title: Advanced Intestinal Cancers often Maintain a Multi-Ancestral Architecture.
abstract: A widely accepted paradigm in the field of cancer biology is that solid tumors are uni-ancestral being derived from a single founder and its descendants. However, data have been steadily accruing that indicate early tumors in mice and humans can have a multi-ancestral origin in which an initiated primogenitor facilitates the transformation of neighboring co-genitors. We developed a new mouse model that permits the determination of clonal architecture of intestinal tumors in vivo and ex vivo, have validated this model, and then used it to assess the clonal architecture of adenomas, intramucosal carcinomas, and invasive adenocarcinomas of the intestine. The percentage of multi-ancestral tumors did not significantly change as tumors progressed from adenomas with low-grade dysplasia [40/65 (62%)], to adenomas with high-grade dysplasia [21/37 (57%)], to intramucosal carcinomas [10/23 (43%]), to invasive adenocarcinomas [13/19 (68%)], indicating that the clone arising from the primogenitor continues to coexist with clones arising from co-genitors. Moreover, neoplastic cells from distinct clones within a multi-ancestral adenocarcinoma have even been observed to simultaneously invade into the underlying musculature [2/15 (13%)]. Thus, intratumoral heterogeneity arising early in tumor formation persists throughout tumorigenesis.
authors.affiliation: Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Zahm
authors.affiliation: Laboratory for Optical and Computational Instrumentation (LOCI), University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Laboratory of Cell and Molecular Biology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Szulczewski
authors.affiliation: Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Leystra
authors.affiliation: Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Terrah J
authors.initials: TJ
authors.lastname: Paul Olson
authors.affiliation: Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Linda
authors.initials: L
authors.lastname: Clipson
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Albrecht
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Malisa
authors.initials: M
authors.lastname: Middlebrooks
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Thliveris
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Matkowskyj
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Biostatistics and Medical Informatics and Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Newton
authors.affiliation: Laboratory for Optical and Computational Instrumentation (LOCI), University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Laboratory of Cell and Molecular Biology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Halberg
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000236:Adenoma / Q000235:genetics / Q000473:pathology*; D000818:Animals; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology*; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002999:Clone Cells / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D019143:Evolution, Molecular; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D017930:Genes, Reporter; D019426:Integrases / Q000235:genetics; D007413:Intestinal Mucosa / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology*; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009030:Mosaicism; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology*; D022661:RNA, Untranslated / Q000235:genetics; D051381:Rats; D019076:Transgenes; D059016:Tumor Microenvironment
chemical_list: C493321:Fabp1 protein, rat; D050556:Fatty Acid-Binding Proteins; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D008164:Luminescent Proteins; D022661:RNA, Untranslated; C045073:Cre recombinase; D019426:Integrases