The F1000 Scientific Community

It is a great thing that so much amazing scientific research is being done right now in the world. Those elegant studies that have developed into interesting stories that expand our knowledge of science are a joy to read. These often feature in the "top" journals and may make headlines (hopefully written up within a useful context). There are other hidden gems that may not immediately jump out, but on further reading reveal a crucial piece of information that helps with your own research puzzle, or provides a protocol that allows you to do something you didn't realize was possible. Basically there is a lot of science written and published by an ever increasing number of journals, the trouble is prioritizing what to read!

How to keep abreast of the most exciting research in your field? RSS feeds and pub med/Google scholar searches are fine if you are very specific about what you search for but you still need to make a decision about what terms to look for or which journals to follow. On the first day of my PhD I was given the group's "Journal Watch" list, a many times photocopied sheet of paper with 20 or so journal TOCs and AOPs to check regularly. Email alerts for these journals can be useful but you still have to trawl through the table of contents, that is if the email doesn't get inadvertently junked or skipped over. Review articles and perspectives are brilliant for guiding you towards excellent primary articles, but only if you are looking for at a specific gene, pathway, disease etc.

During my PhD I was very lucky to be able to write with my supervisor as an associate faculty member of the Faculty of 1000 (F1000). For this we wrote short pieces highlighting exciting developments in the field of Leukocyte Activation. This F1000 Prime service is an excellent way to be alerted to articles that are not just published in high impact journals, but those that are having a real impact on researchers post peer-review. Articles are selected by faculty members and rated for their contribution to the field (with a metric value to match), this ensures you can see the best recommended papers easily. A personalised homepage and email alerts can be tailored to your key words. I found this service immensely useful during my PhD and enjoyed writing for F1000 so much that I started this blog, albeit with a focus on open access articles and better explanations for non-scientists.

So I was excited when I saw a netoworking event in London organised by the F1000 to meet with staff and users of the service. There was a lively discussion about reaearch, open access publishing, scientific communication and data metrics. It was during this event that I discovered I could continue my passion for F1000 as a specialist, explaining and promoting their services including F1000 prime, which I was familiar with from use during my PhD, as well as F1000 Posters, F1000 Trials and F1000 Research. So I have once again joined the F1000 community (see the great new badge on the left of my blog), and I am keener than ever to help F1000 grow and to communicate the exciting advances in disseminating research where it matters! I am currently trialling a new Journal club feature of the F1000 website, so expect more about how this goes very soon!

Resistance to the leukemia treatment Imatinib can lay dormant and affect future treatment options

Normal cells that form the tissues of our body can be transformed into cancer by mutations within multiple genes that tell the cells how to behave. Mutations can come about in a number of different ways. Small changes in how a gene codes for just one of the amino acids that make up a protein can completely alter the activity of a protein. For example, KRas is a signalling protein with normally undergoes cyclical turning on and off when the cell needs it to help with growth, however a mutated active form a KRas cannot be turned off and goes on to allow cells to grow almost uncontrolled. Larger changes to genes may also occur with whole genes lost or moved around in the DNA. In fact in cancer cells DNA can become very messy!

A very important and well known mutation that was discovered in a leukaemia called chronic myelogenous leukemia (CML) is called the "Philadelphia Chromosome". This occurs when two large structures of DNA called chromosomes (humans have 23 pairs of chromosomes in each cell) swap small pieces; part of chromosome 9 is swapped with part of chromosome 22 making the former longer and the latter shorter. This new chromosome 22 is what is known as the "Philadelphia Chromosome". As a consequence, two genes BCR and ABL, which are not normally associated at the DNA level, become fused together to form the oncogene BCR-ABL. As an oncogene, BCR-ABL is crucial in driving cancer, it is most commonly associated with CML and other leukemias.

Many drugs for treating and managing cancer involve targeting a gene in cancer cells which is either found at a higher level or only slightly modified; because BCR-ABL is a completely different gene that is only found in cancer cells it was an attractive target for drug development. Indeed, an inhibitor of BCR-ABL called Imatinib/Gleevec has been immensely successful in treating CML. A number of patients respond well at first, but their cancer cells acquire a resistance to Imatinib; this occurs because the BCR-ABL protein becomes further mutated. Doctors can switch to using other BCR-ABL inhibitors such as Nilotinib/Tasigna, however some mutations in BCR-ABL also confer resistance to Nilotinib as well. 

