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These cells were identifiable as they fluoresced green, whereas all other cells fluoresced red.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cell lineage tracing revealed that many intestinal tumors from our mouse model were derived from at least two founding cells, those expressing the activated PI3K (green) and those which did not (red). Heterotypic tumors with a multi\u2010ancestral architecture as evidenced by a mixture of green and red cells exhibited increased tumor growth and invasiveness. Clonal architecture also had an impact on tumor response to low\u2010dose aspirin. Aspirin treatment resulted in a greater reduction of heterotypic tumors derived from multiple founding cells as compared to tumors derived from a single founding cell.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data indicate that genetically distinct tumor\u2010founding cells can contribute to early intratumoral heterogeneity. The coevolution of the founding cells and their progeny enhances colon tumor progression and impacts the response to aspirin. These findings are important to a more complete understanding of tumorigenesis with consequences for several distinct models of tumor evolution. They also have practical implications to the clinic. Mouse models with heterogenous tumors are likely better for predicting drug efficacy as compared to models in which the tumors are highly homogeneous. Moreover, understanding how interactions among different populations in a single heterotypic tumor with a multi\u2010ancestral architecture impact response to a single agent and combination therapies are necessary to fully develop personalized medicine.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cnr2.1459","type":"journal-article","created":{"date-parts":[[2021,7,10]],"date-time":"2021-07-10T08:51:47Z","timestamp":1625907107000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Multi\u2010ancestral origin of intestinal tumors: Impact on growth, progression, and drug efficacy"],"prefix":"10.1002","volume":"5","author":[{"given":"Alyssa A.","family":"Leystra","sequence":"first","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology University of Wisconsin\u2010Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Division of Gastroenterology and Hepatology University 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