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 . 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: firstname.lastname@example.org.
- 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.
2 thoughts on “Cancer stem cells, shifting tides and an expanding understanding: guest post by Aaron Goldman”
Alessandro, thanks for the kind note. That is a super interesting question. If you are asking if I think it creates a substrate for a mutational evolution, perhaps through natural selection, then I would tend to agree with that hypothesis. One of the things I’m currently doing with a colleague here at BWH is investigating the genetic changes subsequent to the acquisition of drug tolerance. We will hopefully be able to map, soon, which genes are altered over time subsequent to a purely phenotypic adaptation. The natural next question is if stable mutants emerge through a fitness competition or if stochasticity governs acquired stable genetic variants? As I alluded in the post, fitness is emerging as a critical feature of tumor evolution in which response to therapy may inject a new variable. So I think it will be fascinating to understanding how plasticity alters the intercellular heterogeneity of cancer cells and therefore impacts fitness of different subclones.
Very interesting sharing, the idea of taking advantage of the cellular plasticity to sensitize cancer cells to a different drug is fascinating, I hope to read more studies like this one, about a broader range of malignancies! Do you think that this mechanism is actually paving the way to a more stable genetic resistance emergence, or is just a “parallel” strategy, maybe relying on very specific conditions (taxans pressure, very particular cellular subtype)?
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