Text mining top 50 papers reveals hottest 2016 stem cell trends

What are the hottest stem cell trends in the field today?

Depends who you ask, right?

One impartial way to look at stem cell trends is through the lens of publication citations and the focuses of top stem cell papers. In that perhaps somewhat skewed, but interesting approach, the words used in the titles of the 50 most cited research publications of 2016 with the phrases “stem cell(s)” in their titles should tell us something interesting.

top-stem-cell-pub-word-cloud

Fortunately publication citation platforms these days like ISI may it a snap to collect such data with a few tricks. Then I plugged the data into a word cloud generator and ta-da I got the image above.

Cancer is the biggest word. Apparently cancer stem cells are hot in 2016, along with studies specifically on human stem cells with “human” as the second biggest word.

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Top 10 Google Stem Cell News Stories: Perspectives

What does Google think (if Google does indeed think) are top 10 stem cell news stories right now?

I took a screen shot below.

Here are some thoughts on those stories.

top-stem-cell-headlines

First, lung organoids are neat, but they have been grown before by several groups. Why is that the top story? I’d have to ask Google. Better PR? Still looks interesting and could have real impact for lung disease in the future.

The second story is on the transplantation of allogeneic IPS cells into monkeys without immunosuppression.This is an important finding with clinical impact from Dr. Takahashi’s group.

That third story seems odd to me. Seems like an over the top claim.

The fourth one with its “for the first time” I’m not so sure about and number five seems to be on the same story. I have doubts about that trial given the lack of detail and the potential for harm to patients. It sounds premature.

Then we have cancer stem cell stories at number six and another at number eight.

Number seven and ten both refer to the experience of one patient in the Asterias stem cells for spinal cord injury trial. Number ten’s headline is dubious from a scientific perspective with its “as a result” claiming the stem cells made the man better for sure. I really hope that’s true, but we don’t know yet although more recent data on more patients is encouraging. Controls are needed in the long run to iron things out.

Number nine is about stem cell clinics. It seems to be the only one mentioning the historic FDA stem cell meeting this week.

Thought provoking talk from John Dick at #ISSCR2016 on cancer stem cells

Professor_John_Dick_FRS

Wikipedia photo

Dr. John Dick gave a great talk yesterday on cancer stem cells here at ISSCR 2016. Below I summarize his talk and as always with these meeting blogs, the post is not polished and is more of a stream of the speaker’s main points. He started out broadly with a nice introduction to this area of research.

There’s a lot of controversy around cancer stem cells (CSC). How many tumors have CSCs? How different are cells within the same tumor?

The normal hierarchical organization of hematopoiesis is disrupted in AML. Are CSC properties clinically relevant in leukemia?

Here the focus is on leukemic stem cells (LSC).  If a patient’s cells can engraft a mouse then that patient has much worse survival. This engraftment predicts relapse. They have developed a LSC prognostic score. NMP1mut FLT3-ITD neg cells are mentioned. miRNA signatures and epigenetics matter for survival. Big picture conclusion: stem cell properties are very important to the disease.

More genetic studies. Branching tumor evolution during leukemia development: what is the role of stem cells? They did deep targeted sequencing of the genes known to be important for AML. They discovered a common ancestor gene commonly mutated in AML. (Shlush, Nature 2014). DNMT3a mutation was present in the common ancestor cell. Leukemia blasts can have the DNMT3a and NPM1C alleles, but many only have one marker (suggesting clonal evolution).

This raises many interesting questions.

Where does relapse come from? What is cellular origin? Did the chemo induce changes? Or are there residual cells that then spur a tumor comeback?

There’s no definitive marker for LSC.

Evidence of a long evolution in the preleukemic phase. One model is that relapse originates from rare LSC that evolve before diagnosis and survive therapy.

A fascinating point–cells that preferentially grow in the mouse xenograft are not the predominant one in the patient at presentation but rather the ones that will later kill the patient through relapse. Another model is that relapse stems from a rare CD33+ subset.

Knoepfler Lab 2015: Our mission and research

Knoepfler LabMany of this blog’s readers ask about my own lab’s research. What is the focus of the work in the Knoepfler Lab?

You can go check out our lab website, but I thought it might be time again to blog about what we are all about as a lab and what we have been up to most recently. I am fortunate to have an exceptional team of researchers in my lab.

Our mission is to advance knowledge toward two main goals: (1) the development of new, safe, and effective stem cell-based regenerative medicine therapies, and (2) catalyzing novel cancer therapies, particularly for childhood brain tumors and other pediatric neuronal cancers. Related to this, we are also investigating how the brain normally grows during development. In short, the research we do mainly converges towards the goal of advancing science to get new stem cell and cancer therapies off the ground. To this end we use innovative molecular, developmental, and cellular biological techniques as well as genetics and genomics approaches.

H3.3 testes

We are particularly interested in a field of science called epigenetics. We all know about the genome where our genes are coded, but the genome doesn’t do anything without the epigenome (global and specific epigenetic events), which consists primarily of DNA methylation and histone modifications. Each cell’s epigenomic state orchestrates the genes that are on and off, which in turn collectively controls how that cell behaves (e.g. how a stem cell stays a stem cell or differentiates) or in the case of cancer and other diseases, how it misbehaves. We recently published a review article on the connections between epigenetics, cancer, and stem cells.

As it turns out, stem cells and cancer cells are unfortunately highly related cell types, perhaps even cellular siblings. For example, we showed in a novel paper a couple years back that the process of cellular reprogramming to make iPS cells is in some ways remarkably similar to the process of turning normal cells into cancer cells. This paper has stirred quite a bit of discussion.

What else have we been up to lately?

