10th Annual Scientific conference of

Istituto Toscano Tumori (ITT)( )

MOLECULAR BASIS OF PROGRESSION IN PANCREATIC CANCERIN PANCREATIC CANCER

Niccola FunelNiccola Funel

Division of Surgical, Molecular and Ultrastructural Pathology Division of General and Transplantation Surgery, and Regional Referral Center for Pancreatic Diseases Treatment

University and Hospital of Pisa Pisa July 3rd, 2015

Background

Pancreatic ductal adenocarcinoma (PDAC) is the fifthPancreatic ductal adenocarcinoma (PDAC) is the fifthmost common cause of death by cancer in the westernworld Because of the anatomic localization of theworld. Because of the anatomic localization of thepancreas and the delay of clinical symptoms, PDAC isd t t d i 85% f ti t t d d tdetected in 85% of patients at advanced stage.

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

PDAC ProgressionNormal ductNormal duct

IPMNsPanIN 1Early Alterations

K-Ras

MCNsPanIN 2

K-Ras

P16 Loss

EGFR amplificationMCNs

Late Alterations

P53 mutation/loss

PanIN 3

PDAC

Smad4 mutation/loss

BRCA2/LKB1

PDAC

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

PDAC ProgressionNormal ductNormal duct

IPMNsPanIN 1

MCNsPanIN 2

ACINAR DUCTAL METAPLASIA (ADM)

MCNs

PanIN 3

PDACPDAC

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

BackgroundEpithelial cells

(PDAC)(PDAC)

Stromal Cells

H b PDAC ll hibit

Stromal Cells

However, because PDAC usually exhibits anintense desmoplastic reaction, the molecularstudy of the entire tumor may not reflect the reallevels of some gene expressions.g p

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

Background

Several studies showed that the inflammatory andSeveral studies showed that the inflammatory andfibroblast cells in the stromal tissue, which representsth b d ' l tt t t fi ht t f d llthe body's normal attempt to fight transformed cells,were characterized by different levels of geneexpression pattern with respect to tumor cells.

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

Primary Cell Cultures

Primary Cell Cultures

Laser Microdissection

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

Orthotopic Mouse Model Specimens

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

CYB5A AND CHROMOSOME 18

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

CYB5A AND CHROMOSOME 18

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

CYB5A AND CHROMOSOME 18

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

CYB5A AND CHROMOSOME 18

Autophagy Modulators

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

MICRORNA (miR-21)

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

c-Met Oncogene

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

Our ITT ProjectIPMNs and PDACs Lesions

Quantification of MUCs and some mRNAs inibiting their expressionmRNAs inibiting their expression

Mutation Analyses of 20 most import gene involved in cancerimport gene involved in cancer

progression

Statistical AnalysesAnalyses

Best BiologicalMarkers

New Chip tayroled for IPMN (B t Si ifi t M k )

Best Supportive Care

Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Emergency Medicine,University of Pisa, Italy

(Best Significant Markers)pp

Pancreas UnitSurgey PathologyProf. Ugo BoggiDr. Fabio CanigliaDr. Francesca Costa

Prof. Daniela CampaniDr. Niccola FunelDr. Luca E. Pollina

Dr. Nelide DelioDr. Vittorio PerroneDr. Fabio Vistoli

Dr. Pinuccia Faviana

PharmacologyDr. Fabio Vistoli

RadiologyProf Carlo Bartolozzi Oncology

gyDr. Elisa Giovannetti

Prof. Carlo BartolozziDr. Carla CappelliDr. Salvatore Mazzeo

OncologyProf. Alfredo FalconeDr. Chiara CapparelloDr. Sara CaponiDr. Enrico Vasile