Systems biology in cancer research

What is systems biology?

= Molecular physiology?“…physiology is the science of the mechanical,

physical, and biochemical functions of humans …”Wikipedia

“Systems biology is a … study field that focuses on the systematic study of complex interactions in biological systems, thus using a new perspective (holism instead of reduction) to study them. … Because the scientific method has been used primarily toward reductionism, one of the goals of systems biology is to discover new emergent properties that may arise from the systemic view used by this discipline in order to understand better the entirety of processes that happen in a biological system.“

Wikipedia

What is cancer?

A disease of many genes

and their interactions

Cancer attractors: A systems view of tumors… Sui Huang, Ingemar Ernberg, Stuart Kauffman

Friday, April 21, 2023

Biological complexity: reduction is crucial.

Tool complexity ≠ Vision complexity

Modelling. What is a model?

•Topological vs. quantitative

•Relevance vs. causality

The Cancer Genome Atlas Research Network.

2008

Wholesome vision:All proteins?All interactions?All diseases?All organisms?

Human Protein Atlas

Oncomine

Friday, April 21, 2023

FunCoup: a data integration framework to discover

functional coupling

Amouse

Bmouse

?*

Human

Fly

Rat

Yeast

Andrey Alexeyenko and Erik L.L. Sonnhammer. Global networks of functional coupling in eukaryotes from comprehensive data integration. Genome Research. Published in Advance February 25, 2009

FunCoup: recapitulation of known cancer pathways

Figure 5 from:The Cancer Genome Atlas Research Network Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008 Sep 4. [Epub ahead of print]

The same genes submitted to FunCoup No TCGA data were used. Outgoing links are not shown.

FunCoup was queried for any links between members of TGFβ pathway (left blue circle) and habituées of known cancer pathways (members of at least 7 out of 18 groups; right blue circle). MAPK1 and MAPK3 belonged to both categories.

TGFβ <-> cancer pathway cross-talk

Friday, April 21, 2023

What is FEASIBLE in systems biology?

• Holistic view?

• Comparison between healthy and ill?

• Disease prevention?

• Drug targets?

From genes to pathways

Inositol phosphate metabolism

Glioblastoma (TCGARN, 2008)

Enrichment of functional groups

Enrichment analysis in the networks turns to be more powerful than on gene lists

Group 1

Group 2

Discerning cancer-specific wiringPathway network of

normal vs. tumor tissues

Edges connect pathways given a higher (N>9; p0<0.01; pFDR<0.20) number of gene-gene links (pfc>0.5) between them (seen as edge labels). Known pathways (circles) are classified as:

•signaling,•metabolic,•cancer,•other disease.

Blue lines: evidence from mRNA co-expression under normal conditions + ALL human & mouse data.

Red lines: evidence from mRNA co-expression in expO tumor samples + ALL human data + mouse PPI.

Node size: number of pathway

members in the network.

Edge opacity: p0.

Edge thickness: number of gene-gene links.

Level of functional groups

Zebrafish transcriptome under dioxin treatment

Accounting for edge features:dioxin- “enabled” vs. “sensitive” links

Andrey Alexeyenko, Deena M Wassenberg, Edward K Lobenhofer, Jerry Yen, Erik LL Sonnhammer, Elwood Linney, Joel N Meyer Transcriptional response to dioxin in the interactome of developing zebrafish. PLoS One

Single molecular markers are often far from perfect. Combinations (signatures) should perform better.

How to select optimal combinations?

×

Severity,Optimal treatment,

Prognosisetc.

Biomarker signatures in the network

Sonic hedgehog pathway

Functional couplingtranscription ? transcription transcription ? methylation methylation ? methylation mutation methylation mutation transcriptionmutation ? mutation

+ mutated gene

Cancer data for basic research: a testbed

Tumour tcga-02-0114-01a-01w

Cancer individuality

There is a CAUSATIVE gene network behind each individual cancer

Cancer individuality in clinic

Functional couplingtranscription ? transcription transcription ? methylation methylation ? methylation mutation methylation mutation transcriptionmutation ? mutation

+ mutated gene

Conclusions:

• Cancer is a disease of multiple alternatives,

hence PERSONALIZED medicine.

• Systems biology: enormous complexity, great

challenge.

• Focus on feasible today, think of possible in

the future.

• Descriptive and analytic HUMAN language?