A recent study in the British Cancer Journal found that mutations in BCR-ABL that become undetectable following treatment with Imatinib, can reemerge years later after treatment is changed to Nilotinib. This occurs in part due to a process called clonal expansion. A mutation which gives a cancer cell a growth or survival advantage compared to other cells within a tumour can be expanded, as these cells take over to form the bulk of the tumour.

It is therefore even more important for doctors to check which mutations of BCR-ABL are present in cancer cells when choosing treatment options, to prevent reemergence of mutations that will make cancer cells resistant.

Mentioned Articles

Parker WT, Yeoman AL, Jamison BA, Yeung DT, Scott HS, Hughes TP, Branford S.

BCR-ABL1 kinase domain mutations may persist at very low levels for many years and lead to subsequent TKI resistance.

Br J Cancer. 2013 Sep 17;109(6):1593-8. doi: 10.1038/bjc.2013.318

Cancer Research UK: Imatinib (Glivec)

http://www.cancerresearchuk.org/cancer-help/about-cancer/treatment/cancer-drugs/imatinib

Cancer Research UK: Nilotinib (Tasigna)

http://www.cancerresearchuk.org/cancer-help/about-cancer/treatment/cancer-drugs/nilotinib

Claudin 1 is a driver of EMT in primary liver cancer

Cancer of liver cells (hepatocellular carcinoma) is often diagnosed late as it may grow slowly and for unnoticed for years; consequently most patients present with advanced disease, the outlook for which is currently very poor. The process of epithelial to mesenchymal transition (EMT), which is required for many cancers to undergo metastasis and set up secondary tumours in other organs and tissues, occurs in advanced disease and in the case of liver cancer very little is known about EMT.

A recent study published in the journal Oncogene shows that a molecule that is normally involved in holding epithelial cells together in tissues, Claudin 1, can in fact promote EMT and allow cancer cells to become more invasive. Increased levels of Claudin 1 in liver cancer cells causes promotion of genes involved in EMT through up-regulation of key transcription factors ZEB1 and SLUG. Another important EMT transcription factor, SNAIL, was shown to not be involved, but interestingly a protein called c-Abl was found to be very important for this process.

c-Abl, is best known for being part of a mutation that occurs commonly in a form of leukaemia called CML and a number of drugs targeting c-Abl have been developed to treat CML. For example, Imatinib (Glivec) is an inhibitor that blocks the BCR-Abl fusion oncogene product which has been very useful for doctors  treating CML. In this present study, the group showed that by silencing the protein c-Abl in cells that have Claudin 1 over-expressed, they could reverse the up-regulation of ZEB1 and SLUG and prevent the invasiveness conveyed by EMT. This study demonstrates that in the future when doctors look at hepatocellular carcinoma they could look for increased levels of Claudin 1 as a possible indicator of the invasiveness of the cancer. With more work, this marker could be validated and possibly even exploited as a druggable target for the treatment of liver cancer.

Mentioned Articles

Suh Y, Yoon CH, Kim RK, Lim EJ, Oh YS, Hwang SG, An S, Yoon G, Gye MC, Yi JM, Kim MJ, Lee SJ.

Claudin-1 inducesepithelial-mesenchymal transition through activation of the c-Abl-ERK signalingpathway in human liver cells.

Oncogene. 2013 Oct 10;32(41):4873-4882. doi: 10.1038/onc.2012.505.

Brief: A test for potentially harmful human induced pluripotent stem cells

Yamashita et al. have produced a method for determining if human induced pluripotent stem cells (iPSC) are likely to form tumours and published their results in Scientific Reports.

Taking a patient's cells, engineering them to gain stem cell properties, such as being able to self-renew and develop into multiple different cell types, and re-injecting them into that patient's tissue is an emerging new therapeutic field. However there are concerns that these cells, once transplanted into a patient, may become cancerous. The methods used to make human iPSCs often involves making normal cells express stem cell factors (which in themselves can be oncogenic - cancer forming) and the oncogene c-myc.

