¿cómo puede la dieta modificar la genómica del cáncer?... · pc 1.5 up/do wn-2 +2 0 fc s cale...

¿Cómo puede la dieta modificar la genómica del cáncer?

Gloria Pascual Angulo

Stem Cells and Cancer labInstitut de Recerca Biomèdica-Barcelona

Cancer stem cell heterogeneity within tumors

represents a therapeutic challenge

Primary TumourMetástasis

Metástasis

Metástasis

Metástasis

Molecular information about Disease Progression

Quiescent/Slow cycling population

Metastasis-Initiating CellsLong-term slow-cycling in 1ary tumor

CD36+ (fatty acid membrane transporter)

Sensitive to dietary fat levels

High Fatty Acid metabolism

Therapeutic targeting through

CD36 inhibition

Operate in many human tumors

Multi-organ metastasisPascual et al, Nature 2017

Landyani et al, Oncogene 2018

NEW QUESTIONS…

Which dietary fatty acids are pro-

metastatic?

Why are fatty acids pro-metastatic?

Is CD36+ an epigenetically-established

CD36+ cells

- Gastric cancer- Prostate cancer

- Renal cancer- Bladder cancer

- Lung SCC- Melanoma

- Breast (Luminal A/B)- Glioblastoma (intracraneal invasion)

- AML/CML chemoresistance- Melanoma therapy resistance

- Pancreatic carcinoma therapy resistance

so far…

Pascual et al., Nature 2017Benitah SA, Cell Stress (2018)

Pascual et al., DDM reviews (2018)

High fat diet boosts metastasis through CD36

PRIMARY TUMOUR

LN METASTASIS

60% Fat

CD36 RECEPTOR MUTANT CD36 RECEPTOR

The pro-metastatic effects of palmitic acid persist for a very long time

PA-treated (14 days post)

Untreated

Serial OSCC injection GFP+from primary tumours

UNTREATED PA-TREATED 14D post

Palmitic Acid pro-

metastatic memory

(epigenetic state?)

Epigenetic drivers of tumourigenesis and cancer metastasis.Seminars in Cancer Biology. 2017

Epigenetic driver of cancer metastasis?

Selection of particular epigenetic changes could provide a selective advantage for the cancer cells to successfully metastasize

Are all Fatty-Acids increasing metastatic potential of MICs?

Palmitic acid, but not linoleic or oleic, enhances the metastatic potential of MICs

Short-time effectPascual, G., Domínguez, D. et al.Manuscript under revision

CD44+

Oral squamous cell carcinoma SCC-25 pluc GFP [PLKO and shCD36]VDH15 pluc GFP [PLKO and shCD36]

Melanoma

501mel Cherry plucGFP [PLKO and shCD36]

Models

A Model to study in vivo long-term effects of diet in tumor cells and tumor progression

*

Lymph nodemetastasis

Lungmetastasis

Patient-derived xenograft

Pascual, G., Domínguez, D. et al.Manuscript under revision

Ex vivo Lung Metastasis BLI***

Primary Tumour

Lung Metastasis

Orthotopic Melanoma Model


2ry Recipient- Primary Tumours

CD36+ CD36+

Oleic vs Control Palm vs Control

PC 1.5 up/down

-2

+2

0

FC Scale

CD36- CD36-

10-6

10-5

10-4

10-3

10-2

10-1

100

Response to interferon-betaRegulation of nervous system development

Regulation of apoptotic processRegulation of neuron dif erentiation

AngiogenesisNitrogen utilization

ChemotaxisEpithelium development

Regulation of transcription by RNA polymerase IIPositive regulation of RNA metabolic process

Response to lipidImmune response

VDH-15 CD36+

Biological Process Palm Diet Up

P value

VDH-15 CD36-


P value

10

NeurogenesisProteolysis

Neuron di erentiationPositive regulation of cellular protein metabolic process

Neuron projection morphogenesisRegulation of intracellular signal transduction

AngiogenesisResponse to lipid

Response to oxidative stressCell chemotaxis

Immune responseCell migration

Epidermal cell di erentiationEpidermis development

0

10-5

10-1

0

10-1

5

VDH-15 CD36+Palm Diet vs Control Diet

Up-regulated Up-regulatedDown-regulatedDown-regulated

0

0 2.5 5-2.5-5

1

2

3

4

5

0 2.5 5-2.5-5

0

1

2

3

4

5

VDH-15 CD36-Palm Diet vs Control Diet

log2(Fold Change)log2(Fold Change)

