Principal Investigator

Bruce Marc
Awardee Organization

University Of Chicago
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

CXCR4 as a target for colon cancer chemoprevention

The risk of colorectal cancer (CRC) is substantially higher in populations consuming Western diets (WDs) and animal models confirm this association. WD-induced tumor promotion requires epidermal growth factor receptor (EGFR) signals that are driven by increased EGFR ligands. EGFR ligand release is controlled by proteinase ADAM17. Colonocyte deletion or pharmacological blockade of ADAM17 suppressed tumorigenesis. Chemokine receptor CXCR4 is expressed on colonocytes up-regulated with cancer progression and can activate ADAM17. The role of CXCR4 in diet-promoted tumorigenesis has not been elucidated. We found that WD up-regulated both CXCR4 and its ligand Sdf1α (aka CXCL12) in colonic mucosa. Together, these data suggest that CXCR4 is a targetable upstream regulator of WD-promoted tumor development by signaling transactivated colon cancer cell EGFR via an ADAM17-dependent mechanism. While CXCR4 is rarely mutated in cancer, its expression is up-regulated by transcription factors (TFs) and epigenetic changes, further evidence that factors such as diet regulate its activity. In preliminary studies, MSX-122, a CXCR4 inhibitor well tolerated in clinical trials, reduced colon tumor incidence by nearly 70% in azoxymethane (AOM)-treated Apc+/Min mice. Moreover, mice deleted of colonocyte CXCR4 developed fewer tumors than CXCR4+/+ mice on an Apc-deficient background. We hypothesize that CXCR4 is required for WD-promoted tumorigenesis, and that natural product (NP) inhibition of CXCR4 is a promising chemopreventative strategy. Studies that dissect CXCR4 regulation and effector signals and identify novel NP inhibitors could converge to uncover new targets for CRC prevention. To study the role of CXCR4 in tumor promotion by WDs and identify novel inhibitors, we propose three specific aims: Aim 1 To determine if CXCR4 activity is required for WD-promoted tumorigenesis. 1a)To assess the ability of CXCR4 inhibitor MSX-122 to suppress AOM tumorigenesis. We will compare MSX effects in Std diet and WD in premalignant and malignant phases and assess effector signals by RNAseq and EGFR activation. 1b) To genetically assess the role of CXCR4 in CRC, comparing colonocyte null CXCR4Δ/Δ mice to CXCR4+/Δ and CXCR4+/+ mice (all on Apc deficient background) and measure end points described in aim 1a. Aim 2a: To determine effects WD and neoplastic progression on TFs and histone modifications regulating Sdf1α and CXCR4 locally using ChIP assays and assess global effects of diet and tumorigenesis using chromatin ATAC-seq and DNA methylation by nano-5hmC-seal using organoids from conditional Apc-CXCR4 model. 5mC and 5hmC signals discovered globally, for example, regulate local histone modifications. 2b) To assess Sdf1αCXCR4 gene regulation and effector signals in human colonic tumorigenesis using organoids as in 2a. Aim 3a To screen NP libraries for CXCR4 inhibitory activity. CXCR4 reporter assays (Ca2+ transients, migration assays and ligand-binding) will be used to confirm computationally predicted NP hits 3b Promising agents identified in aim3a will be prioritized and tested for chemopreventive efficacy in mouse models.


  • Souris JS, Leoni L, Zhang HJ, Pan A, Tanios E, Tsai HM, Balyasnikova IV, Bissonnette M, Chen CT. X-ray Activated Nanoplatforms for Deep Tissue Photodynamic Therapy. Nanomaterials (Basel, Switzerland). 2023 Feb 9;13. (4). PMID: 36839041
  • Stuckel AJ, Khare T, Bissonnette M, Khare S. Aberrant regulation of CXCR4 in cancer via deviant microRNA-targeted interactions. Epigenetics. 2022 Dec;17(13):2318-2331. Epub 2022 Sep 6. PMID: 36047714
  • Pekow J, Hernandez K, Meckel K, Deng Z, Haider HI, Khalil A, Zhang C, Talisila N, Siva S, Jasmine F, Li YC, Rubin DT, Hyman N, Bissonnette M, Weber C, Kibriya MG. IBD-associated Colon Cancers Differ in DNA Methylation and Gene Expression Profiles Compared With Sporadic Colon Cancers. Journal of Crohn's & colitis. 2019 Jul 25;13(7):884-893. PMID: 30753380
  • Stuckel AJ, Zhang W, Zhang X, Zeng S, Dougherty U, Mustafi R, Zhang Q, Perreand E, Khare T, Joshi T, West-Szymanski DC, Bissonnette M, Khare S. Enhanced CXCR4 Expression Associates with Increased Gene Body 5-Hydroxymethylcytosine Modification but not Decreased Promoter Methylation in Colorectal Cancer. Cancers. 2020 Feb 26;12. (3). PMID: 32110952
  • Stuckel AJ, Zeng S, Lyu Z, Zhang W, Zhang X, Dougherty U, Mustafi R, Zhang Q, Joshi T, Bissonnette M, Choudhury SR, Khare S. Epigenetic DNA Modifications Upregulate SPRY2 in Human Colorectal Cancers. Cells. 2021 Oct 2;10. (10). PMID: 34685612
  • Souris JS, Zhang HJ, Dougherty U, Chen NT, Waller JV, Lo LW, Hart J, Chen CT, Bissonnette M. A novel mouse model of sporadic colon cancer induced by combination of conditional Apc genes and chemical carcinogen in the absence of Cre recombinase. Carcinogenesis. 2019 Nov 25;40(11):1376-1386. PMID: 30859181
  • Stuckel AJ, Zeng S, Lyu Z, Zhang W, Zhang X, Dougherty U, Mustafi R, Khare T, Zhang Q, Joshi T, Bissonnette M, Khare S. Sprouty4 is epigenetically upregulated in human colorectal cancer. Epigenetics. 2023 Dec;18(1):2145068. Epub 2022 Nov 16. PMID: 36384366
  • Khare T, Bissonnette M, Khare S. CXCL12-CXCR4/CXCR7 Axis in Colorectal Cancer: Therapeutic Target in Preclinical and Clinical Studies. International journal of molecular sciences. 2021 Jul 9;22. (14). PMID: 34298991
  • Zhang R, Chen D, Fan H, Wu R, Tu J, Zhang FQ, Wang M, Zheng H, Qu CK, Elf SE, Faubert B, He YY, Bissonnette MB, Gao X, DeBerardinis RJ, Chen J. Cellular signals converge at the NOX2-SHP-2 axis to induce reductive carboxylation in cancer cells. Cell chemical biology. 2022 Jul 21;29(7):1200-1208.e6. Epub 2022 Apr 15. PMID: 35429459
  • Cui XL, Nie J, Ku J, Dougherty U, West-Szymanski DC, Collin F, Ellison CK, Sieh L, Ning Y, Deng Z, Zhao CWT, Bergamaschi A, Pekow J, Wei J, Beadell AV, Zhang Z, Sharma G, Talwar R, Arensdorf P, Karpus J, Goel A, Bissonnette M, Zhang W, Levy S, He C. A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation. Nature communications. 2020 Dec 2;11(1):6161. PMID: 33268789