Clonal populations of mammalian cells are inherently heterogeneous. They contain cells that display non-genetic variability resulting from gene expression noise and the fact that gene networks have multiple stable states. These stable, heritable variants within one cell type can exhibit different levels of responsiveness to environmental conditions. Hence, they could in principle serve as a temporary substrate for natural selection in the absence of mutations. We suggest that such ubiquitous but non-genetic variability can contribute to the somatic evolution of cancer cells, hence accelerating tumour progression independently of genetic mutations.

Directed cell migration is critical for tissue morphogenesis and wound healing, but the mechanism of directional control is poorly understood. Here we show that the direction in which cells extend their leading edge can be controlled by constraining cell shape using micrometer-sized extracellular matrix (ECM) islands. When cultured on square ECM islands in the presence of motility factors, cells preferentially extended lamellipodia, filopodia, and microspikes from their corners. Square cells reoriented their stress fibers and focal adhesions so that tractional forces were concentrated in these corner regions. When cell tension was dissipated, lamellipodia extension ceased. Mechanical interactions between cells and ECM that modulate cytoskeletal tension may therefore play a key role in the control of directional cell motility.

Development of drug resistance, the prime cause of failure in cancer therapy, is commonly explained by the selection of resistant mutant cancer cells. However, dynamic non-genetic heterogeneity of clonal cell populations continuously produces meta-stable phenotypic variants (persisters), some of which represent stem-like states that confer resistance. Even without genetic mutations, Darwinian selection can expand these resistant variants, which would explain the invariably rapid emergence of stem-like resistant cells. Here, using quantitative measurements and modeling we show that appearance of multi-drug resistance in HL60 leukemic cells following treatment with vincristine is not explained by Darwinian selection but by Lamarckian induction. Single-cell longitudinal monitoring confirms the induction of multi-drug resistance in individual cells. Associated transcriptome changes indicate a lasting stress-response consistent with a drug-induced switch between high-dimensional cancer attractors. Resistance-induction correlates with Wnt-pathway up-regulation and is suppressed by β-catenin knock-down, revealing a new opportunity for early therapeutic intervention against resistance development.