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: [email protected]

  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.

Review of Vogelstein “Bad Luck” Cancer & Stem Cell Paper in Science

There are so many big questions about cancer. They resonate with me very strongly as a cancer researcher and a cancer survivor myself (more on my cancer story here).

  • What really causes cancer?
  • Why does it feel sometimes like we are struggling so much in the “War on Cancer”?
  • What is the role of stem cells in cancer and are there “cancer stem cells“?
  • What can we do to better prevent cancer or treat cancer once it happens?

A new Science paper by Cristian Tomasetti and Bert Vogelstein from Hopkins seeks to provide some possible answers to these kind of fundamental cancer questions.

The paper, entitled “Variation in cancer risk among tissues can be explained by the number of stem cell divisions”, argues that the more that the normal stem cells of a given tissue proliferate over one’s lifetime, the more common it is to find cancers sprouting up in that same tissue.

This relationship was reported as significant with essentially an 80% correlation. You can see the relative correlation for specific types of cancer as well below in Figure 1 from the paper.

They postulate that the relationship between stem cell proliferation and cancer is linked together mechanistically by mutations that randomly arise in stem cells each time that they divide.

cancer stem cells

The paper is summed up in the journal in one sentence: “Errors arising by chance during normal stem cell division explain more cancers than do hereditary or environmental factors.” It’s a very attractive notion, but how solid is it? I’m still thinking it through.

The authors argue that a substantial proportion of human cancer are simply due to bad luck. What this means, if you accept that notion, is that for those of us who get cancer much of the time there would have been nothing that we could have done differently to prevent it and further that the genes we got from our parents may not have played major roles. It’s an intriguing, provocative paper that makes some bold assertions, but there are some issues that leave some of the key issues remaining as theories.

The most difficult issue is how to consistently and accurately calculate the number of lifetime stem cell divisions in a series of diverse tissues. This is extremely difficult and it’s not difficult to imagine such calculations being off by one or more orders of magnitude. Going through their supplemental data frankly I still am not sure how convincingly this was achieved. It’s not a simple matter by any stretch of the imagination.

Another factor is that not all cancers are going to originate with stem cells. Some tumors arise from progenitor cells or from differentiated cells that de-differentiate.

Further, many organs have more than one type of stem or precursor-like population. How does one handle that in modeling?

It is also possible that epigenetics play a substantial role in the argued for proliferation-associated cancers. For example, with every stem cell division there may be an increased risk not only of mutations, but also of epigenetic changes (in some forms called epi-mutations) that over time transform the normal stem cells into cancer cells.

I found this paper very thought provoking, but it’s just a start in a way. Let’s see what others find when they attempt similar calculations.

Update

Other folks’ take on the papers are more skeptical:

Bob O’Hara & GrrlScientist

Aaron Meyer

 

Knoepfler Lab: Our mission and research

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

You can go check out our lab website, but I thought it might be time 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.

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, which consists primarily of DNA methylation and histone modifications. Each cell’s epigenetic 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 just 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 last year 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 CIRM, we are working on three main areas and you can see these themes reflected in the lst 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 (see here for more on that). In our newest paper, published just a few days ago, we show how Miz-1 binds to DNA. This should hopefully help the field understand Myc a lot better too.

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 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. Update: We are excited about our new paper on H3.3 in germ cells, which I discuss in more depth here including its relevance for brain tumors.

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 cancer treatments and regenerative medicine therapies.

 

Stem Cells An Insider’s Guide: More on My New Book

Knoepfler Stem Cell Insiders BookIn about a month my new book, Stem Cells: An Insider’s Guide, should be available as an e-book from the publisher and from Amazon. It’s available for pre-order now at Amazon here. The “real” book (i.e. the one made of paper) should be available in September. The book costs $29. Any writers out there interested in doing a review please contact me.

As I’ve said before, I wrote this book in part because I wanted to learn more about stem cells and had gone looking in vain to find a stem cell book that had what I was looking for: opinions, cutting edge ideas, an easy reading style that at the same time wouldn’t insult one’s intelligence….I couldn’t find anything like that so I decided to try to write one.

I also enjoy humor in what I read and that was completely lacking in books on stem cells. It’s also generally lacking in science books overall. I tried to inject some humor into my book.

I thanked some people in the preface to my book who have been instrumental in helping me not only with the book, but also the past 3 years with advocacy and learning stem cell street smarts to be frank. My book is in one way an attempt to bottle up their collective wisdom and stir in some opinions of my own.

In the book I tried to call it like I see it in terms of key challenges and even secrets and misdeeds, but I also focus on the positive.

For example, I highlighted 4 stem cell biotech good citizens…any guesses on which four companies I called out for their positive actions?

I’ve also picked out 11 of the most important diseases/injuries and talk about how stem cells might work to treat or even cure them in the future:

  • Alzheimer’s Disease (AD)
  • Amyotrophic Lateral Sclerosis (ALS)
  • Arthritis
  • Autism
  • Cancer
  • Chronic Obstructive Pulmonary Disease (COPD)
  • HIV/AIDS
  • Huntington’s Disease
  • Multiple Sclerosis
  • Parkinson’s Disease (PD)
  • Spinal Cord Injury (SCI)

I also have an entire section on stem cell patient rights and another on great patient advocates.

I am excited as this book gets nearer to reality. I hope you will read it and find it interesting. Even if you do not agree with some of my opinions, I’m betting you’ll find it makes you think in new ways about stem cells. My primary goals to get people thinking and talking more about stem cells, to challenge them, and to provide an entertaining, even fun read.

How baldness can cure kid’s cancer: find out & please help!

St. Baldrick'sHi everyone,

St. Baldrick’s is the top children’s cancer foundation and does amazing work for kids with cancer and their families.

Their top fundraising event is a head-shaving program where people make pledges in support of a “shavee” who gets their head shaved in solidarity with kids with cancer who often lose their hair due to treatment.

I’ve formed a St. Baldrick’s UC Davis School of Medicine fundraising team and I’m also a shavee myself this year.

I did it last year too and was surprised I didn’t look too bad with a totally bald head.

As a cancer survivor myself, I feel very strongly about this amazing organization. They have also supported pediatric cancer research ongoing in my lab on cancer stem cells.

Please consider pledging a donation here by sponsoring me as I get my head shaved. Every donation helps!

Thank you,

Paul