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- All Subjects: Evolution & development
Description
Life history theory offers a powerful framework to understand evolutionary selection pressures and explain how adaptive strategies use the life history trade-off and differences in cancer defenses across the tree of life. There is often some cost to the phenotype of therapeutic resistance and so sensitive cells can usually outcompete resistant cells in the absence of therapy. Adaptive therapy, as an evolutionary and ecologically inspired paradigm in cancer treatment, uses the competitive interactions between drug-sensitive, and drug-resistant subclones to help suppress the drug-resistant subclones. However, there remain several open challenges in designing adaptive therapies, particularly in extending this approach to multiple drugs. Furthermore, the immune system also plays a role in preventing and controlling cancers. Life history theory may help to explain the variation in immune cell levels across the tree of life that likely contributes to variance in cancer prevalence across vertebrates. However, this has not been previously explored. This work 1) describes resistance management for cancer, lessons cancer researchers learned from farmers since adaptive evolutionary strategies were inspired by the management of resistance in agricultural pests, 2) demonstrates how adaptive therapy protocols work with gemcitabine and capecitabine in a hormone-refractory breast cancer mouse model, 3) tests for a relationship between life history strategy and the immune system, and tests for an effect of immune cells levels on cancer prevalence across vertebrates, and 4) provides a novel approach to improve the teaching of life history theory. This work applies lessons that cancer researchers learned from pest managers, who face similar issues of pesticide resistance, to control cancers. It represents the first time that multiple drugs have been used in adaptive therapy for cancer, and the first time that adaptive therapy has been used on hormone-refractory breast cancer. I found that this evolutionary approach to cancer treatment prolongs survival in mice and also selects for the slow life history strategy. I also discovered that species with slower life histories have higher concentrations of white blood cells and a higher percentage of heterophils, monocytes and segmented neutrophils. Moreover, larger platelet size is associated with higher cancer prevalence in mammals.
ContributorsSeyedi, Seyedehsareh (Author) / Maley, Carlo (Thesis advisor) / Blattman, Joseph (Committee member) / Anderson, Karen (Committee member) / Wilson, Melissa (Committee member) / Huijben, Silvie (Committee member) / Gatenby, Robert (Committee member) / Arizona State University (Publisher)
Created2023
Description
Cancer is a disease which can affect all animals across the tree of life. Certain species have undergone natural selection to reduce or prevent cancer. Mechanisms to block cancer may include, among others, a species possessing additional paralogues of tumor suppressor genes, or decreasing the number of oncogenes within their genome. To understand cancer prevention patterns across species, I developed a bioinformatic pipeline to identify copies of 545 known tumor suppressor genes and oncogenes across 63 species of mammals. I used phylogenetic regressions to test for associations between cancer gene copy numbers and a species’ life history. I found a significant association between cancer gene copies and species’ longevity quotient. Additional paralogues of tumor suppressor genes and oncogenes is not solely dependent on body size, but rather the balance between body size and longevity. Additionally, there is a significance association between life history traits and genes that are both germline and somatic tumor suppressor genes. The bioinformatic pipeline identified large tumor suppressor gene and oncogene copy numbers in the naked mole rat (Heterocephalus glaber), armadillo (Dasypus novemcinctus), and the two-fingered sloth (Choloepus hoffmanni). These results suggest that increased paralogues of tumor suppressor genes and oncogenes are these species’ modes of cancer resistance.
ContributorsSchneider-Utaka, Aika Kunigunda (Author) / Maley, Carlo C (Thesis advisor) / Wilson, Melissa A. (Committee member) / Tollis, Marc (Committee member) / Arizona State University (Publisher)
Created2019