Reference SummaryBoutin AT, Genes Dev 2017 Feb 15;31(4):370-382

Title

Oncogenic Kras drives invasion and maintains metastases in colorectal cancer.

Authors

Boutin AT; Liao WT; Wang M; Hwang SS; Karpinets TV; Cheung H; Chu GC; Jiang S; Hu J; Chang K; Vilar E; Song X; Zhang J; Kopetz S; Futreal A; Wang YA; Kwong LN; DePinho RA

Journal

Genes Dev

Volume

31

Issue

4

Year

2017

Pages

370-382

Abstract

Human colorectal cancer (CRC) is a major cause of cancer mortality and frequently harbors activating mutations in the KRAS gene. To understand the role of oncogenic KRAS in CRC, we engineered a mouse model of metastatic CRC that harbors an inducible oncogenic Kras allele (Krasmut ) and conditional null alleles of Apc and Trp53 (iKAP). The iKAP model recapitulates tumor progression from adenoma through metastases. Whole-exome sequencing revealed that the Krasmut allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated Krasmut signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-beta pathway as a key mediator of Krasmut -driven invasiveness. Genetic extinction of Krasmut resulted in specific elimination of the Krasmut subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease. This faithful CRC model provides genetic evidence that Krasmut drives CRC invasion and maintenance of metastases.

Links

J:242160 – Mouse Genome Informatics
28289141 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine - Colon tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Large Intestine - Colon

observed

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine - Colon tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Large Intestine - Colon

observed

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine adenoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Large Intestine

27

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine adenoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Large Intestine

34

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine adenoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Intestine - Large Intestine

57

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn/+ Intestine - Large Intestine adenoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Large Intestine

64

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine adenoma
  • doxycycline
Intestine - Large Intestine

0

C57BL/6-Apctm2Rak/+ Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine adenoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Large Intestine

0

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Trp53tm1Brn Intestine - Large Intestine adenoma
  • 4-hydroxytamoxifen (4-OHT)
  • doxycycline
Intestine - Large Intestine

0

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Large Intestine

63.84

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
(Unspecified organ)

16

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine tumor
  • doxycycline
(Unspecified organ)

16

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Large Intestine

60.34

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Intestine - Large Intestine

85.07

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn/+ Intestine - Large Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Large Intestine

72.73

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine tumor
  • doxycycline
Intestine - Large Intestine

0

C57BL/6-Apctm2Rak/+ Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Large Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Large Intestine

5.77

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Trp53tm1Brn Intestine - Large Intestine tumor
  • 4-hydroxytamoxifen (4-OHT)
  • doxycycline
Intestine - Large Intestine

0

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Small Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Small Intestine

10.98

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Small Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Small Intestine

5.17

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Small Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Intestine - Small Intestine

0

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn/+ Intestine - Small Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Small Intestine

0

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Small Intestine tumor
  • doxycycline
Intestine - Small Intestine

13.33

C57BL/6-Apctm2Rak/+ Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine - Small Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine - Small Intestine

1.92

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Trp53tm1Brn Intestine - Small Intestine tumor
  • 4-hydroxytamoxifen (4-OHT)
  • doxycycline
Intestine - Small Intestine

0

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine adenocarcinoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

observed - 26

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine adenocarcinoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

0 - 73.68

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine adenocarcinoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Intestine

28

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn/+ Intestine adenocarcinoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

9

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine adenocarcinoma
  • doxycycline
Intestine

0

C57BL/6-Apctm2Rak/+ Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine adenocarcinoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

7.6

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Trp53tm1Brn Intestine adenocarcinoma
  • 4-hydroxytamoxifen (4-OHT)
  • doxycycline
Intestine

0

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine adenocarcinoma - moderately differentiated
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

observed

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine adenocarcinoma - moderately differentiated
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

observed

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine adenocarcinoma - poorly differentiated
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

observed

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine adenocarcinoma - poorly differentiated
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

observed

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine adenoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

observed

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine adenoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

0 - observed

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

observed - 65.52

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

0 - 74.83

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Intestine

85.07

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn/+ Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

observed - 72.73

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine tumor
  • doxycycline
Intestine

13.33

C57BL/6-Apctm2Rak/+ Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Tg(Vil1-cre/ERT2)23Syr Trp53tm1Brn Intestine tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
  • doxycycline
Intestine

observed - 7.69

C57BL/6-Apctm2Rak Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy Tg(tetO-Kras*G12D)#Rdp Trp53tm1Brn Intestine tumor
  • 4-hydroxytamoxifen (4-OHT)
  • doxycycline
Intestine

0

C57BL/6 Intestine tumor
  • 4-hydroxytamoxifen (4-OHT)
  • doxycycline
Intestine

observed