Reference SummaryDeStefano Shields CE, Cancer Discov 2021 Feb 25;():

Title

 Bacterial-Driven Inflammation and Mutant BRAF Expression Combine to Promote Murine Colon Tumorigenesis That Is Sensitive to Immune Checkpoint Therapy.

Authors

 DeStefano Shields CE; White JR; Chung L; Wenzel A; Hicks JL; Tam AJ; Chan JL; Dejea CM; Fan H; Michel J; Maiuri AR; Sriramkumar S; Podicheti R; Rusch DB; Wang H; De Marzo AM; Besharati S; Anders RA; Baylin SB; O'Hagan HM; Housseau F; Sears CL

Journal

 Cancer Discov

Volume

Issue

Year

 2021

Pages

Abstract

 Colorectal cancer is multifaceted, with subtypes defined by genetic, histologic, and immunologic features that are potentially influenced by inflammation, mutagens, and/or microbiota. Colorectal cancers with activating mutations in BRAF are associated with distinct clinical characteristics, although the pathogenesis is not well understood. The Wnt-driven multiple intestinal neoplasia (Min(ApcDelta716/+)) enterotoxigenic Bacteroides fragilis (ETBF) murine model is characterized by IL17-dependent, distal colon adenomas. Herein, we report that the addition of the BRAF (V600E) mutation to this model results in the emergence of a distinct locus of midcolon tumors. In ETBF-colonized BRAF (V600E) Lgr5 (Cre)Min (BLM) mice, tumors have similarities to human BRAF (V600E) tumors, including histology, CpG island DNA hypermethylation, and immune signatures. In comparison to Min ETBF tumors, BLM ETBF tumors are infiltrated by CD8(+) T cells, express IFNgamma signatures, and are sensitive to anti-PD-L1 treatment. These results provide direct evidence for critical roles of host genetic and microbiota interactions in colorectal cancer pathogenesis and sensitivity to immunotherapy. SIGNIFICANCE: Colorectal cancers with BRAF mutations have distinct characteristics. We present evidence of specific colorectal cancer gene-microbial interactions in which colonization with toxigenic bacteria drives tumorigenesis in BRAF (V600E) Lgr5 (Cre)Min mice, wherein tumors phenocopy aspects of human BRAF-mutated tumors and have a distinct IFNgamma-dominant immune microenvironment uniquely responsive to immune checkpoint blockade.

Links

 J:307164 – MGI References
33632774 – National Library of Medicine/PubMed

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon - Distal tumor
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon - Distal

72.97 - 100
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon - Distal tumor
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon - Distal

82.93 - 100
C57BL/6-Apctm1Mmt/+ Krastm4Tyj/+ Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon - Distal tumor
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon - Distal

55.56 - 100
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon - Distal tumor Intestine - Large Intestine - Colon - Distal

very low
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon - Distal tumor Intestine - Large Intestine - Colon - Distal

very low
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon - Distal tumor
  • Bacteroides fragilis
  • anti-PD-L1 (Cd274)
 Intestine - Large Intestine - Colon - Distal

100
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon - Distal tumor
  • Bacteroides fragilis
  • anti-PD-L1 (Cd274)
 Intestine - Large Intestine - Colon - Distal

100
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon - Proximal tumor
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon - Proximal

0 - 100
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon - Proximal tumor
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon - Proximal

9.76 - 97.56
C57BL/6-Apctm1Mmt/+ Krastm4Tyj/+ Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon - Proximal tumor
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon - Proximal

11.11 - 33.33
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon - Proximal tumor
  • Bacteroides fragilis
  • anti-PD-L1 (Cd274)
 Intestine - Large Intestine - Colon - Proximal

100
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon - Proximal tumor
  • Bacteroides fragilis
  • anti-PD-L1 (Cd274)
 Intestine - Large Intestine - Colon - Proximal

71.43
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon adenoma
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

observed
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon adenoma
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

observed
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon adenoma - microadenoma
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

58.33
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon adenoma - microadenoma
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

86.67
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon adenoma - microadenoma Intestine - Large Intestine - Colon

very low
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon adenoma - microadenoma Intestine - Large Intestine - Colon

very low
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon adenoma - tubular
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

observed
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon adenoma - tubular
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

observed
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon adenoma - villous
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

observed
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon dysplasia
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

observed
C57BL/6J Intestine - Large Intestine - Colon tumor
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

0
C57BL/6-Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon tumor
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

0
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon tumor
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

observed - 100
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon tumor
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

observed - 100
C57BL/6-Apctm1Mmt/+ Krastm4Tyj/+ Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon tumor
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

77.78
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

very low
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

very low
C57BL/6-Apctm1Mmt/+ Intestine - Large Intestine - Colon tumor
  • Bacteroides fragilis
  • anti-PD-L1 (Cd274)
 Intestine - Large Intestine - Colon

100
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon tumor
  • Bacteroides fragilis
  • anti-PD-L1 (Cd274)
 Intestine - Large Intestine - Colon

100
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon tumor - serrated
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

observed
C57BL/6-Apctm1Mmt/+ Braftm1Mmcm/+Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon tumor - sessile
  • Bacteroides fragilis
 Intestine - Large Intestine - Colon

observed