The Network Structure of Cancer Ecosystems

Ever since Paget’s seed-and-soil and Ewing’s connectivity hypotheses to explain tumor metastasis (1, 2), it has become clear that cancer progression can be envisaged as an ecological phenomenon. This connection has flourished during the past two decades (3–7), giving rise to important insights into the ecology and evolution of cancer progression, with therapeutic implications  (8–10). Here, we take a metapopulation view of metastasis (i.e. the migration to and colonization of, habitat patches) and represent it as a bipartite network, distinguishing source patches, or organs that host a primary tumor, and acceptor patches, or organs colonized ultimately from the source through  metastasis. Using 20,326, biomedical records obtained from literature, we  show that: (i) the network structure of cancer ecosystems is non-random, exhibiting a nested subset pattern as has been found both in the distribution of species across islands and island-like habitats (11–13), and in the distribution of among species interactions across different ecological networks (14–16); (ii) similar to ecological networks, there is a heterogeneous distribution of  degree (i.e., number of connections associated with a source or acceptor organ); (iii) there is a significant correlation between metastatic incidence (or  the frequency with which tumor cells from a source organ colonize an acceptor one) and arterial blood supply, suggesting that more irrigated organs have a higher probability of developing metastasis or being invaded; (iv) there is a positive correlation between metastatic incidence and acceptor organ degree  (or number of different tumor-bearing source organs that generate metastasis in a given acceptor organ), and a negative one between acceptor organ degree and number of stem cell divisions, implying that there are preferred sink organs for metastasis and that this could be related to average acceptor organ cell longevity; (v) there is a negative association between organ cell turnover and source organ degree, implying that organs with rapid cell turnovers tend to generate more metastasis, a process akin to the phenomenon of propagule pressure in ecology (17); and (vi) the cancer ecosystem network exhibits a modular structure in both source and acceptor patches, suggesting that some of them share more connections among themselves than with the rest of the network. We show that both niche-related processes occurring at the organ level as well as spatial connectivity and propagule pressure contribute to metastatic spread and result in a non-random cancer network, which exhibits a truncated power law degree distribution, clustering and a nested subset structure. The similarity between the cancer network and ecological networks highlights the importance of ecological approaches in increasing our understanding of patterns in cancer incidence and dynamics, which may lead to new strategies to control tumor spread within the human ecosystem.