Tumor diversity and the trade-off between universal cancer tasks

Abstract

Recent advances have enabled powerful methods to sort tumors into prognosis and treatment groups. We are still missing, however, a general theoretical framework to understand the vast diversity of tumor gene expression and mutations. Here we present a framework based on multi-task evolution theory, using the fact that tumors need to perform multiple tasks that contribute to their fitness. We find that trade-offs between tasks constrain tumor gene-expression to a continuum bounded by a polyhedron whose vertices are gene-expression profiles, each specializing in one task. We find five universal cancer tasks across tissue-types: cell-division, biomass and energy, lipogenesis, immune-interaction and invasion and tissue-remodeling. Tumors that specialize in a task are sensitive to drugs that interfere with this task. Driver, but not passenger, mutations tune gene-expression towards specialization in specific tasks. This approach can integrate additional types of molecular data into a framework of tumor diversity grounded in evolutionary theory.

Cancer Hallmarks Define a Continuum of Plastic Cell States between Small Cell Lung Cancer Archetypes

“…Archetypal analysis has been used on systems ranging from cancer to development in order to explore heterogeneous gene expression by finding archetypes, or "pure subtypes," in gene expression space that best explain the heterogeneity seen in the samples. [37][38][39][40][41][42][43][44][45][46] Using AA on SCLC cells from cell lines and tumors gives us the flexibility to understand how plastic cells may pass through intermediate states, 26,47 which cannot be described in a discrete-clustering framework, to transition between subtypes.…”

New Insights into Therapy-Induced Progression of Cancer

“…The EMT is directly related to metastasis and invasion of tumor cells. In the model of breast cancer, Hausser's group shows that the main processes necessary for tumor progression, i.e., cell division, maintenance or increase in biomass and energy, lipogenesis, immune interactions, invasion, and tissue remodeling, cannot occur simultaneously [102]. Other groups of researchers also notice the difficulty of simultaneous processes of proliferation and invasion [103][104][105].…”

“…Other groups of researchers also notice the difficulty of simultaneous processes of proliferation and invasion [103][104][105]. Hence, a tumor cell has to choose whether to maintain its metabolism on glucose or lipids, actively proliferate, avoid an immune response, or metastasize [102]. As will be discussed below, proliferative activity and being at a certain stage of the cell cycle can increase or decrease the sensitivity of tumor cells to the effects of therapy.…”

Mathematical Model of a Personalized Neoantigen Cancer Vaccine and the Human Immune System: Evaluation of Efficacy

“…Therapeutic strategies that incorporate personalized cancer vaccines have gained attention due to successes in targeting multiple tumor-specific mutations [6]. However, there is an immense diversity in tumor gene expression and mutations; how these affect outcomes for individual patients is poorly understood [7]. Tumor-specific antigens (TSAs), or neoantigens, carry the amino acid substitutions derived from random somatic mutations that are expressed only on tumor cell surface.…”

“…These neo-sequences carry somatic mutations exhibiting sequences that are different from the wild type, and hence can be recognized as non-self by the host immune system having a high probability of eliciting a cancer specific immune response. From the large number of neo-sequences identified, the selection of the few neo-sequences (to be used as neoantigens in cancer vaccines) is largely based on the affinity of the neoantigens peptides to the patient's major histocompatibility complex-I (MHC-I) and MHC-II proteins [7]. The individualized immunotherapies designed based on these principles have the potential to be specific, efficacious, and safe [9][10][11].…”