-log10(P

valu

e)

-log10(P

valu

e)

PLKO-CD36+ Control DietPLKO-CD36- Control DietPLKO-CD36+ Palm DietPLKO-CD36- Palm DietshCD36-CD36- Control DietshCD36-CD36- Palm Diet

PLKO-CD36+CTD

PLKO-CD36+PALMD

PLKO-CD36-PALMD

PLKO-CD36-CTD

shCD36-CD36-PALMD

shCD36-CD36-CTD

VDH-15 Principal Component Analysis


0

1

2

3

4

-6 -3 0 3

Up-regulated Up-regulatedDown-regulatedDown-regulated

-6 -3 0 3 6

0

1

2

3

4

SCC-25 CD36+Palm Diet vs Control Diet

SCC-25 CD36-Palm Diet vs Control Diet

log2(Fold Change)

-log10(P

valu

e)

log2(Fold Change)

-log10(P

valu

e)

P value

SCC-25 CD36-


10-1

5

10-1

0

10-5

100

Muscle adaptationNeuron migration

Drug metabolic processNeuron di erentiation

Collagen-activated signaling pathwayNeurogenesis/Generation of neurons

Schwann cell development/di erentiation

Myelination in peripheral nervous systemPeripheral nervous system axon regeneration

Blood vessel remodelingTissue morphogenesis

Response to lipidCell migration

SCC-25 CD36+


10-6

10-5

10-4

10-3

10-2

10-1

100

Positive regulation of myelination

Response to xenobiotic stimulus

Synaptic signalingFibroblast growth factor production

Response to fructose

Vasculature development

Connective tissue developmentNeurogenesis

Cell migrationNeuron di erentiation

Peripheral nervous system developmentAxonogenesis

Tissue morphogenesis

p value

Palm diet also molecularly converts CD36-

into CD36+

In shCD36, CD36- cells, are not able to

respond to palm diet

Incluir Análisis más profundo del shCD36?

Incluir Análisismásprofundo de Olive Diet?

SCC-25 Principal Component Analysis


Molecular characterization of fat-exposed cancer cells- RNA Microarrays


Molecular characterisation palm-exposed cancer cells


Is Palmitic Acid establishing an epigenetic memory?

Fatty acid metabolism is epigenetically altered in metastatic tumors

Rinaldi et al, Cell Stem Cell (2016)Rinaldi et al, eLife (2017)

The nexus of chromatin regulation and intermediary metabolism. Nature, 2013.

Cell Line Assay Time

SCC-25(Established

OSCC)

Patient-derived OSCCs

RNA-Seq• 4 Days• 14 Days

ATAC-Seq

• 4 Days• 14 Days

h/MeDIP-Seq

ChIP-Seqs

Cell Line Histone Mark Time

SCC-25(Established OSCC)

Patient-derived OSCCs

H3K4me1

• 4 Days• 14 Days

H3K4me3

H3K27me3

H3K27ac

H3K9ac

H3K9me3


H3K4me3 (i.e. promoters) shows a significant memory of palmitic acid

UNTREATED-4d

UNTREATED-14d

TREATED-4d TREATED-14d

150

729

PA-Induced Memory PCA: Condition+Factor

Principal Component #1 [94%]

Pri

ncip

al C

om

po

nen

t #2 [

2%

]

−0.6

−0.4

−0.2

0.0

0.2

−0.30 −0.25 −0.20

●●

●

●

●

●

●

●

●

●

●

●

12

3

1

2

3

1

2

3

1

2

3

Days4:UntreatedDays4:TreatedDays14:UntreatedDays14:Treated


H3K4me1 (i.e. enhancers) does not retain the memory of palmitic acid

Who establishes the metastatic epigenetic memory of

dietary palmitic acid?

