Aberrant cell state plasticity mediated by developmental reprogramming precedes colorectal cancer initiation

作者全名："Bala, Pratyusha; Rennhack, Jonathan P.; Aitymbayev, Daulet; Morris, Clare; Moyer, Sydney M.; Duronio, Gina N.; Doan, Paul; Li, Zhixin; Liang, Xiaoyan; Hornick, Jason L.; Yurgelun, Matthew B.; Hahn, William C.; Sethi, Nilay S."

作者地址："[Bala, Pratyusha; Rennhack, Jonathan P.; Aitymbayev, Daulet; Morris, Clare; Moyer, Sydney M.; Duronio, Gina N.; Doan, Paul; Li, Zhixin; Yurgelun, Matthew B.; Hahn, William C.; Sethi, Nilay S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA; [Bala, Pratyusha; Rennhack, Jonathan P.; Moyer, Sydney M.; Li, Zhixin; Yurgelun, Matthew B.; Hahn, William C.; Sethi, Nilay S.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA; [Bala, Pratyusha; Rennhack, Jonathan P.; Moyer, Sydney M.; Li, Zhixin; Hornick, Jason L.; Yurgelun, Matthew B.; Hahn, William C.; Sethi, Nilay S.] Harvard Med Sch, Boston, MA 02115 USA; [Bala, Pratyusha; Rennhack, Jonathan P.; Aitymbayev, Daulet; Moyer, Sydney M.; Li, Zhixin; Hahn, William C.; Sethi, Nilay S.] Broad Inst Massachusetts Inst Technol, Cambridge, MA 02142 USA; [Bala, Pratyusha; Rennhack, Jonathan P.; Aitymbayev, Daulet; Moyer, Sydney M.; Li, Zhixin; Hahn, William C.; Sethi, Nilay S.] Harvard Univ, Cambridge, MA 02138 USA; [Yurgelun, Matthew B.] Chongqing Med Univ, Dept Gastroenterol, Affiliated Hosp 1, Chongqing, Peoples R China; [Hornick, Jason L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA USA; [Yurgelun, Matthew B.; Sethi, Nilay S.] Dana Farber Canc Inst, Dept Med Oncol, Div Gastrointestinal Oncol, Boston, MA 02115 USA"

通信作者："Sethi, NS (通讯作者)，Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Sethi, NS (通讯作者)，Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA.; Sethi, NS (通讯作者)，Harvard Med Sch, Boston, MA 02115 USA.; Sethi, NS (通讯作者)，Broad Inst Massachusetts Inst Technol, Cambridge, MA 02142 USA.; Sethi, NS (通讯作者)，Harvard Univ, Cambridge, MA 02138 USA.; Sethi, NS (通讯作者)，Dana Farber Canc Inst, Dept Med Oncol, Div Gastrointestinal Oncol, Boston, MA 02115 USA."

来源：SCIENCE ADVANCES

ESI学科分类：Multidisciplinary

WOS号：WOS:000969642900024

JCR分区：Q1

影响因子：11.7

年份：2023

卷号：9

期号：13

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Cell state plasticity is carefully regulated in adult epithelia to prevent cancer. The aberrant expansion of the normally restricted capability for cell state plasticity in neoplasia is poorly defined. Using genetically engineered and carcinogen-induced mouse models of intestinal neoplasia, we observed that impaired differentiation is a conserved event preceding cancer development. Single-cell RNA sequencing (scRNA-seq) of premalignant lesions from mouse models and a patient with hereditary polyposis revealed that cancer initiates by adopting an aberrant transcriptional state characterized by regenerative activity, marked by Ly6a (Sca-1), and reactivation of fetal intestinal genes, including Tacstd2 (Trop2). Genetic inactivation of Sox9 prevented adenoma formation, obstructed the emergence of regenerative and fetal programs, and restored multilineage differentiation by scRNA-seq. Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. These studies indicate that aberrant cell state plasticity mediated by unabated regenerative activity and developmental reprogramming precedes cancer development."

基金机构："Harvard Digestive Disease Center; NIH [P30DK034854, NIH 5 P30 CA06516]; NCI Cancer Center [K00 CA212221]; Claudia Barr Award; NIH NIDDK [K08 (DK120930)]; Virtual Scholar Award from the Department of Defense [CA201084]; philanthropic support from the Jimmy Fund Walk (Opiela Family)"

基金资助正文："We thank the Harvard Digestive Disease Center and NIH grant P30DK034854 for core services, resources, technology, and expertise. Dana-Farber/Harvard Cancer Center is supported, in part, by an NCI Cancer Center Support Grant no. NIH 5 P30 CA06516. J.P.R. is supported by NIH K00 CA212221. This work was funded by the Claudia Barr Award, NIH NIDDK K08 (DK120930), Virtual Scholar Award from the Department of Defense (CA201084) to N.S.S., and philanthropic support from the Jimmy Fund Walk (Opiela Family) and Howard and Wendy Cox to the Sethi laboratory."