Multicolor lineage tracing reveals clonal architecture and dynamics in colon cancer

Abstract

Colon cancers are composed of phenotypically heterogeneous tumor cell subpopulations with variable expression of putative stem cell and differentiation antigens. While in normal colonic mucosa, clonal repopulation occurs along differentiation gradients from crypt base toward crypt apex, the clonal architecture of colon cancer and the relevance of tumor cell subpopulations for clonal outgrowth are poorly understood. Using a multicolor lineage tracing approach in colon cancer xenografts that reflect primary colon cancer architecture, we here demonstrate that clonal outgrowth is mainly driven by tumor cells located at the leading tumor edge with clonal axis formation toward the tumor center. While our findings are compatible with lineage outgrowth in a cancer stem cell model, they suggest that in colorectal cancer tumor cell position may be more important for clonal outgrowth than tumor cell phenotype.

Microenvironmental cues in cancer stemness

“…This characteristic tumour proliferation at a holistic level is consistent with a model of surface tumour growth, and accurately predicted the rate of macroscopic tumour expansion. The authors conclude that CRC grows from surface expansion while the central bulk of the tumour contributes little to tumour growth (Figure 1), which is supported by another recent publication 11 .…”

Collective motion conceals fitness differences in crowded cellular populations

“…Compared to non-mechanical models, selection is less efficient in weeding out deleterious mutations, which can be rescued by an environmental change. Mechanical screening e↵ects merely require steric interactions and could therefore substantially a↵ect the evolutionary dynamics in any crowded cellular population, such as biofilms, multi-cellular tissues or tumors [38,22,21], by increasing clonal interference [17,25], promoting the accumulation of dele- Figure 4: Slow purging of costly drug resistance mutations can lead to resurgent growth upon drug application. a) Fluorescent micrographs of thin sectors originating from single cells of a slower growing mutant phenotype (yellow, s = 0.06) interspersed in a wild type colony (blue).…”

“…Such mechanical screening of fitness di↵erences allows the mutants to leave more descendants than expected under non-mechanical models, thereby increasing their chance for evolutionary rescue [2,5]. Our work suggests that mechanical interactions generally influ-ence evolutionary outcomes in crowded cellular populations, which has to be considered when modeling drug resistance or cancer evolution [1,22,34,30,36,42]. As a model system for crowded cellular populations, we focused on colonies of the budding yeast Saccharomyces cerevisiae [33].…”

SmartCodes: functionalized barcodes that enable targeted retrieval of clonal lineages from a heterogeneous population

“…If one considers heterogeneity in cancer, it is as yet unclear how many clonal lineages are relevant to disease progression. Certainly, studies to date would argue for multiple lineages, perhaps showing genetic or phenotypic diversity [20,21] that could impact properties relevant to progression and outcome. The methods that we describe perform well beyond the ability to enrich relevant clones from mixtures of the expected relevant complexity, placing the SmartCode strategy in a position to facilitate studies of how cellular heterogeneity impacts nearly every aspect of disease progression.…”