solid • Keratinization• Stroma• Expansile

PATHWAY PATHOLOGY

De novo HairMorphogenesis

AE-13“Hard Keratin”(Hair Keratin)

WNT PATHWAYDevelopmental

• Myoepithelium • Branching Ductules • Acinar or Solid • Keratinization• Stroma• Expansile

PERLSPERLS

• Controlled vocabulary. What do YOU mean? (Diagnostic Terminology)

• Description Logic: How do YOU describe it? (Characteristics)

• Objects: How will YOU represent it? (Images)

• Machine Languages: Will MY computer understand and integrate it? Will THEIR computers retrieve and use it? (Protocols)

• Integration: Pathology will integrate structure and function. BUT, Pathologists will need to learn and use computer languages.

Molecular HierarchyMolecular HierarchyExpression MicroArraysExpression MicroArrays

Desai KV, Xiao N, Wang W, Gangi L, Greene J, Powell JI, Dickson R, Furth P, Hunter K, Kucherlapati R, Simon R, Liu ET, Green JE. Initiating oncogenic event determines gene-expression patterns of human breast cancer models. Proc Natl Acad Sci U S A 2002 May 14;99(10):6967-72

ERBB/RASMYC/p53-Rb

PERLSPERLS

Desai KV, Xiao N, Wang W, Gangi L, Greene J, Powell JI, Dickson R, Furth P, Hunter K, Kucherlapati R, Simon R, Liu ET, Green JE. Initiating oncogenic event determines gene-expression patterns of human breast cancer models. Proc Natl Acad Sci U S A 2002 May 14;99(10):6967-72

MYC/p53-Rb

ERBB/RAS

INTEGRATION INTEGRATION of of

STRUCTURE AND FUNCTIONSTRUCTURE AND FUNCTION

CONTEXT

GEMS and PERLSGEMS and PERLS

CONCLUSIONS:CONCLUSIONS:

1. Structure and Function: • Genotype (genes) predicted by the structure of the tumor

(phenotype).• Pathway Pathology identifies the “target genes”

2. Integration requires controlled vocabulary and description logic.

3. Validation requires the detailed characterization by the pathologists and their colleagues.

Cory Abate-Shen, Birgit Anderegg, Andrew Arnold, Allan Balmain, Peter Barry, Mina Bissell, Alexander Borowsky, Chris Bowlus, Debbie Cabral, Chen, Chester, Lewis Chodosh, Steven Chua, Clemensia Colmenares, Denise Connolly, Corley, Jerry Cunha, Jim DeGregori, Gerald Denis, Chuxia Deng, Micheal DiGiovanna, Dube, David Eberhard, Ecsedy, Ellis, Ari Elson, Adrain Erlebacher, Linda Foote, Gerth, Laurie Glimcher, Jeff Gregg, Alain Guimond, Paul Gumerlock, Tom Hamilton, Michelle Harrington, John Hassell, Jim Hechler, Claudia Hofmann, Kathleen Hruska, Jeff Hsu, Kent Hunter, John Hutchinson, Yulia Kaluzhny, M. Kavanaugh, Michelle Kelliher, James Kim, Dani Kitzberg, Jeanine Kleeman, John Klingensmith, Backesh Kumar, Kurihara, Esther Landesmen, Allan Lau, TeriLaufer, Ben Leader, Michel Lebel, Aya Leder, Phil Leder, Eva Lee, Fred Lee, Lin, Kent Lloyd, J. Lund, Carol MacLeod, Phil Mack, Jeannie Maglione, Albert Man, Mani, Shyamala-Harris, Jennifer Michaelson, Kieko Miyoshi, Mills, Misa, Moran, Amy Moser, Bill Muller, A. Nissim, O’Neil, Chris Ormandy, Bob Oshima, JH Park, Quadri, Glenn Radice, Ann Ranger, Katya Ravid, Andrea Rosner, Tom Rothstein, Pradip Roy-Burman, Cornelius Rosse, Robert Russell, Enriqu Saez, Saquib, Earl Sawai, Charles Sawyers,Emmitt Schmidt, Schneider, Nicole Schreiber-Agus, Peter Seigel, Dave Seldin, Stu Sell, Michael Shen, Trevor Shepherd, Rachel Sheppard, David Sherr, Stuart Schnitt, Toshi Shioda, Jonathan Shillingford, Shyamala Mani, Ranu Nandi, Katherine Siminovitch, Radek Skoda, G. Sonenshein, Michael Song, Z. Song, Lisa Stubbs, Amy Sung, R. Sung, Amy Lanping, R. Taneja, Ann Thor, George Thomas, Tilghman, N. Tulchin, Terry Van Dyke, Barbara Vanderhyden, P. Vogt, BenVollrath, Judy Walls, Walter Witke, Kay-Uwe Wagner, Y.Z. Wang, L Wang, M. Weinstein, M. Weiss, Chris Westphal, Don White, Jolene Windle, Hong Wu, Larry Young, Youd, Cindy Zahnow, Lianxing Zheng, BenRich, DaGong Wang, Lothar Henninghausen, NCI BioInformatics, Apelon.

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