By making these iPSCs into cartilage and monitoring for the formation of tumours, the group could see which iPSCs were potentially harmful. This test could prove crucial in validating iPSCs for regenerative medicine.

Mentioned Articles

Yamashita A, Liu S, Woltjen K, Thomas B, Meng G, Hotta A, Takahashi K, Ellis J, Yamanaka S, Rancourt DE.

Cartilage tissue engineering identifies abnormal human induced pluripotent stem cells.

Sci Rep. 2013 Jun 13;3:1978. doi: 10.1038/srep01978.

Micro-RNAs and Retinoic Acid take their Toll on prostate and breast cancer

One of the first lines of defence against infection is the innate immune system. This mounts a non-specific response to infectious agents including bacteria and viruses. Recognition of bacterial and viral components is accomplished by a family of receptors called Toll Like Receptors (TLRs) found on the surface of innate immune cells. TLRs can also be expressed by other cells such as cancer cells.

Previous studies have shown that activation of TLRs can affect the levels of micro RNAs (miRNAs) in cells and therefore regulate which proteins are expressed (I have mentioned the role of miRNAs in cancer in previous posts). In this present study, Galli et al. found that activation of TLR3 in prostate and breast cancer cells caused an increase in four miRNAs. These miRNAs target a class of proteins called DNA methyltransferases, resulting in the loss these proteins from the cancer cells. Without these DNA methyltransferases a protein called retinoic acid receptor beta (RARβ) is produced by the cancer cells.

In a breakthrough, the group showed that drugging tumours first with an activator of TLR3 followed by retinoic acid (an activator of RARβ), caused tumours to be smaller compared to control treated tumours. This study therefore presents promising pre-clinical data for the treatment of breast and prostate cancer with this exciting combination therapy.

Mentioned Articles

Galli R, Paone A, Fabbri M, Zanesi N, Calore F, Cascione L, Acunzo M, Stoppacciaro A, Tubaro A, Lovat F, Gasparini P, Fadda P, Alder H, Volinia S, Filippini A, Ziparo E, Riccioli A, Croce CM.

Toll-like receptor 3(TLR3) activation induces microRNA-dependent reexpression of functional RARβand tumor regression.

Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9812-7. doi: 10.1073/pnas.1304610110. Epub 2013 May 28.

Chen R, Alvero AB, Silasi DA, Steffensen KD, Mor G.

Cancers take theirToll--the function and regulation of Toll-like receptors in cancer cells.

Oncogene. 2008 Jan 7;27(2):225-33. doi: 10.1038/sj.onc.1210907.

Researchers hot on the TRAIL of new combination therapy for glioblastoma

Some cancers are particularly difficult to treat, particularly brain tumours. Glioblastoma is an aggressive form of cancer in the brain which, although responds initially to treatment, is refractory and often always fatal. Treating cancerous cells with a protein called TRAIL is a specific treatment which causes cancer cell death in around 50% of cancer cell lines. Bagci-Onder et al. employ some interesting molecular techniques to studying the effect of TRAIL on glioblastoma cell viability.

Neuronal stem cells were used to deliver soluble TRAIL protein to glioblastoma cells and the way in which this happens was modelled by artificially colouring both cell types and watching their interactions when grown together. Two out of three glioblastoma cell lines tested were sensitive to TRAIL treatment and underwent a form of highly controlled cell death called apoptosis.

The killing of these cells by TRAIL treatment was dependent on the levels of two proteins on the cell surface called death receptors; death receptor 4 (DR4) and death receptor (DR5). The group observed that the higher the levels of these receptors, the more receptive to TRAIL treatment the cells were. This led the group to postulate that increasing death receptor expression could enhance the effectiveness of TRAIL in treating glioblastoma.

To see how they could increase death receptor expression in cancerous cells, the group used a panel of different drugs known to affect the way cells function. They found that targeting histone deacetylases (HDACs) [see previous post] with a drug called MS-275 caused an increase in death receptor levels at the surface of cells. As expected, this also led to an increased sensitivity to TRAIL treatment. Importantly, the one glioblastoma cell line which was initially resistant to TRAIL treatment became sensitive to the killing power of TRAIL if cells were also treated with MS-275. This study highlights a potential new combination treatment for glioblastoma.

