Tumor ecology: investigating intra-tumoral metabolic heterogeneity

Hershey, Benjamin (2023). Tumor ecology: investigating intra-tumoral metabolic heterogeneity. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00015dfe

Abstract

Many patients with non-metastatic breast tumors are successfully treated. However, small tumor cell populations such as those found in micro-metastases present a major hurdle to successful therapy. Throughout nature the fitness of individual organisms, from viruses to large mammals, is modulated by population density. This phenomenon, termed the Allee Effect, means that sparse populations are more vulnerable to extinction than their denser counterparts. Despite its prevalence in nature, it is still unclear what role the Allee Effect plays in governing the growth of small cancer cell populations. To address this question the MDA-MB-231 cell line, representative of triple negative breast cancer, was selected as a model system. A cohort of six distinct lineages was then isolated from the parental culture. Using an imaging-based approach, their growth was measured across a range of populations sizes in: regular, population, or clone conditioned media. The screen revealed the presence of a “Weak Allee Effect.” Moreover, cross-feeding experiments demonstrated that the lineages were able to circumvent this ecological obstacle to growth by collaborating through soluble factor exchange. Upon longitudinal co-culture of the six lineages, a minimal interacting community made up of three members emerged. In vivo, orthotopic co-injection of these three lineages together resulted in greater metastatic burdens than those observed following injection of the single lineages alone. This data suggests that small, distinct populations of triple negative breast cancer cells cooperate with one another though soluble factor exchange in order to overcome an Allee Effect and improve fitness. Characterizing these lineages using multiple omics approaches revealed that the soluble factor(s) underly this synergistic community can be metabolic in nature. Our results suggest that community assembly based on metabolite exchange plays an important role in the fitness of small populations of breast cancer cells both in vitro and in vivo, and highlights the role of the Allee Effect as an impediment to growth for distinct lineages of breast cancer cells.