Heterogeneous Tumor Subpopulations Cooperate to Drive Invasion

Abstract

SummaryClonal selection and transcriptional reprogramming (e.g., epithelial-mesenchymal transition or phenotype switching) are the predominant theories thought to underlie tumor progression. However, a “division of labor” leading to cooperation among tumor-cell subpopulations could be an additional catalyst of progression. Using a zebrafish-melanoma xenograft model, we found that in a heterogeneous setting, inherently invasive cells, which possess protease activity and deposit extracellular matrix (ECM), co-invade with subpopulations of poorly invasive cells, a phenomenon we term “cooperative invasion”. Whereas the poorly invasive cells benefit from heterogeneity, the invasive cells switch from protease-independent to an MT1-MMP-dependent mode of invasion. We did not observe changes in expression of the melanoma phenotype determinant MITF during cooperative invasion, thus ruling out the necessity for phenotype switching for invasion. Altogether, our data suggest that cooperation can drive melanoma progression without the need for clonal selection or phenotype switching and can account for the preservation of heterogeneity seen throughout tumor progression.

Lyapunov–Schmidt and Centre Manifold Reduction Methods for Nonlocal PDEs Modelling Animal Aggregations

“…5(a)-(d) show a travelling pulse behaviour exhibited by the u 2 population that moves away from population u 1 (which is mostly stationary -although even this population spreads a bit). This faster spreading of the u 2 cells compared to the u 1 cells is consistent with experimental observations (Chapman et al, 2014;Wojciechowska & Patton, 2015). The movement of u 2 population eventually stops near the boundary (due to the periodic boundary conditions, the leftmoving and right-moving subgroups can sense each other across the boundary).…”

“…DYNAMICS OF CANCER CELLS. Experimental studies (Chapman et al, 2014) have shown that cancer cells can switch from a homogeneous type of invasion to a heterogeneous type of invasion described by invading chains (Chapman et al, 2014;Friedl & Wolf, 2003;Wojciechowska & Patton, 2015). Here, we assume that u 1 cells can mutate into u 2 cells at a constant rate M. We can derive a model for heterogeneous cancer cell populations by considering the equations…”

“…By incorporating this assumption, we aim to bring a more realistic approach to the models since the various intra-tumour cell sub-populations have been shown to be distinct not only in their adhesion capabilities but also in their motility and metastatic potential (Marusyk & Polyak, 2010). Moreover, we are interested in investigating the effect of mutation on the spreading speed of the mutated cancer cells, since the invasion levels of the mutant cancer cells are higher compared to those of "normal" cancer cells (Chapman et al, 2014;Wojciechowska & Patton, 2015). Also, while previous nonlocal models have assumed constant adhesive interactions, here we will assume that these adhesive interactions depend on the level of integrins.…”

Distinctive properties of metastasis-initiating cells

“…This kind of cooperation has been further characterized in other models proposing a leading invasive cell followed by "opportunistic" cells ( Fig. 5B; Chapman et al 2014;Westcott et al 2015). This synergy is in agreement with the observation that CTC clusters have dramatically increased metastatic potential compared with single CTCs (Aceto et al 2014) and the polyclonal nature of metastases (Gundem et al 2015;Maddipati and Stanger 2015).…”

Mathematical modelling of cancer invasion: The multiple roles of TGF-β pathway on tumour proliferation and cell adhesion

“…Cancer cells can switch from a homogeneous type of invasion to a heterogeneous type of invasion described by (directionally moving) invading chains. 12 Therefore, we assume that the movement of the early stage cancer cell population u 1 is governed by random motility (which underlines a homogeneous type of invasion), as well as directed motility in response to cell-cell and cell-matrix adhesive forces (which underlines the heterogeneous type of invasion).…”