In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2381-2381
Abstract:
Background: Intratumoral heterogeneity has been linked to tumor progression and chemotherapy resistance in the clinic. Recent models of colorectal tumor evolution indicate that heterogeneity likely arises early during the first few cell divisions and is maintained in a non-Darwinian fashion with discrete clones coevolving. However, how this heterogeneity arises is not fully understood. We propose that some cancers are derived from multiple unique ancestors, and that discrete clones enhance establishment, growth, progression, and resistance to therapy. Methods: Mice carrying the Min allele of Apc and expressing a constitutively active form of PI3K in a subset of colonic epithelial cells develop multiple adenomas and adenocarcinomas in the colon. Cell lineage tracing and fluorescent endoscopy were used to follow the progeny of individual founding cells through establishment, growth, progression, and response to targeted therapy. Cell sorting and 3D tumor spheroid co-culture were used to further examine the growth behavior and treatment response in vitro. Results: Nearly half (44%; 30/68) of the tumors were derived from at least two ancestral clones. The presence of multiple clones was associated with an increased likelihood of a tumor becoming invasive (p = 0.006). Moreover, each clone was more invasive within multi-ancestral tumors than within their homotypic counterparts, indicating that the increased invasion is shared among clones rather than owing to a single dominant clone (p = 0.05). Additionally, the presence of both clones appeared to protect susceptible clones from targeted therapy. In vitro experiments demonstrated that co-evolved clones adopted similar growth patterns, whereas independently evolved clones did not. Conclusions: Taken together, these data strongly indicate that distinct tumor founding cells and their coevolving progeny can contribute to tumor establishment and moreover can enhance growth and survival during tumor progression and response to therapy. Citation Format: Alyssa A. Leystra, Brook Luers, Junbo Son, Chelsie K. Sievers, Amanda M. Wisinger, Alexander R. Schwartz, Christopher D. Zahm, Kristina A. Matkowskyj, Dawn M. Albrecht, Linda Clipson, Dustin A. Deming, Michael A. Newton, Richard B. Halberg. A multiancestral model of colorectal cancer: in vivo evidence that early heterogeneity contributes to cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2381.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2016-2381
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
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