Microbiome and cancer(oncobiome)

Christian Jobinchristian.jobin@medicine.ufl.edu

Department of Medicine and Department of Infectious Diseases & PathologyUniversity of Florida, Gainesville

Are intestinal bacteria bystander to the carcinogenic process?

R. Justin Davies, Richard Miller & Nicholas ColemanNature Reviews Cancer 5, 199-209 (March 2005)

10-15 years

Garre%,W.S.(2015).TheJournalofCellBiology210,7–8.

Microbiota and Humans

Humans are a composite of microorganisms

Rapid colonization early in life set microbiota

Microbial composition varies according to the original seeding

Microbial composition varies according to the original seeding

C-section C-section + vaginal sponge

The environment represents another important source of microbial exposure

(seeding and transient)

Double threat phenomenon

Inside Outside

Outside

Microbes and cancer: The infectious route

~4 X 1030 microbes on earth

Epstein-Barr virus (EBV): LymphomasHuman papillomavirus virus: Cervical cancer and other cancers Human herpes virus: Kaposi’s sarcomaHepatitis B virus (HBV) and hepatitis C virus (HCV): non-Hodgkin lymphoma, liver cancerHelicobacter species: stomach, biliary tract, and gallbladder cancer.

10 organisms are designated as carcinogenic

(International Agency for Cancer Research)

Microbes and cancer: Intestinal biota

Diabetes { Dietlife-styleGenetics

cancer

microbiota

neurodisorders

cardiovascular

Rx response

IBD-CRC

Obesity

Intestinal microbiota in health/diseases

Bugs going global

Diabetes

infection

Rheumatoid arthritis

Diabetes

microbiota

CRC

Microbiota composition in colorectal cancer?

Next Generation Sequencing

State of microbial dysbiosis in CRC patients

Adenocarcinoma

Enterococcus, Escherichia/Shigella, Klebsiella, Streptococcus, and Peptostreptococcus

Lachnospiraceae

AdenomaFirmicutes, Bacteroidetes, Fusobacterium and Proteobacteria

Coriobacteridae, Roseburia, Fusobacterium,

Providencia and Faecalibacterium

Enterobacteriaceae

Sobhani I, et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One.) 2011;6(1):e16393.

Wang T, et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J. 2011 Aug 18;6(2):320–9.

Sanapareddy N, et al. Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans. ISME J. 2012 Oct;6(10):1858–68.

Marchesi JR, et al. Towards the Human Colorectal Cancer Microbiome. Ahmed N, editor. PLoS One. 2011 May 24;6(5):e20447.

Chen W, et al. Human Intestinal Lumen and Mucosa-Associated Microbiota in Patients with Colorectal Cancer. Moschetta A, editor. PLoS One. 2012 Jun 28;7(6):e39743.

Castellarin M, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome research. 2012 Feb;22(2):299–306.

Kostic AD, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome research. 2012 Feb;22(2):292–8.

McCoy, A. N., et al. Fusobacterium Is Associated with Colorectal Adenomas. 2013 PloS one, 8(1), e53653.

Burns, M.B.,et al Virulence genes are a signature of the microbiome in the colorectal tumor microenvironment. 2015 Genome Medicine 1–12.

Feng, Q., et al. (2015). Gut microbiome development along the colorectal adenoma–carcinoma sequence. Nat Commun 6, 1–13.

Functional impact of CRC-dysbiosis?

Drilling down the microbiome world

target

Microbiome o’mics approaches(metagenome, metatranscriptome,

proteome, metabolome)

gnotobiotics, humanized mice, microbial gene manipulation, bioreactors,

structural chemistry, small molecules

Informative but associative results

functional?

How to dissect contribution of microbes in carcinogenesis?

Germ-free

Next Generation Sequencing

“Humanized” mice

Arthur et al 2012 Science Oct 5;338(6103):120-3.

The enemy within

ctl E.coli pks E.coli pks

Comet Assay: 16S V6 Microbiome analysis

IL-10-/- (CRC)

WT (non-CRC)

Drilling down the microbiome world

Adenocarcinoma

Enterococcus, Escherichia/Shigella, Klebsiella, Streptococcus, and Peptostreptococcus

Lachnospiraceae

AdenomaFirmicutes, Bacteroidetes, Fusobacterium and Proteobacteria

Coriobacteridae, Roseburia, Fusobacterium, and Faecalibacterium

Enterobacteriaceae

Microbial dysbiosis in CRC patients

Biofilm correlates with 5X increase CRC rates

How to dissect contribution of microbe in carcinogenesis?

“Humanized”mice

RIGH

T

LEFT

Ascend

ing

Cecum

Transverse

Descending

SigmoidRectum

Hepa=cFlexure

Biofilm

SplenicFlexure

NoBiofilm

Microbes and cancer: Bacteria as therapeutic adjuvant?

Microbes and cancer therapy

Dendritic cells

TLR2

intestinal bacteria (Bifidobacterium,

bacteroides)

? ?

Naive T cell (CD8)

Enhanced responsivenessto immunotherapy

Immunotherapy

Anti-PD-1/PD-L1Anti-CTLA-4

Enhanced CD8

Antigen uptake

Tumor cells

Anti-tumor responses

Antigen presenting cells

Microbes and cancer: Now what?

“Cancer Microbiota”

Cancer

Prebiotics-ProbioticsDietary manipulation

Rx targeting microbial cancer genes

Generation of biomarkers(diagnostic, prognostics, treatment)

bacteriophage therapy

Anti-cancer adjuvant

Bacteriotherapy

Jobin Lab

Sarah Tomkovich Anthony Fodor

R01 DK73338R01 DK47700R01 AT08623 R21 CA195226

RO1 minority supplementUF Research Opportunity Seed Fund

UF SoM GatoradeGenome Canada

Fundings:

UNC-Charlotte

Xiaolun Sun

Josee Gauthier

Ernesto Perez-Chanona

University of Florida

Steven BrunerJarrod Moussa

Raad GharaibehChristina Ohland

John Hopkins

Christine CraigCynthia Sears

INSERM Toulouse

Ayaka ShimaEric Oswald

Danielle Ferrugeti

Temple University

Ang SunJean Pierre Issa

Ye Yang

Jillian Pope

Rachel Newsome

Sasha Oleksandr