Supported by NIH and Alex’s Lemonade Stand Foundation, we are working on three main areas and you can see these themes reflected in the list of our recent publications.

First, we have a long-standing interest in a cancer-related gene called MYC. Some have speculated that every human cancer in one way or another has some problem with MYC, usually too much of it. At the same time, however, Myc proteins are essential for normal stem cell function. As a result Myc ends up being quite the Dr. Jekyll and Mr. Hyde kind of character. As with any molecule or person for that matter, Myc does not act alone. Lately we’ve been getting more interested in a key cofactor of Myc called Miz-1.

Second, we are excited about a relatively newer area of epigenetic and chromatin research focused on a molecule called histone variant H3.3. Histones come in different forms and histone variants are cool and interesting because they don’t follow the normal rules for histones. Histone variants such as H3.3 can become part of chromatin (the combination of DNA and histones) basically any time in any kind of cells. For most histones their ability to do that is much more sharply constrained. This makes a variant such as H3.3 far more dynamic and important to decision-making processes by cells such as stem cells and cancer cells.

In the case of H3.3, two genes make the same identical H3.3 protein. We call these genes A and B, short, for H3f3a and H3f3b. In 2013 we reported in our Bush, et al. paper the phenotype of the first knockout of an H3.3-coding gene in mice with our knockout of the B gene. About half the time, mice lacking the B gene do not make it through development and have a host of problems including an inability to properly segregate their chromosomes during cell division that leads in turn  to DNA damage and apoptosis (cell death). The surviving B knockout mice are pretty much all infertile. It’s notable that mutations in H3.3 occur in humans and are strongly linked to childhood cancer. Last year we also published a review article in Cancer Cell on the H3.3-cancer connection, which involves two particularly disastrous tumors in children called glioblastoma and DIPG. We are excited about our new H3.3 paper on its function in germ cells, which I discuss in more depth here including its relevance for brain tumors. In the image above you can see H3.3 loss-of-function testes with unusual histone mark levels.

Third, we are studying two genes that also function in stem cells and cancer called DPPA4 and DPPA2. It is fascinating to think about how certain genes like these, H3.3, and Myc, can function normally in stem cells, but then with a monkey wrench in the system they can cause cancer. In the case of DPPA4 and DPPA2, they have long been known to be important stem cell genes, but it was only in 2013 that our lab discovered and published in the journal Stem Cells that they are also oncogenes. Surprisingly, it is still largely an open question how the Dppa4 and Dppa2 proteins actually work.

Overall one can see that we work at the interface of stem cells, cancer, and developmental tissue growth and investigate how epigenetic machinery orchestrates the regulatory events involved.

Finally, we are committed to educational outreach and advocacy for evidence-based innovative medical treatments and regenerative medicine therapies.

Cancer stem cells, shifting tides and an expanding understanding: guest post by Aaron Goldman

Aaron GoldmanBy Aaron Goldman

Much like the winter weather we’ve been enduring on the east coast, cancer research is advancing at a rapid clip! For decades, researchers have considered pools of “cancer stem cells” (CSC) as the subsets within a tumor which both initiate progression and underpin the failure of therapy. Over the past 5 years, however, a number of published studies have expanded this concept by putting a greater emphasis on the inherent plasticity of cancer cells allowing for reversibility in the cell hierarchy and invoking new evolutionary dynamics to understand the progression of disease and resistance to therapies.

Just last week we published a study which investigated the origins of adaptive resistance to standard-of-care, cytotoxic chemotherapy. We focused our efforts on aggressive subtypes of breast cancer employing primary human tumor explants, in-vivo models and computational biology [1]. Despite the pervading dogma, we found something quite surprising: non-CSC (defined by low expression of classical biomarkers such as CD44) were found to transiently-transition to a CD44Hi drug resistant phenotype with a putative capacity to re-initiate tumor development following cessation of treatment. Induction of this reversible phenotype unmasked vulnerable signaling addictions within the cells (primarily through a Src Family Kinase known as ‘Hck’). We discovered that timing the sequence of therapies could be leveraged to 1.) Transition cells into this temporally-vulnerable phase offering a window of opportunity to then 2.) target Hck with established pharmacological agents. The result was a superior tumor response to the temporally-constrained combination regimens.

In the course of this work we made some intriguing observations. While the classical definition of a breast CSC is based largely on the mesenchymal-like CD44HiCD24LO phenotype, following exposure to chemotherapy we determined that cells were inducing both CD44 and CD24 to rewire redundant survival signals. This was exciting because it suggested a phenotypic switch in which cells were shifting into a state that took on some features that were suggestively ‘stem-like’, yet doing so imperfectly or at least incompletely. Could there be a new role for non-CSC in chemotherapy relapse?

These studies have led us to new appreciations and insights for the power of cellular plasticity, which can allow a reconstruction of non-genetic behavior to rewire survival instincts in cells. In contrast to a classic hierarchical model, this behavior was more consistent with a continuum of phenotypes in which cells can transition imperfectly, incompletely or with varying requisite features of “CSC” to adapt to and overcome stress. With these findings, our hope is that they open new interpretations and grow with the CSC field as it continues its evolution in the spectrum of therapy response. It will be exciting to see how cellular plasticity and the CSC model merge with evolutionary dynamics and cellular fitness, efforts which will no doubt provide a full picture of tumor evolution to inspire persisting therapeutic strategies in the not too distant future.

Many thanks to you, Paul, for the opportunity to connect with a diverse and knowledgeable audience and share some discussions! If readers have questions they can leave comments or email them: goldman1@mit.edu.

  1. Goldman, A., et al., Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition. Nat Commun, 2015. 6: p. 6139.