Mentioned Articles

Bagci-Onder T, Agarwal A, Flusberg D, Wanningen S, Sorger P, Shah K.

Real-time imaging of the dynamics of death receptors and therapeutics that overcome TRAIL resistance in tumors.

Oncogene. 2013 Jun 6;32(23):2818-27. doi: 10.1038/onc.2012.304. Epub 2012 Jul 23.

"Types of primary brain tumours : Cancer Research UK : CancerHelp UK." Cancer Research UK: the UK's leading cancer charity : Cancer Research UK . N.p., n.d. Web. 13 June 2013. 

Integral role for Pyk2 in breast tumour outgrowth and metastasis to the lung

There exist a number of well-defined markers of the epithelial to mesenchymal transition (EMT), a process crucial for the outgrowth of tumours to new areas of the body (metastasis), and now a signalling protein Pyk2 has been welcomed into the fold.

Focal Adhesion Kinase (FAK) is an established regulator of EMT in response to the pro-EMT signalling protein Tumour Growth Factor Beta (TGFβ), a recent study has revealed that some of FAK’s functions also require Pyk2 and suggests important roles for Pyk2 in tumour metastasis. A previous study by Sun et al. from The University of Hong Kong has also described a role for Pyk2 in driving EMT in liver cancer (hepatocellular carcinoma).

Normal human breast cells transformed to be cancer-like and cells from patients with aggressive (invasive ductal cell carcinoma, with reaccurance after 5 years) show high levels of Pyk2 protein. One breast cancer cell line is a mixture of less aggressive and more aggressive cancer cells, within these different cell populations the group observed vastly different levels of Pyk2 protein.

This increased Pyk2 expression was associated with increased growth of cells in a three dimensional tumour-like environment. In fact, growth of cells in this 3D model can enhance Pyk2 expression in breast cancer cell lines in a manner that is independent of the pro-EMT factor TGFβ. When growing two dimensionally (i.e. on a plastic culture surface) breast cancer cells show low levels of Pyk2, however treatment TGFβ could increase Pyk2 levels, but not to the same extent as observed in the 3D model. The group suggest that the 3D model exhibits autocrine TGFβ signalling (where TGFβ released by one cell acts directly upon the same cell). Importantly, not only do the cells make more Pyk2, but there are higher levels of the active form of Pyk2 (phosphorylated Pyk2). The signalling mechanism which links TGFβ to the increased Py2k levels observed was shown to involve the actions of a transcription factor called Smad4, this pathway was observed clearest in aggressive breast cancer cells.

Metastasis requires a dramatic change in the shape of cells (a novel mechanism of this was previously described in a past post); the classical EMT shape change is induced by TGFβ, however this was independent of Pyk2. It appears that FAK is the key protein involved here.

The group went on to show that whilst up-regulation of Pyk2 in breast cancer cells is required along with FAK for acquisition of an EMT signature, Pyk2 alone is indispensable for their ability to outgrow their initial “primary” tumour site and metastasise to the lung. Pyk2 could therefore present a therapeutic target for the treatment of invasive, pre-metastatic breast cancer.

Mentioned Articles

Wendt MK, Schiemann BJ, Parvani JG, Lee YH, Kang Y, Schiemann WP.

TGF-β stimulates Pyk2 expression as part of an epithelial-mesenchymal transition program required for metastatic outgrowth of breast cancer.

Oncogene. 2012 Jun 18. doi: 10.1038/onc.2012.230. [Epub ahead of print]

Sun CK, Ng KT, Lim ZX, Cheng Q, Lo CM, Poon RT, Man K, Wong N, Fan ST.

Proline-rich tyrosine kinase 2 (Pyk2) promotes cell motility of hepatocellular carcinoma through induction of epithelial to mesenchymal transition.

PLoS One. 2011 Apr 20;6(4):e18878. doi: 10.1371/journal.pone.0018878.