impact of microbiota in colorectal cancer€¦ · © vall d'hebron institute of oncology...

© Vall d'Hebron Institute of Oncology (VHIO)

Elena Elez MD PhD (Colon Cancer Program)

IMPACT OF MICROBIOTA IN COLORECTAL CANCER

[email protected]


DISCLOSOURES

• Personal financial interests, honoraria for advisory role, travel grants,

research grants (past 5 years): Hoffman La-Roche, Sanofi Aventis,

Amgen, Merck Serono, Servier, MSD

• Institutional financial interests, my institition received honoraria due to

my investigator contribution in clinical trials from: Hoffman La-Roche,

Sanofi Aventis, Amgen, Merck Serono, MSD, Boehringer Ingelheim,

AbbVie, Array Pharmaceuticals, Pierre-Fabre, Novartis

© Vall d'Hebron Institute of Oncology (VHIO) Van Cutsem E, et al. J Clin Oncol. 2015 Mar 1;33(7):692-700. 2. Douillard JY, et al. N Engl J Med. 2013 Sep 12;369(11):1023-34.

THE RETROSPECTIVE STORY OF CRC

More than a decade to “know how”

Following with the retrospective storyof CRC…


ALREADY KNOWN FOR DECADES

Aries et al 1969 Gut: 10. 334-335 First published report suggesting importance of microbiota in bowel cancer (St. Mary’s Hospital, London)


CONCEPTS

• BIOFILM: Encrustations formed from microbes (bacteria, algae, fungi, plankton, or protozoa)

embedded in an extracellular polymeric substance matrix that is secreted by the microbes.

They occur on body surfaces such as teeth; inanimate objects, and bodies of water

• MICROBIOTA: The full collection of microbes (bacteria, fungi, virus, etc.) that naturally exist

within a particular biological niche such as an organism, soil, a body of water, etc.

• MICROBIOME: The full collection of microbes (bacteria, fungi, virus, etc.) that naturally exist

within a particular biological niche such as an organism, soil, a body of water, etc. Basically

refers to genes

• DISBIOSIS: Changes in quantitative and qualitative composition of MICROBIOTA. The changes

may lead to altered host-microbial interaction or homeostatic imbalance that can contribute

to a disease state often with inflammation.

Source: MESH


DATA WE CAN NOT MISS

• Microbiota reflects a biological ecosystem that intensely communicates with the host

• During the last decade, a hype in microbiota research allowed to delineate the compositionand some functions of the intestinal microbiota

• Current estimates suggest that the gastrointestinal tract contains as much bacteria as cellscomposing the human body

Sender et al. Plos Biology 2016


RESEARCH PARADIGMS F2F

CRC ONCOLOGY DIGESTOLOGY AND MICROBIOMICS


• Despite enormous efforts and substantial progress in understanding the composition

of the human intestinal microbiota, many functional aspects remain unresolved.

• This may be partly due to the complexity of the human intestinal microbiota, with a

plethora of unpredictable host-microbe, microbe-microbe, and environmental

interactions.

LEADING WITH COMPLEXITY

Grand Challenge UK


It is expected that CRC burden will substantially increase in the next two decades consequent toadoption of a western lifestyle

Age-standardised CRC incidence and mortality and human development index (HDI)

THE INCREASING PROBLEM OF CRC

Arnold et al. Gut 2017


• The microbiota transduces nutrient

signals from the diet to the host.

• Monotonous diets lead to a reduction

in biodiversity of the microbiota:

infection + inflammation

• The microbiota is a plausible target for

modifying or preventing the adverse

effects of undernutrition and

overnutrition.

DIET AND MICROBIOTA

Shanahan et al. Gut 2017


DIET REGULATES COMPOSITION OF MICROBIOTA

Shanahan et al. Gut 2017

Microbiota in overnutrition

• Microbiota has been related with the risk of

developing obesity and metabolic disorders

• Diet-induced obesity in experimental animals

links with changes in the microbiota and

suggests that the dietary impact exceeds that

of genetics and immunity.

• HH faecal microbial transplantation has also

demonstrated the beneficial influence of a

microbiota from a lean donor with improved

insulin sensitivity in obese recipients


ALL INTAKE HAS A “COST”

• Antibiotic (ATB) exposure earlier in life (20–39 and 40–59) SSassociates with an increased risk for colorectal adenoma (>60)

✓ ATB ≥2 m age 20-39 OR of 1.36 (95% CI 1.03 to 1.79).

✓ ATB ≥2 m age 40-59 OR of 1.69 (95% CI 1.24 to 2.31).

• Recent ATB use (within 4 years) was not associated with risk ofcolorectal adenoma.

• The association of ATB with CRC and the potential mediating role of

the gut microbiome in carcinogenesis must be considered

• There is a potential need to limit the use of antibiotics and sourcesof inflammation that may drive tumor formation.

