“Oncología Básica”

How are cancer cells created?...Changes in paradigms

Isidro Sánchez-García (isg@usal.es)

1X Simposium Bases Biológicas del Cáncer y Terapias Personalizadas

Salamanca, 18-19 de Mayo, 2017

1. Alteración proliferación

2. Apoptosis

3. Tumor

4. Angiogénesis

5. Alteraciones genéticas (mutaciones, fusiones génicas, etc.)

6. Clonalidad

¿Cuáles de estas propiedades son carácterísticas del cáncer?

Cuando se observa cáncer en un individuo al

menos contiene 1000 millones de células (109)

El cáncer surge en un organismo inmuno competente

-Líneas celulares

-Modelos de ratones inmudeprimidos

-Xenografts

LA INVESTIGACIÓN CLÍNICA CARECE DE CONTROLES ADECUADOS:

EL MISMO INDIVIDUO NO PUEDE SER TRATADO Y NO TRATADO

Approvals in 2016: questioning the

clinical benefit of anticancer

therapiesChristopher M. Booth & Joseph

C. Del PaggioPublished online: 20

February 2017p135 |

doi:10.1038/nrclinonc.2017.18Patients

with cancer expect to derive a meaningful

clinical benefit from anticancer

treatments, especially considering that

such therapies are associated with

adverse events and, often, substantial

financial costs. We have evaluated new

anticancer agents approved by the FDA

in 2015 and 2016 using the ESMO

Magnitude of Clinical Benefit Scale and

ASCO Value Framework, and conclude

that many agents only offer marginal

value.

Why early stages in cancer are important?

Oncogene-celltargetinteraction Clinicalmalignant tumor mass

“billion-cellthreshold”

(Oncologyremissionmeans 0 ---- 109cells)

Why is important to know the etiology of cancer?

Cancer within a tissue

normal tissue

Therapeutic target

CSC

Human cancer development

genetic program: -specific cancer cell targets, -biomarkers, -predict cancer response, etc

mouse and human

normal stem cells

are similar

How tostud yearly stages in cancer?

Outline

1- Current model of cancer

2- Tumoral epigeneticstem cell reprogrammimghypothesis

3- Experimental validation and clinical application

4- Implications in the development and treatment of cancer

Current model of cancer

Do the oncogenes have a modeofactionthatisnothomogeneous

throughoutthecancercellpopulation?

-Heterogenous tumor cellcomposition.

-Initiatinggeneticalterationispresent in both CSC anddifferentiated tumor cells.

-Homogenousmodeofactionfor oncogenes withincancercells.

-Briefinactivationof oncogenes can cause cancerremission in modelsystems:oncogeneaddition

-However, unfortunately, thet herapiesbasedonthiscancermodelfailtoeradicatetumours in humans.

Classical model for the role of human cancer gene defects in tumour cell fate specification

Traditionally, the human cancer genetic defects have been thought to act on cells already committed

to a differentiation program, in such a way that the tumoural phenotype is derived from that of the initial differentiated target cell

Alternative model for the role of human cancer gene defects in tumour cell fate specification

Alternativeview in which the oncogenic lesion acts on stem/progenitor cells by imposing

a given, oncogene-specific, tumour-differentiated cell fate.

Human Cancer tissue

Genetic defect is present in both CSC

and differentiated tumor cells

In vivo experimental model of tumoural stem cell reprogramming

Genetic defect is only present in CSC

?

Oncogene-induced plasticity and CSC

Stem cell

compartment CSC proliferating cells

Stem cell

compartment Differentiated cells

Genotype Phenotype

Translocation Genetic

product Tumour type

t(12;16)(q13;p11) FUS-DDIT3 Myxoid Liposarcoma

t(16;21)(p11;q22) FUS-ERG Acute myeloid leukaemia

t(9;22)(q34;q11) BCR-ABLp190 B acute lymphoblastic

leukaemia

t(9;22)(q34;q11) BCR-ABLp210 Chronic myeloid

leukaemia

t(9;22)(q34;q11) BCR-ABLp230 Chronic neutrophilic

leukemia

t( ?;3)( ?;q27) ?+ BCL6 DLBCL/ Follicular

lymphoma

Written on his blackboard at time of his death, in 1988

Reprogramming in malignancies originated from stem cells

In vivo experimental model of tumoural stem cell reprogramming

EMBO J. 28(1):8-20 (2009).

Cell Cycle 8:1314-1318 (2009)

N Engl J Med. 360(3):297-299 (2009)

1- Proof of principle experiment

2- Chronic myeloid leukemia (CML) stem cells are not oncogene addicted and the therapies

that biochemically target BCR-ABL do not eliminate them (CML stem cells).

3-First animal model aniticipating human clinical results in the CSC field

4-Results were confirmed in human patients two years later

Can thishypothesis be extrapolatedtoothermalignancies?

Ewing

sarcoma

CML

Synovial

sarcoma

B-

cellhyperplas

ia

Multiplemyel

oma

MALT

lymphoma

ABC-

DLBCL

Stem/Progenitor

cell

BCR-

ABLp210

EWS-

FLI-1

SYT-

SSX2

HGAL

MafB

MALT1

BCL6

Oncogene. 2012.

Genes & development. 2010.

Nature communications. 2014.

Nature communications. 2013.

Proc NatlAcadSci USA. 2012.

Cell Cycle. 2012.

Embo J. 2012.

Cell Cycle. 2012.

Cell Cycle. 2012.

EmboJ. 2009.

The New England journal of medicine. 2009.

Cell Cycle. 2009.