• H3K4me3 ChIP-seq - CTRL PLKO vs SETD1A KD (palmitic versus control)

Cell TypeHistone

MarkTime Point FDR FC

#Diff Peaks UP PA

#Diff Peaks DOWN PA

VDH-15 SETD1A KD H3K4me3 14 Days 0.05 1 215 116

Cell TypeHistone

MarkTime Point FDR FC

#Diff Peaks UP PA

#Diff Peaks DOWN PA

VDH-15 CTRL PLKO H3K4me3 14 Days 0.05 1 857 25

Inhibition of Setd1a prevents the H3K4me3 memory induced by dietary palmitic acid

CH

RD

L1 L

ocu

s

VDH15 CTRL UNT 14DVDH15 CTRL PA 14DSETD1A KD UNT 14DSETD1A KD PA 14D

SER

PIN

A1

Lo

cus

Inhibition of Setd1a prevents the H3K4me3 memory induced by dietary palmitic acid

VDH15 CTRL UNT 14DVDH15 CTRL PA 14DSETD1A KD UNT 14DSETD1A KD PA 14D

Inhibition of Setd1a prevents the metastatic spreading in oral cancer


H3K4me3 memory induced by dietary palmitic acid

GO Biological Process


NES 1.51

Nominal Pvalue 0.05NES 1.50

Nominal Pvalue 0.04

CD36+Palm vs Control Diet Enrichment

VD

H-1

5

NES 1.59

Nominal Pvalue 0.01

NES 1.57

Nominal Pvalue 0.01

NES 1.74

Nominal Pvalue 0.001

NES 3.17




CD36-Palm vs Control Diet Enrichment

NES 3.55


Nominal Pvalue 0.0


SC

C-2

5

Palm Diet-induced memory

Neural-related

Include stainings as link for the next part (trasncriptomics of neural stroma)

NES 1.51


Nominal Pvalue 0.04


VD

H-1

5

NES 1.59

Nominal Pvalue 0.01

NES 1.57

Nominal Pvalue 0.01

NES 1.74

Nominal Pvalue 0.001

NES 3.17





NES 3.55


Nominal Pvalue 0.0


SC

C-2

5

Palm Diet-induced memory

Neural-related

Include stainings as link for the next part (trasncriptomics of neural stroma)

NEURAL-RELATED SIGNATURE PALM-EXPOSED CANCER CELLS

• Transcription/Modulator Factor activity• Secreted Factors/Neurite outgrowth• Neurotransmitter release/Receptor

Activity

Is the acquisition of a neural-related signature of OSCC related with

metastasis?

Epithelia Stroma

PLKO-CD36bright

PLKO-CD36bright

PLKO-CD36dim

PLKO-CD36dim

shCD36-CD36dim

shCD36-CD36dim

-6 -3 0 3 6

0

1

2

3

4

Muscle adaptation

Drug metabolic process

Collagen-activated signaling pathway

Blood vessel remodeling

SCC25 CD36bright

Palm Diet vs Control Diet

log2(Fold Change)

Up-

regulated

Down-

regulated

-log10(P

valu

e)

100

10-5

10-1

0

10-1

5

Pvalue

SCC-25 CD36bright

Palm Diet Biological Process Up

50uM

50uM

50uM

50uM

SCC-25 PLKO-Control Diet-2ry recipientNEF-LKT-14Dapi

SCC-25 shCD36-Control Diet-2ry recipientNEF-LKT-14Dapi

SCC-25 PLKO Palm Diet-2ry recipientNEF-LKT-14Dapi

SCC-25 shCD36-Palm Diet-2ry recipientNEF-LKT-14Dapi

B C

D

10-6

0

10-4

0

10-2

0

100

pvalue

Biological Process UPPPalm Diet vs Control Diet

Extracellular matrix organizationCell migration

Collagen bril organizationResponse to growth factor

Cell-matrix adhesion Supramolecular ber organization

Response to lipidNeuron di erentiation

NeurogenesisSecretion

Reg. of nervous system developmentBlood vessel remodelingSprouting angiogenesis

Actin cytoskeleton organizationResponse to steroid hormone

InnervationGliogenesis

Neuron recognitionHypothalamus cell migration

Serotonin uptake

G

6

4

2

0

-5 0

UP-RegulatedDOWN-Regulated

log2(Fold Change)