Cao et al. Gut 2017


RESULT: “VOGELGRAM” PROMOTION

Sears et al. Cell Host and Microbes Rev 2014


HOW DID WE GET HERE?

Bullman et al. Science 2017


• CRC is frequently associated with dramatic alterationsin the microbial composition of the tumor andadjacent mucosa, commonly termed as dysbiosis

• Dysbiosis is partly characterized by the expansion ofbacterial taxa; however, dominant species in CRCevolution remain poorly defined.

• Experimental evidence for an important role ofFusobacterium nucleatum (Fn), Escherichia coli, andBacteroides fragilis is emerging

• Depleted bacterial species in intestinal tumorigenesisis less well studied due to a lack of appropriatetechniques.

MICROBES AND CRC CARCINOGENESIS

Tilg et al. Cancer Cell 2018

ROS: Reactive oxygen species


• Complex communities of bacteria and archaea arepresent in almost all environments, includingmicrobiomes that are closely associated withhumans, animals and plants

• Next-generation sequencing of PCR-amplified SSU(small subunit) ribosomal RNA (also known as 16SrRNA) genes from these communities

• Recently performed metagenomic studies havefurther supported the notion that CRC isassociated with a certain gut microbiomesignature

Yarza et al. Nat Rev Micr 2014

CHARACTERIZING MICROBIOME



Nature Rev Gastroenterology & Hepatology 2012


Mucosal biopsy samples should be used instead

of, or at least in conjunction with, stool samples

Practical challenges: disruption of the biofilm

when the biopsy is performed and the effect on

the microbiota of bowel preparation prior to

colonoscopy

Fresh stool samples should be used instead of

frozen samples (processing can alter the gut

microbiota).

Shot gun: Entire genomes of all the organisms

present in the sample, as opposed to only the 16S

sequences. Less susceptible to the biases that are

inherent in targeted gene amplification.

Fraher et al. Nature Rev Gastroenterology & Hepatology 2012



Relative prevalence of key oncogenic alterations at specific primary tumor locations in patients with metastatic colorectal cancer

THE RIGHT VS LEFT STORY

Loree JM et al. Clin Cancer Res 2018 Mar 1;24(5):1062-1072


MICROBIOME AND CRC CARCINOGENESIS

Drewes et al. BJC 2016Dejea et al. PNAS2014


34 tumours subtyped by RNA-sequencing derivedgene expression and determined relativeabundances of bacterial taxonomic groups using16S rRNA amplicon metabarcoding.

16S rRNA analysis showed enrichment ofFusobacteria and Bacteroidetes, and decreasedlevels of Firmicutes and Proteobacteria in CMS1.

CMS2 was enriched for Selenomas and Prevotellaspecies, while CMS3 had few significantassociations

MICROBIOMA AND CMS

Purcell et al. Scientiffic Reports 2017


FUSOBACTERIUM (+) COLORECTAL CANCER

F. nucleatum RNA ISH analysis ofmatched primary colorectal tumors andliver metastases

Fusobacterium was not detected in normal liver tissue

Bullman et al. Science 2017

© Vall d'Hebron Institute of Oncology (VHIO) Bullman et al. Science 2017

FUSOBACTERIUM (+) COLORECTAL CANCER

Treatment of Fusobacterium-colonized PDXs with metronidazole reduces tumor growth in vivoFusobacterium and co-occurring anaerobes persist in colon adenocarcinoma PDXs.


FN+ CRC: is this a subgroup of CRC ?

1. DIET: Higher long-term prudent dietary pattern scores were associated with a

lower risk of F nucleatum–positive colorectal cancers but not F nucleatum–

negative cancers. Mehta et al. JAMA Oncol (2017)

2. LOCATION: An higher rate of FN+ CRC is found in righ side colon, with a

decreasing trends across the bowel subsite. Mima et al. Clin and Transl Gastroenterology (2016).

3. MOLECULAR: Higher abundance of FN in MSI-HIGH CRC as compared to MSS.

Enriched in CMS1. Purcell et al. Sci Reports (2017)

4. PROGNOSIS: FN abundance is associated with poor prognosis. Mima et al. Gut (2016)


Characterization of the transcriptomic subtypes of CRC, encompassing tumor, stromal and immune

components reveal convergent pathway dependencies

THE COMPREHENSIVE CLASSIFICATION OF CRC


INTERNATIONAL CHALLENGES


OPTIMISTICC


OPTIMISTICC: Work Packages

CONFIDENTIAL


Thank youElena Elez MD PhD Colon Cancer ProgramMedical Oncology DepartmentVall d’Hebron Institute of Oncology (VHIO)[email protected]

impact of microbiota in colorectal cancer€¦ · © vall d'hebron institute of oncology...

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