Multi‐ancestral origin of intestinal tumors: Impact on growth, progression, and drug efficacy

Abstract

Background: Data are steadily accruing that demonstrate that intestinal tumors are frequently derived from multiple founding cells, resulting in tumors comprised of distinct ancestral clones that might cooperate or alternatively compete, thereby potentially impacting different phases of the disease process.Aim: We sought to determine whether tumors with a multi-ancestral architecture involving at least two distinct clones show increased tumor number, growth, progression, or resistance to drug intervention.Methods: Mice carrying the Min allele of Apc were generated that were mosaic with only a subset of cells in the intestinal epithelium expressing an activated form of PI3K, a key regulatory kinase affecting several important cellular processes. These cells were identifiable as they fluoresced green, whereas all other cells fluoresced red.Results: 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-ancestral 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-dose aspirin. Aspirin treatment resulted in a greater reduction of

Temporal recording of mammalian development and precancer

“…Lastly, clonal analysis and temporal recording applied to the Apc Min/+ mouse model functionally validated the possibility of polyancestral tumor initiation, to the extent that barcoded mutations can be traced back to multiple normal epithelial cell ancestors. The integrative analysis of the HTAN colorectal precancer atlas and mouse barcoding data allowed us to delineate factors that affect the earliest stages of tumor development, including clonal composition [107, 115, 116] and molecular signatures influencing the clonal fitness landscape [94, 105, 117]. Overall, our data suggests a continuum of selective pressures during tumorigenesis that modulates transition from a polyancestral composition in the early precancer stage to a monoancestral composition in the advanced cancer stage [20, 85, 94, 118].…”