PLKO Palm vs PLKO Control

SCC-25/VDH-15

Neural-enriched stroma

5

DEGsUP/DOWN

in (F)6

4

2

0

-lo

g1

0(P

va

lue

)

shCD36 Palm vs PLKO Control

-5 0 5log2(Fold Change)

SCC-25/VDH-15


-lo

g1

0(P

va

lue

)

E

F

H

Figure 3

Response to lipid

Neuron di erentiation

Neuron migration

Neurogenesis/Generation of neurons



SCC-25 Principal

Component Analysis

I

HUMAN-[CD36-]

HUMAN-[CD36+]

Mouse

Schwann celldevelopment

neuron projectionregeneration

CTD

PALMD

CTD

PALMD

PALMD

CTD

SCC-25 - H3K4me3 in vitro ChIPs GO Analysis (14D post-PA):

UP-regulated Neural-related GO terms

GO

Bio

log

ical P

ro

cess

GO

Bio

log

ical P

ro

cess

0 2 4 6 8

axonogenesisaxon guidance

cell morphogenesis involved in neuron dif erentiationglycosaminoglycan metabolic process

sprouting angiogenesisregulation of neuron projection development

chondroitin sulfate proteoglycan biosynthetic processaxon development

heart contractionspinal cord dorsal/ventral patterning

-Log (pvalue)

14D PA UP

VDH-15 - H3K4me3 in vivo ChIPs GO Analysis (2ary PTs):


0 2 4 6 8

regulation of p38MAPK cascadebranching morphogenesis of an epithelial tube

forebrain regionalizationvasculogenesis

lung developmentneuron projection morphogenesis

cell morphogenesis involved in neuron dif erentiationregulation of angiogenesis

regulation of Wnt signaling pathwaynegative regulation of cell communication

-Log (pvalue)

UP in 2ary PALM-Diet Tumours

A

f

Cell migration

OliveControl Palm

Strategy for enrichment in mouse “tumour-neural stroma”

Neural Stem/ progenitorsInmature/Intermediate progenitorsNeuron-like cells (?)Mature neurons (X)

Glial Cellsof PNS

Glial Cellsof CNS

ModelsOral squamous cell carcinoma SCC-25 pluc GFP [PLKO and shCD36]VDH15 pluc GFP [PLKO and shCD36]

Melanoma501mel Cherry plucGFP [PLKO and shCD36]

A

Palm-

PLKO

Palm-

shCD36

Control-

shCD36

Control-

PLKO

B

PC1 (65.3%)-50 0 50 100

PALM Diet (A)

CONTROL Diet (B)

PALM Diet (B)

OLEIC Diet (B)

VDH15 Neural-enriched stroma

-20

-10

010

20

30

40

PC

2(1

1.5

%)

SCC-25 PLKO-Palm Diet

2ry Recipient/Primary tumour

GFP+

GFP-CD31-

CD31+

CD31-BV-710

GFP

Dapi-

32.7

60.0

0.46

GFP+

GFP-CD31-

CD31+

CD31-BV-710GFP

22.1

72.3

0.47

Dapi-

SCC-25 PLKO-Control Diet

CD45-PE-Cy7

Neu

ral M

ix-A

PC

APCbrightCD45low

Neural-enriched fractionGFP-CD31-

5.73

Mouse

CD45bright

CD45-PE-Cy7

Neu

ral M

ix-A

PC

Neural-enriched fractionGFP-CD31-

APCbrightCD45low

9.29

Mouse

CD45bright

MouseMouse

C

-2

0-1

01

02

00

PC1 (53.3%)

PC2 (11.6%)

PLKO- PALM

VDH- 1 5

Neural-enriched fraction

2ry recipient

E

40-20 0 20

-20

-10

010

PC1 (48.5%)

PC

2 (

13

.9%

)

PLKO- Control Diet

PLKO- Palm Diet

shCD3 6 - Control D iet

shCD3 6 - Palm Diet

PLKO- PALM

Neural-enriched stroma puri cation

Neural-enriched stroma puri cation

CD36 depletion in OSCC

SCC- 2 5

Neural-enriched fraction

2ry recipient

Supplementary Figure 10

D

F

Palm-exposed cells are able to modify the tumourneural-associated stroma in a CD36-dependent manner


