Pathology as Integrative Research 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

PATHOLOGYPATHOLOGY CONTEXT INTEGRATION INTEGRATIONof STRUCTURE AND FUNCTION

PATHOLOGY 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 New Challenge VERIFICATION: Yes, that is a tumor of the mammary gland. VALIDATION: …a malignant neoplasm of the mammary gland (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 match the 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. PERLS of 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. PERLS

PERLS 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 OF HUMAN 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) GEMS

GEM MAMMARY TUMOR MORPHOLOGY 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 cancers are 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 cancers are repeated.

Breast Cancer Associated with c-erbB2 HUMAN MOUSE HUMANMOUSE GEMS

PERLS 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 TUMORS that 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? GEMS 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 TUMOR MORPHOLOGY 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

GEM MAMMARY TUMORS Unique GENE-SPECIFIC “SIGNATURE” PHENOTYPE: c-erbB2, myc, ras, IGF-2, SV40 Tag, ret-1, others RASMYCNEU STRUCTURE and FUNCTION

PERLS 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 PATHWAY ERBB PATHWAY ERBB2 ANTI-SMOOTH MUSCLE ACTIN WNT1 Myoepithelium Branching Ductules Acinar or Solid Keratinization Stroma Expansile PATHWAY PATHOLOGY

PERLS 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 PATHWAY Developmental Anti-CK8 Myoepithelium Branching Ductules Acinar or Solid Keratinization Stroma Expansile

PATHWAY PATHOLOGY De novo Hair Morphogenesis AE-13 “Hard Keratin” (Hair Keratin) WNT PATHWAY Developmental Myoepithelium Branching Ductules Acinar or Solid Keratinization Stroma Expansile

PERLS 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 Hierarchy Expression 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): ERBB/RASMYC/p53-Rb PERLS

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): MYC/p53-Rb ERBB/RAS INTEGRATIONof STRUCTURE AND FUNCTION CONTEXT GEMS and PERLS

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.

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