Tumor suppression by modulating stem cell fitness. James DeGregori University of Colorado Denver School of Medicine

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1 Tumor suppression by modulating stem cell fitness James DeGregori University of Colorado Denver School of Medicine

2 Natural Selection can explain cancer incidence at the species level Intrinsic TS Integral TS Age Ø The evolution of long-lived multicellular animals required the selection for potent tumor suppressive mechanisms. Ø There is minimal selection against cancer beyond the age where most animals would already be dead by other causes. Ø Better tumor suppression would require additional energy in early life, which would come with a cost.

3 Conventional View é Number of oncogenic mutations Cancer Adaptive Oncogenesis Model Healthy, Young Low Environmental Insult; Aging ê Cell Fitness, Altered Microenvironment Fitness é Selection for adaptive mutations Cancer High

4 High stem cell pool fitness is tumor suppressive Malignant genotypes D Malignant genotypes WT genotype Fitness WT genotype Young, healthy stem cell pool D Old or damaged stem cell pool D DeGregori, J. (2011). Evolved tumor suppression: why are we so good at not getting cancer? Cancer Research, 71:

5 Model for how vertebrates with large differences in somatic cell numbers and lifespans similarly avoid cancer through reproductive years. Increased risk of somatic evolution in larger animals Decreased risk of somatic evolution in larger animals Is the effective population size for SCs bigger in bigger animals? SC number/tissue: target size for oncogenic hits Lifespan (time available to accumulate mutations) Buffering capacity of tissue to maintain fitness Chance of mutation fixation by drift Ability of a fit stem cell pool to impede somatic cell evolution

6 Why does cancer increase with age? Accumula'on of oncogenic muta'ons. Changes in cellular microenvironment. Chronic inflamma'on. Decreased immune surveillance. Does reduc*on of cellular fitness lead to selec*on for specific adap*ve oncogenic muta*ons?

7 Signaling in B- progenitors Declines with Age Henry et. al; PNAS; December 14, 2010 vol. 107 no

8 Bcr- Abl Becomes Adap*ve in Aged Backgrounds by Allevia*ng Aging- Associated Signaling Defects Henry et. al; PNAS; December 14, 2010 vol. 107 no

9 Ø Signaling defects in old B-progenitors contribute to reduced fitness (as determined using competitive transplantation assays. Ø Bcr-Abl restores signaling, promoting selection for Bcr-Abl expression. Ø Selection for Bcr-Abl within old B-progenitor pools leads to increased leukemogenesis. Henry et. al; PNAS; December 14, 2010 vol. 107 no

10 What else underlies fitness defects in old B-progenitors?

11 Anabolic and catabolic pathways decrease in old B-progenitors

12 Aging is not a program but programs can mediate aging and aging can be deprogrammed.

13 Old B Cell Progenitors Exhibit Metabolic Defects 1.0 TCA Cycle Intermediates Energy Lactate TCA p=0.01 p=0.018 p=0.032 n.s. p= p= Rela*ve Amount Citrate Y Citrate O Glutamine Y Glutamine O Glutamate Y Glutamate O 0.0 Adenosines Y Adenosines O Creatine Y Creatine O 0.0 Lactate Y Lactate O

14 ATP Levels are Decreased in Old B cell Progenitors Relative to Young Ones 80 p< Relative ATP amount Young Y B220 B cell Progenitors Old O B220 Young Myeloid Cells Old

15 Model for Bcr-Abl Adaptation in an Aged Background Young B cell Progenitors Old B cell Progenitors Old B cell Progenitors + Bcr- Abl anabolism anabolism

16 A. Predominant Model Aging Accumula'on of deleterious muta'ons Accumula'on of oncogenic muta'ons Decline in progenitor cell fitness and 'ssue func'on Cancer B. Adap've Oncogenesis Model Aging Accumula'on of deleterious muta'ons, epigene'c changes & microenvironmental perturba'ons Accumula'on of oncogenic muta'ons Decline in progenitor cell fitness and 'ssue func'on Increased selec'on for adap$ve oncogenic muta'ons Cancer

17 2.5-5Gy Previous Irradiation (IR P ) 2 months IR P IR P Number of Lin neg Sca1 + Cells Day7 # Lin neg Sca1 +

18 Prior irradiation and HSC fitness Previously irradiated HSC exhibit maintenance defects that are specific, reproducible, somatically heritable, and reversible. Evolved to deal with the occasionally damaged cell? Programmed Mediocrity? Occasional Damaged Cell Will be weeded out Total Body Irradiation

19 Hmmm. Could programmed mediocrity be a mechanism to maintain tissue fitness in youth, but which contributes to tissue decline in old age?

20 THE LAB Francesca Alvarez-Calderon Mark Gregory *Courtney Fleenor *Curtis Henry Vadym Zaberezhnyy *Matias Casas Selves Rodrigo Maegawa *Biniam Adane THE $$$ NCI/NIA Flow Cytometry Karen Helm Christine Childs Former: *Andriy Marusyk Other Natalie Serkova Andrea Mertz Art work: Michael and Gayle DeGregori

21 So why do kids get cancer? 1) Given expansion of progenitor populations, a mutation can more easily become fixed even if not advantageous. 2) More recent evolution has substantially altered the human brain and immune systems, and a low risk of childhood leukemias affecting these tissues has been a tradeoff (although advantages of a more developed brain and better immune system outweighed the low leukemia risk). 3) There are dietary and genetic factors which correlate with reduced folate and/or reduced dntp synthesis, which may reduce progenitor fitness, and thus may contribute to childhood cancers. 4) Our immune systems did not evolve to deal with modern conditions, but to conditions with more antigen and pathogen exposures early in life. Thus, our hematopoietic systems are not truly adapted to modern life. 5) Translocations common to childhood leukemias are more likely to occur in fetal or childhood development.