Palm-exposed cells are able to modify the neural stroma in a CD36-dependent manner


PLKO-CD36bright

PLKO-CD36bright

PLKO-CD36dim

PLKO-CD36dim

shCD36-CD36dim

shCD36-CD36dim

-6 -3 0 3 6

0

1

2

3

4

Muscle adaptation

Drug metabolic process

Collagen-activated signaling pathway

Blood vessel remodeling

SCC25 CD36bright

Palm Diet vs Control Diet

log2(Fold Change)

Up-

regulated

Down-

regulated

-log10(P

valu

e)

100

10-5

10-1

0

10-1

5

Pvalue

SCC-25 CD36bright

Palm Diet Biological Process Up

50uM

50uM

50uM

50uM

SCC-25 PLKO-Control Diet-2ry recipientNEF-LKT-14Dapi

SCC-25 shCD36-Control Diet-2ry recipientNEF-LKT-14Dapi

SCC-25 PLKO Palm Diet-2ry recipientNEF-LKT-14Dapi

SCC-25 shCD36-Palm Diet-2ry recipientNEF-LKT-14Dapi

B C

D

10-6

0

10-4

0

10-2

0

100

pvalue

Biological Process UPPPalm Diet vs Control Diet

Extracellular matrix organizationCell migration

Collagen bril organizationResponse to growth factor

Cell-matrix adhesion Supramolecular ber organization

Response to lipidNeuron di erentiation

NeurogenesisSecretion

Reg. of nervous system developmentBlood vessel remodelingSprouting angiogenesis

Actin cytoskeleton organizationResponse to steroid hormone

InnervationGliogenesis

Neuron recognitionHypothalamus cell migration

Serotonin uptake

G

6

4

2

0

-5 0

UP-RegulatedDOWN-Regulated

log2(Fold Change)

PLKO Palm vs PLKO Control

SCC-25/VDH-15


5

DEGsUP/DOWN

in (F)6

4

2

0

-lo

g1

0(P

va

lue

)

shCD36 Palm vs PLKO Control

-5 0 5log2(Fold Change)

SCC-25/VDH-15


-lo

g1

0(P

va

lue

)

E

F

H

Figure 3

Response to lipid

Neuron di erentiation

Neuron migration

Neurogenesis/Generation of neurons



SCC-25 Principal

Component Analysis

I

HUMAN-[CD36-]

HUMAN-[CD36+]

Mouse

Schwann celldevelopment

neuron projectionregeneration

CTD

PALMD

CTD

PALMD

PALMD

CTD

SCC-25 - H3K4me3 in vitro ChIPs GO Analysis (14D post-PA):


GO

Bio

log

ical P

ro

cess

GO

Bio

log

ical P

ro

cess

0 2 4 6 8

axonogenesisaxon guidance

cell morphogenesis involved in neuron dif erentiationglycosaminoglycan metabolic process

sprouting angiogenesisregulation of neuron projection development

chondroitin sulfate proteoglycan biosynthetic processaxon development

heart contractionspinal cord dorsal/ventral patterning

-Log (pvalue)

14D PA UP

VDH-15 - H3K4me3 in vivo ChIPs GO Analysis (2ary PTs):


0 2 4 6 8

regulation of p38MAPK cascadebranching morphogenesis of an epithelial tube

forebrain regionalizationvasculogenesis

lung developmentneuron projection morphogenesis

cell morphogenesis involved in neuron dif erentiationregulation of angiogenesis

regulation of Wnt signaling pathwaynegative regulation of cell communication

-Log (pvalue)

UP in 2ary PALM-Diet Tumours

A

f

Cell migration

Functional RelationHuman Palm/OSCC-Neural-enriched Stroma


0.1

0.3

0.2

0.4

1.0

No

rma

lise

d P

ho

ton

u

x 1

0E

6

PLKO

CTD

shEGR2

PALM CTD PALM CTD PALM

#38_9 #40_9

CTD PALM

shGAL

#73_4

n.s.

*

n.s.n.s.

