The Daily Sign-Out

Systems biology for studying cancer

This month's issue of Future Oncology has a well-written editorial from Dr. John McDonald from Georgia Tech regarding systems biology in cancer research.  This is a free download and I highly recommend it as a nice overview contrasting the traditional "reductionist" approach to cancer cell biology research versus the emerging application of a systems biology approach.

First, it is appreciated that the traditional approach has grudgingly yielded some valuable insight into cancer cell biology which has led to the development of "rationally designed" targeted therapies.  But while many of these therapies have had some initial impact for patients enrolled in clinical trials (and even some dramatic responses), I think it is fair to say that they also have not radically shifted overall survival or long-term outlook of the most common lethal cancers.

However, we are beginning to realize the potential for combining high-throughput molecular technologies with computational strategies and capabilities for combining multidimensional datasets to find inferred network relationships.  Dr. McDonald refers to this as the "top-down" approach.  He contrasts this with the traditional reductionist "bottom-up" approach which links human oncogenes or tumor suppressor genes with known interacting genes previously characterized in experimental models using cancer cell lines or animal models to identify signaling pathways implicated with cancer.  He stresses that these approaches are by no means mutally exclusive but indeed are complementary.

The systems approach starts with establishing a list of component parts.  Using new technologies, we can now speak of the genome, transcriptome, proteome, metabolome, etc.  The revolutionary step is using sophisticated computer models to detemine how these various components interact and which of these interactions are relevant for cancer initiation and progression and which represent potential druggable targets.

Again, this is a nice appetizer for additional reading on this exciting area!

Evidence for tissue-specific differences in EMT

Remodeling of the extracellular matrix is a key process in cancer invasion.  Matrix metalloproteases (MMPs) have been shown to be important in ECM remodeling but identifying individual MMPs with specific roles in various cancers has been difficult due to functional overlap with other proteases.  The current Diseases Models and Mechanisms has an interesting article by Hald et al. in which they demonstrate that double-knockout mice lacking both plasmin and MMP-9 develop inflammatory colonic mass lesions that resemble mucosal prolapse lesions in humans.  In contrast, wound healing in skin in these mice is normal.  The findings indicate tissue-specific differences in ECM remodeling--and thus potential therapeutic targets. Further, this study demonstrates the potential utility of other mouse models for studying ECM remodeling in other tumors.  Provocative stuff and more of the EMT story unravels.

Stem cells and pluripotency articles in Development

Development has updated review articles on stem cells and pluripotency that I think would be of general interest for everyone and are available to download for free.  I really found the article on stem cell biology from a systems perspective especially cool. 

Systems biology approach shows MYB and FOXM1 as master regulators of germinal center proliferation

Back from a relaxing stay-cation as well as ASCO meeting--

The June 2010 issue of Molecular Systems Biology has a fascinating study identifying MYB and FOXM1 as "master regulators" of germinal center proliferation in lymph nodes.  Why should we as pathologists care about this?

What piqued my curiosity here was a connection with my previous post summarizing what I learned at USCAP on the molecular pathology of diffuse large B-cell lymphoma (DLBCL) regarding dysregulated genes in DLBCL (including MYC) and identification of three gene expression subgroups, including the "germinal center B-cell-like" group.

The authors use some fascinating and powerful techniques around a systems biology approach to find master regulator genes controlling specific cellular processes (in this case, germinal center B-cell proliferation) as well as transcriptional regulation of protein complexes whose regulation whose availability must be regulated in a context-dependent manner.

The authors developed is an interaction network specific to human B cells (called the human B-cell interactome, HBCI) by reverse-engineering of transcriptional and post-translational interactions in mature human B cells from a diverse collection of 254 B-cell gene expression profiles derived from normal and malignant mature B cells (Lefebvre et al, 2007).  They further integrated evidence from experimental assays, databases, and literature data mining, filtered by context-specific criteria, using an established evidence integration algorithm.  Then, they used a novel algorithm, the Master Regulator Interference Analysis or MARINa, to interrogate the HBCI to discover MRs of key genetic programs in the germinal center (GC) reaction of antigen-mediated immune response, that is, normal progression through the GC.

They identified MYB and FOXM1 as "master regulators" of GC B cells since 80% of the genes jointly regulated by these transcription factors are activated in the GC.  They also showed that MYB is a transcriptional activator of FOXM1 suggesting that they form a "feed-forward" loop involved in a synergistic activation of a large subset of GC-specific genes.  I don't quite understand their use of the term "feed-forward" loop here--my understanding is that a feed-forward loop is when the anticipated future effect (which hasn't yet happened) triggers the cause in the present (which would otherwise have not have happened).  An example is when there is a rumored or predicted shortage of a commodity, which leads to hoarding in anticipation of the shortage, which in turn causes a shortage to occur.  It seems that this should be called a reinforcing feedback loop but whatever.

But they also validated that common MYB/FOXM1 targets were affected by silencing either MYB or FOXM1 using gene expression profiling.  Specifically, they showed that downstream targets and other MRs are bound by MYB and FOXM1 in their promotor regions after MYB or FOXM1 silencing.  Moreover, silencing of MYB and FOXM1 showed a decreased in proliferating cells in GCs and an increase in apoptotic cells.  They further examined specific targets involved in the formation of a protein complex predicted by their model and found that about half of the MYB/FOXM1 targets cluster within a complex including novel interactions with pre-replication and mitotic proteins.  They found that two mitotic kinases inferred in the complex, BUBR1 and AURKA, physically interact with MCM3 which are all direct targets of MYB and FOXM1.

My summary doesn't do justice to this paper (due to my own shortcomings in understanding) but if you're interested in lymphomas and/or systems biology, this is well-worth a read.