PROSPECT - Stem cell models

ABSTRACT Our vision is to unravel and ultimately reverse the intricate network of causal factors throughout the life course that disrupts biological homeostasis to promote colorectal cancer (CRC) among individuals younger than age 50-years. Uniting leading scientific minds in early-onset colorectal cancer (EOCRC) research and complementary

fields, we have embraced disruptive, transdisciplinary approaches spanning cells to individuals to populations to address the core Grand Challenge to “Determine why the incidence of early-onset cancers is rising globally”. We will address specific questions of “the mechanisms linking lifetime exposures with cancer initiation and

promotion” by focusing on EOCRC as an ideal model for early-onset cancer due to the availability of well- characterized animal models and well-established and prevalent precursor lesion, the adenomatous polyp (adenoma), offering a unique opportunity for interception and prevention. Our work will transform the field by

directly addressing our overarching goal to “identify and understand the processes through which different biological and environmental factors cause early-onset cancers”, and reverse the burden in a timely, effective, feasible, inclusive fashion. Our team, both working independently and in collaboration, has uncovered several

risk factors that are likely to be drivers for the rising incidence for EOCRC. We are now uniquely positioned to translate etiologic understanding to actionable prevention by identifying novel factors, including environmental and social determinants, and deepening our understanding into overlooked dimensions of exposure throughout

the life course. The unprecedented scope and scale of our proposal can only be supported through Cancer Grand Challenges since our “high-risk” disruptive approach requires deep interactions between work packages (WP)s led by leaders in diverse disciplines. This will enable incorporation of fresh perspectives to move beyond

traditional risk-factor epidemiology toward an integrated, mechanistically-informed model with population scale and cellular resolution of the multiple and cumulative “hits” that promote EOCRC to inform the development of actionable prevention. Our innovations intersect epidemiology, small molecule discovery, genomics, stem cell

biology, immunology, and computational biology with these key features: 1) harmonization of diverse cohorts with data and biospecimens collected across the lifecourse; 2) innovative and reliable analysis of small molecules to detect novel exposures; 3) high-resolution technologies for analysis of target tissues; 4) model systems

capable of interrogating accumulating exposures across the lifespan and their impact on the cellular ecosystem; 5) prevention through risk assessment and pharmacologic/lifestyle interventions. Collectively, our work will serve as an exemplar for transforming research into other early-onset cancers.