Otherpatholo

gies?

¿?

Are there evidences of tumoral epigenetic stem cell reprogramming??

CSC

compartment

Tumor

differentiated cells

Normal

differentiated cells Normal stem cell

compartment

Wt Stem Cells

Cancer Stem Cells

Wt B Cells

Tumor B Cells

Segmean. HpaII

Se

gm

ea

n. M

sp

I

Red points are the 323

CSC-specific differentially

hypomethylated genes

Identification of a cytosine hypomethylation signature in Sca1-Bcl6

Tumourstem cell reprogramming and therapeutic implications

Reprogramming the cancer epigenome to an alternative lineage cell fate, non-tumoral fate, losing their malignancy?

Tumour stem cell reprogramming largely relies on epigenetic modifications. These, unlike genetic changes, can be erased, manipulated, and

reinitiated, thereforeimplying that anti-tumour reprogramming strategies can provide a new window of opportunity to interfere with the cancer

fate-inducing change.

CSCs do not have oncogene addition

Oncogenes cannot be used as a target to kill CSCs

BUT, Tumour stem cell reprogramming is a specific CSC target

Could we use it to prevent/kill CSCs?

Cancer progression also involves CSC evolution

Evolutionary speciation or ancestral tree, from

Charles Darwin’s 1837 Transmutation notebook B

Semin Cancer Biol. 2010

Geneticapproachtoidentify CSC maintenance genes and

genes/locires ponsible for different therapeutic response, etc

F1 B6 x FVB

X

Resistant strain (B6)

Susceptible Strain (FvB)

High CANCER phenotype variability (tumor

phenotype and genetics)

Population with high genetic variability primed for CANCER

(inherited and/or adquired susceptibilities)

potential

environmental

riskfactors/

carcinogentostu

dy gene-

enviromentinter

actions

F1 Backcross

±

Study physiological variability

Different risk factor exposure

susceptibility

Study genomic (SNPs) and epigenetic variability

before and after to identify risk factors

Human

Mouse

Infection

exposure

No Infection exposure

PAX5Δ/+

Pax5+/-

Pax5+/- Pax5+/-

Pax5Δ/-

PAX5Δ/-

Susceptible

pre-B cell

pB-ALL

pB-ALL

A

C

D

Susceptible

pre-B cell Preleukemic

pre-B cell

? B

?

PAX5Δ/+ PAX5Δ/+

CancerDiscov. 2015 Sep 25. pii: CD-15-0892

Aging. 2015 Sep;7(9):607-8

Therealisationthatidentifyingthisnewdiseasemechanismisnot, to

paraphrase Winston Churchill, "theend, orthebeginningoftheend,

butperhapstheendofthebeginning”.

Churchill, W.S.C. Speech at the Lord Mayor’s Luncheon, MansionHouse, London. November 10th, 1942

IBMCC (CSIC/USAL)

Salamanca

Inés González Herrero

Carolina Vicente Dueñas

Idoia García Ramírez

Alberto Martín Lorenzo

Guillermo Rodríguez Hernández

Xiomara Guerrero

Ana Gavilán

Sara Glez de Tena-Dávila

Isidro Sánchez-García

Universidad Salamanca

Hospital Clínico Univ.

Teresa Flores

Oscar Blanco

MD Ludeña

Juan Jesús Cruz

César A. Rodríguez

Gonzalo Varela

Concha Roman

Fco Javier Garcia Criado

Rafael Jiménez

Alberto Orfao

IMP Vienna

Meinrad Busslinger

Transgenic Unit

CNB-CBMSO

Belén Pintado

Verónica Domínguez

Lymphoma

CIMA- Pamplona

Jose A. Martinez-Climent

U. Miami-USA

Izidore Lossos

Cornell Institute (NY)

Ari Melnick

IMB- Salamanca Dionisio Martín-Zanca

Imperial-London

Cristina Lo Celso

Sanger Institute-Cambridge

Natalie Conte

Allan Bradley

Leukemia/BCR-ABL

CBMSO Madrid

César Cobaleda

IBMCC-Salamanca

Alberto Orfao

CBMSO Madrid César Cobaleda

Multyple myeloma

IBMCC-Salamanca

JF San Miguel/Norma

CNIO Madrid

Mariano Barbacid

USC-Santiago Compostela

Angel Carracedo

Lung & Breast

IBMCC-Salamanca

Jesus Perez-Losada

Stanford-USA

Ash Alizadeh

Pediatric leukemia/lymphoma

Med.Uni-Duesseldorf

Arndt Borkhardt

MDACC-USA

Michael Green

Thank you for your attention!!!!

Thetypesofcancersconsideredrangefromthose so rarethatinterestedscientistsprobably outnumberaffectedindividualstothenew plague ofepithelialtumors. Wemake no apologyforincludingrarecancers. The case fortheirstudywas made long ago by William Harvey in a letterwritten in 1657, justbeforehisdeath: ”Natureisnowhere wanttoreveal her innermostsecrets more openlythanwhenshe shows faint traces of herselfawayfromthebeatentrack. Noristhereanysurerroutetotheproperpractice of medicine thanifsomeonegiveshismindovertodiscerningthecustomarylawof naturethroughthecarefulinvestigationofdiseasesthat are ofrareoccurrence” Understandingofrarecancerdiseasecontinuestoprovideprofoundinsightsintobiological processes. Harvey, W. TheCirculationoftheBloodandOtherWritings. Edited by KJ Franklin. London: Everyman’sLibrary, Dent, Dutton;1963: 209.

Wemake no apologyforincludingrarecancers