The evolution of long-lived animals has necessitated acquisition of potent tumor suppressive mechanisms to maximize reproductive success. We hypothesize that the evolution of well-adapted stem cells has conferred resistance to oncogenic mutations, as phenotype- altering genetic/epigenetic change should typically be disadvantageous within a well-adapted cell population. Nonetheless, accumulating damage and increased inflammation with age could alter the cellular fitness of self-renewing cell populations, both by causing damage to stem cells and their niche, or by altering cell developmental programs (such as for hematopoiesis). Alterations in microenvironments together with reductions in the fitness of particular stem and progenitor cell populations will then change the adaptive landscape, selecting for specific oncogenic mutations that are adaptive within this context. Focusing on the hematopoietic system and using mouse models, proposed studies will analyze the mechanisms underlying declining B-progenitor fitness in old age, and how age-associated alterations in the adaptive landscape promote selection for particular oncogenic mutations. We will 1) determine whether observed age-associated changes in B-progenitors are due to alterations in hematopoietic stem cell lineage bias, 2) ask whether manipulation of inflammation and cytokine receptor signaling in mice can impact on aging-associated reductions in hematopoietic progenitor fitness, oncogenic adaptation and leukemogenesis, and 3) dissect the molecular mechanisms underlying impaired B-lymphopoiesis and increased selection for particular oncogenes in old age. These studies should reveal important links between aging, inflammation, hematopoiesis, and leukemogenesis, and could suggest strategies to reduce cancer development with advanced age.

Public Health Relevance

While it is well known that tissue function declines and cancer incidence increases in older mice and humans, the mechanisms underlying these associations are largely unknown. Current paradigms focus on how mutations in key genes controlling cell proliferation contribute to the evolution of cancer. With the studies proposed in this application, we will investigate how the overall health of stem/progenitor cell populations and their resident tissues contributes to the prevention of malignancy. These studies should define novel links between aging, impaired hematopoiesis, and hematopoietic malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA180175-02S1
Application #
8792732
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Ogunbiyi, Peter
Project Start
2013-09-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$53,912
Indirect Cost
$19,130
Name
University of Colorado Denver
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Tippimanchai, Darinee D; Nolan, Kyle; Poczobutt, Joanna et al. (2018) Adenoviral vectors transduce alveolar macrophages in lung cancer models. Oncoimmunology 7:e1438105
DeGregori, James (2017) Connecting Cancer to Its Causes Requires Incorporation of Effects on Tissue Microenvironments. Cancer Res 77:6065-6068
Sullivan, Kelly D; Lewis, Hannah C; Hill, Amanda A et al. (2016) Trisomy 21 consistently activates the interferon response. Elife 5:
Rozhok, Andrii I; Salstrom, Jennifer L; DeGregori, James (2016) Stochastic modeling reveals an evolutionary mechanism underlying elevated rates of childhood leukemia. Proc Natl Acad Sci U S A 113:1050-5
Yadav, Vinod Kumar; DeGregori, James; De, Subhajyoti (2016) The landscape of somatic mutations in protein coding genes in apparently benign human tissues carries signatures of relaxed purifying selection. Nucleic Acids Res 44:2075-84
Rozhok, Andrii I; DeGregori, James (2016) The evolution of lifespan and age-dependent cancer risk. Trends Cancer 2:552-560
Henry, Curtis J; Casás-Selves, Matias; Kim, Jihye et al. (2015) Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors. J Clin Invest 125:4666-80
Rozhok, Andrii I; DeGregori, James (2015) Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations. Proc Natl Acad Sci U S A 112:8914-21
Fleenor, Courtney Jo; Rozhok, Andrii Ivan; Zaberezhnyy, Vadym et al. (2015) Contrasting roles for C/EBP? and Notch in irradiation-induced multipotent hematopoietic progenitor cell defects. Stem Cells 33:1345-58
Henry, Curtis J; Sedjo, Rebecca L; Rozhok, Andrii et al. (2015) Lack of significant association between serum inflammatory cytokine profiles and the presence of colorectal adenoma. BMC Cancer 15:123

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