PLKO

CTD

shEGR2


#38_9 #40_9

CTD PALM

shGAL

#73_4

No

rma

lise

d P

ho

ton

ux 1

0E

5

0.5

1.5

1

2

2.5 Lung MetBLI/Tumour size

LN MetBLI/Tumour size

*

n.s.

n.s.

**

0

25

50

75

100

PLKO

CTD

shEGR2


#38_9 #40_9

CTD PALM

shGAL

#73_4

fre

qu

en

cy o

f m

eta

sta

ses (

%)

MetMet-free

Met Frequency

*

n.s.

n.s.n.s.

Cont

rol D

iet v

s Pa

lm D

iet

pv<0.05

Palm-induced mouse

neural signature

FC (f

old

chan

ge)

NES -1.57

Nominal pvalue 0.03

NES -1.50

Nominal pvalue 0.03PLKO-Palm

Human_Neural-related UPshGAL-Palm

Up-regulatedFC 1.5 pvalue<0.05

11 49655

FC 1.5

PLKO-Palm

Human_Neural-related UP

shEGR2-Palm

Up-regulated

FC 1.5 pvalue<0.05

5 52461

FC 1.5

11 58755

NES -1.49Nominal pvalue 0.008


shGAL-Palm Diet vs PLKO-Control Diet

shEGR2-Palm Diet vs PLKO-Control Diet

Gene

Exp

ress

ion

Figure 4

A VDH-15 - H3K4me3 Set1 KD ChIPs GO Analysis (14D post-PA):

0 1 2 3 4 5

regulation of actin cytoskeleton organizationpeptidyl-tyrosine modif cation

modulation of excitatory postsynaptic potentialregulation of phospholipase C acitvity

positive regulation of excitatory postsynaptic potentialpositive regulation of synaptic transmissionpositive regulation of neuron di erentiation

glycosaminoglycan biosynthetic processcell di erentiation in hindbrain

regulation of dendritic spine development

-Log (pvalue)B VDH-15 - 1ary Diets Tumour BLI

(CTRL pLKO.1 vs :)DK 1teS

Ph

oto

n f

lux

BLI LNmet - Week 3 post-IT

CTRLPLKO.1 CTRL Diet CTRLPLKO.1 PALM Diet 10e5

10e8

10e5

10e7

LNmet Visualization:

02 1064 1066 1068 1061 107

5.0 107

1.0 108

1.5 108

2.0 108n.s.

*

CTRL PLKO.1 CTRL DIET

CTRL PLKO.1 PALM DIET

Set1 KD CTRL DIET

Set1 KD PALM DIETn.s.

*

DOWN in 14D post-PA Set1A KDvs14D UNTR Set1A KD

#38_9

#40_9

Ne

uro

n M

igra

tio

nO

lig

od

en

dro

cy

te

De

ve

lop

me

en

t

5

4

3

2

1

0

-5

-4

-3

-2

-1

PL

KO

sh

CD

36

#98_

99

sh

EG

R2

#4

0_

9

sh

EG

R2

#3

8_

9

sh

GA

L#7

3_

4



Sy

mp

ath

eti

c N

erv

ou

sS

ys

tem

De

ve

lop

me

nt

Gli

al

Ce

ll P

roli

fera

tio

n

C D E

F

G

H

I

J K

L

A

A

A

A

CTRL Diet PALM DietSet1A KDSet1A KD

CHRDL1

Set1A-regulated Neural genes

H3K4me3 Peak Visualization:

CTRL pLKO.1 UNTREATED post 14 Days

CTRL pLKO.1 PA-TREATED post 14 Days

Set1A UNTREATED post 14 Days

Set1A PA-TREATED post 14 Days

GRIP2

Functional Study

0.1

0.3

0.2

0.4

1.0

Norm

alis

ed P

ho

ton

ux 1

0E

6PLKO

CTD

shEGR2


#38_9 #40_9

CTD PALM

shGAL

#73_4

n.s.

*

n.s.n.s.

PLKO

CTD

shEGR2


#38_9 #40_9

CTD PALM

shGAL

#73_4

Norm

alis

ed

Ph

oto

n

ux 1

0E

5

0.5

1.5

1

2

2.5 Lung MetBLI/Tumour size

LN MetBLI/Tumour size

*

n.s.

n.s.

