Paracrine Behaviors Arbitrate Parasite-Like Interactions Between Tumor Subclones.

Explaining the emergence and maintenance of intratumor heterogeneity is an important question in cancer biology. Tumor cells can generate considerable subclonal diversity, which influences tumor growth rate, treatment resistance, and metastasis, yet we know remarkably little about how cells from different subclones interact. Here, we confronted two murine mammary cancer cell lines to determine both the nature and mechanisms of subclonal cellular interactions in vitro. Surprisingly, we found that, compared to monoculture, growth of the "winner" was enhanced by the presence of the "loser" cell line, whereas growth of the latter was reduced. Mathematical modeling and laboratory assays indicated that these interactions are mediated by the production of paracrine metabolites resulting in the winner subclone effectively "farming" the loser. Our findings add a new level of complexity to the mechanisms underlying subclonal growth dynamics.

Cell lineage tracing in human epithelial tissues using mitochondrial DNA mutations as clonal markers.

The study of cell lineages through heritable genetic lineage tracing is well established in experimental animals, particularly mice. While such techniques are not feasible in humans, we have taken advantage of the fact that the mitochondrial genome is highly prone to nonpathogenic mutations and such mutations can be used as clonal markers to identify stem cell derived clonal populations in human tissue sections. A mitochondrial DNA (mtDNA) mutation can spread by a stochastic process through the several copies of the circular genome in a single mitochondrion, and then through the many mitochondria in a single cell, a process called 'genetic drift.' This process takes many years and so is likely to occur only in stem cells, but once established, the fate of stem cell progeny can be followed. A cell having at least 80% of its mtDNA genomes bearing the mutation results in a demonstrable deficiency in mtDNA-encoded cytochrome c oxidase (CCO), optimally detected in frozen tissue sections by dual-color histochemistry, whereby CCO activity stains brown and CCO deficiency is highlighted by subsequent succinate dehydrogenase activity, staining the CCO-deficient areas blue. Cells with CCO deficiency can be laser captured and subsequent mtDNA sequencing can ascertain the nature of the mutation. If all cells in a CCO-deficient area have an identical mutation, then a clonal population has been identified; the chances of the same mutation initially arising in separate cells are highly improbable. The technique lends itself to the study of both normal epithelia and can answer several questions in tumor biology. WIREs Dev Biol 2016, 5:103-117. doi: 10.1002/wdev.203 For further resources related to this article, please visit the WIREs website.

Can oncology recapitulate paleontology? Lessons from species extinctions.

Although we can treat cancers with cytotoxic chemotherapies, target them with molecules that inhibit oncogenic drivers, and induce substantial cell death with radiation, local and metastatic tumours recur, resulting in extensive morbidity and mortality. Indeed, driving a tumour to extinction is difficult. Geographically dispersed species of organisms are perhaps equally resistant to extinction, but >99.9% of species that have ever existed on this planet have become extinct. By contrast, we are nowhere near that level of success in cancer therapy. The phenomena are broadly analogous--in both cases, a genetically diverse population mutates and evolves through natural selection. The goal of cancer therapy is to cause cancer cell population extinction, or at least to limit any further increase in population size, to prevent the tumour burden from overwhelming the patient. However, despite available treatments, complete responses are rare, and partial responses are limited in duration. Many patients eventually relapse with tumours that evolve from cells that survive therapy. Similarly, species are remarkably resilient to environmental change. Paleontology can show us the conditions that lead to extinction and the characteristics of species that make them resistant to extinction. These lessons could be translated to improve cancer therapy and prognosis.

Location, location, location! The reality of life for an intestinal stem cell in the crypt.

The intestinal crypt has become the archetypal system to understand stem cell behaviour in vivo. Advances in lineage-tracing technology have identified rapidly cycling stem cells at the crypt base with prominent expression of 'marker' genes such as Lgr5. Elegant quantitative analysis of lineage-tracing data has shown that each stem cell within the crypt is in continual neutral competition with the others in order to retain its place in the niche and so prevent differentiation into a specialized lineage. Accordingly, it appears that the regulation of the stem cell pool occurs primarily at the level of the stem cell population, as a simple consequence of competition for the limited space within the niche. However, contradictory data showing that cells located away from the crypt base niche can also sometimes function as stem cells has challenged the notion that stemness is fundamentally cell-extrinsic. Writing in Nature, Ritsma and colleagues have resolved this debate by performing in vivo live-imaging of the crypt base. By tracking individual stem cells over time, they showed that the relative positioning of the cell within the niche stochastically regulates its fate. Stem cells located in close proximity to the crypt base were more likely to persist long-term, but peripheral cells could sometimes move into privileged crypt-base positions. Thus, while many cells within the crypt have stem cell potential, only cells lucky enough to reside in the 'Goldilocks zone' behave as functional stem cells in the long term. The hunt for intestinal stem cells is over: the stem cells are simply found in their niche.