IMPACT OF MICROBIOTA IN COLORECTAL CANCER€¦ · © Vall d'Hebron Institute of Oncology (VHIO) Van...
Transcript of IMPACT OF MICROBIOTA IN COLORECTAL CANCER€¦ · © Vall d'Hebron Institute of Oncology (VHIO) Van...
© Vall d'Hebron Institute of Oncology (VHIO)
Elena Elez MD PhD (Colon Cancer Program)
IMPACT OF MICROBIOTA IN COLORECTAL CANCER
© Vall d'Hebron Institute of Oncology (VHIO)
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…
© Vall d'Hebron Institute of Oncology (VHIO)
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)
© Vall d'Hebron Institute of Oncology (VHIO)
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
© Vall d'Hebron Institute of Oncology (VHIO)
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
© Vall d'Hebron Institute of Oncology (VHIO)
RESEARCH PARADIGMS F2F
CRC ONCOLOGY DIGESTOLOGY AND MICROBIOMICS
© Vall d'Hebron Institute of Oncology (VHIO)
• 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
© Vall d'Hebron Institute of Oncology (VHIO)
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
© Vall d'Hebron Institute of Oncology (VHIO)
• 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
© Vall d'Hebron Institute of Oncology (VHIO)
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
© Vall d'Hebron Institute of Oncology (VHIO)
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
© Vall d'Hebron Institute of Oncology (VHIO)
RESULT: “VOGELGRAM” PROMOTION
Sears et al. Cell Host and Microbes Rev 2014
© Vall d'Hebron Institute of Oncology (VHIO)
HOW DID WE GET HERE?
Bullman et al. Science 2017
© Vall d'Hebron Institute of Oncology (VHIO)
• 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
© Vall d'Hebron Institute of Oncology (VHIO)
• 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
© Vall d'Hebron Institute of Oncology (VHIO)
CHARACTERIZING MICROBIOME
Nature Rev Gastroenterology & Hepatology 2012
© Vall d'Hebron Institute of Oncology (VHIO)
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
CHARACTERIZING MICROBIOME
© Vall d'Hebron Institute of Oncology (VHIO)
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
© Vall d'Hebron Institute of Oncology (VHIO)
MICROBIOME AND CRC CARCINOGENESIS
Drewes et al. BJC 2016Dejea et al. PNAS2014
© Vall d'Hebron Institute of Oncology (VHIO)
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
© Vall d'Hebron Institute of Oncology (VHIO)
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.
© Vall d'Hebron Institute of Oncology (VHIO)
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)
© Vall d'Hebron Institute of Oncology (VHIO)
Characterization of the transcriptomic subtypes of CRC, encompassing tumor, stromal and immune
components reveal convergent pathway dependencies
THE COMPREHENSIVE CLASSIFICATION OF CRC
© Vall d'Hebron Institute of Oncology (VHIO)
INTERNATIONAL CHALLENGES
© Vall d'Hebron Institute of Oncology (VHIO)
OPTIMISTICC
© Vall d'Hebron Institute of Oncology (VHIO)
OPTIMISTICC: Work Packages
CONFIDENTIAL
© Vall d'Hebron Institute of Oncology (VHIO)
Thank youElena Elez MD PhD Colon Cancer ProgramMedical Oncology DepartmentVall d’Hebron Institute of Oncology (VHIO)[email protected]