**

0

25

50

75

100

PLKO

CTD

shEGR2


#38_9 #40_9

CTD PALM

shGAL

#73_4

fre

qu

en

cy o

f m

eta

sta

se

s (

%)

MetMet-free

Met Frequency

*

n.s.

n.s.n.s.

Cont

rol D

iet v

s Pa

lm D

iet

pv<0.05

Palm-induced mouse

neural signature

FC (f

old

chan

ge)

NES -1.57

Nominal pvalue 0.03

NES -1.50

Nominal pvalue 0.03PLKO-Palm

Human_Neural-related UPshGAL-Palm

Up-regulatedFC 1.5 pvalue<0.05

11 49655

FC 1.5

PLKO-Palm

Human_Neural-related UP

shEGR2-Palm

Up-regulated

FC 1.5 pvalue<0.05

5 52461

FC 1.5

11 58755





Gene

Exp

ress

ion

Figure 4

A VDH-15 - H3K4me3 Set1 KD ChIPs GO Analysis (14D post-PA):

0 1 2 3 4 5

regulation of actin cytoskeleton organizationpeptidyl-tyrosine modif cation

modulation of excitatory postsynaptic potentialregulation of phospholipase C acitvity

positive regulation of excitatory postsynaptic potentialpositive regulation of synaptic transmission

positive regulation of neuron di erentiationglycosaminoglycan biosynthetic process

cell di erentiation in hindbrainregulation of dendritic spine development

-Log (pvalue)B VDH-15 - 1ary Diets Tumour BLI

(CTRL pLKO.1 vs :)DK 1teS

Ph

oto

n f

lux

BLI LNmet - Week 3 post-IT

CTRLPLKO.1 CTRL Diet CTRLPLKO.1 PALM Diet 10e5

10e8

10e5

10e7

LNmet Visualization:

02 1064 1066 1068 1061 107

5.0 107

1.0 108

1.5 108

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*

CTRL PLKO.1 CTRL DIET

CTRL PLKO.1 PALM DIET

Set1 KD CTRL DIET

Set1 KD PALM DIETn.s.

*

DOWN in 14D post-PA Set1A KDvs14D UNTR Set1A KD

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CHRDL1

Set1A-regulated Neural genes

H3K4me3 Peak Visualization:

CTRL pLKO.1 UNTREATED post 14 Days

CTRL pLKO.1 PA-TREATED post 14 Days

Set1A UNTREATED post 14 Days

Set1A PA-TREATED post 14 Days

GRIP2

Neural-Enriched Stroma


Overall survival

• Metastatic stem cells depend on CD36 to metastasize

• Palmitic Acid promotes the function of MICs through CD36

• Palmitic acid elicits a metastatic epigenetic memory in MICs: Setd1a and H3K4me3

• CD36 and palmitic acid induce innervation of tumors

• Metastatic cells directly reshape tumour innervation

• Epigenetic PA-induced tumor innervation facilitates multi-organ metastasis

CONCLUSIONS

The Stem Cells and Cancer Lab

Diana Dominguez (PhD)Uxue Urricelqui (PhD)

Paloma Solá (PhD)Valentina Zinna (PhD)

Guiomar Solanas (Research Associate)Gloria Pascual (Research Associate)

Alexandra Avgustinova (Postdoc)Magdolna Djurec (Postdoc)

Carmelo Laudana (Bioinformatician)Andrés Castellanos (Research Assistant)

Thanks: IRB Administration + Scientific Services

Collaborators for this projectLuciano di Croce (CRG, Barcelona)

Holger Heyn (CNAG, Barcelona)Ali Shilatifard (Feinberg School of Medicine, USA)

Ramin Shiekhatar (University of Miami)

Salvador Aznar-Benitah

¿Cómo puede la dieta modificar la genómica del cáncer?

Gloria Pascua Angulo

Stem Cells and Cancer labInstitut de Recerca Biomèdica-Barcelona

¿cómo puede la dieta modificar la genómica del cáncer?... · pc 1.5 up/do wn-2 +2 0 fc s cale...

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