Neutrophil extracellular traps induced by chemotherapy inhibit tumor growth in murine models of colorectal cancer
Yamu Li, … , David Bajor, Zhenghe Wang
Yamu Li, … , David Bajor, Zhenghe Wang
Published January 9, 2024
Citation Information: J Clin Invest. 2024;134(5):e175031. https://doi.org/10.1172/JCI175031.
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Neutrophil extracellular traps induced by chemotherapy inhibit tumor growth in murine models of colorectal cancer

Abstract

Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill cancer cells is unexplored. Here, we report that a combination of glutaminase inhibitor CB-839 and 5-FU inhibited the growth of PIK3CA-mutant colorectal cancers (CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRCs attenuated the efficacy of the drug combination. Moreover, NETs were present in tumor biopsies from patients treated with the drug combination in a phase II clinical trial. Increased NET levels in tumors were associated with longer progression-free survival. Mechanistically, the drug combination induced the expression of IL-8 preferentially in PIK3CA-mutant CRCs to attract neutrophils into the tumors. Further, the drug combination increased the levels of ROS in neutrophils, thereby inducing NETs. Cathepsin G (CTSG), a serine protease localized in NETs, entered CRC cells through the RAGE cell surface protein. The internalized CTSG cleaved 14-3-3 proteins, released BAX, and triggered apoptosis in CRC cells. Thus, our studies illuminate a previously unrecognized mechanism by which chemotherapy-induced NETs kill cancer cells.

Authors

Yamu Li, Sulin Wu, Yiqing Zhao, Trang Dinh, Dongxu Jiang, J. Eva Selfridge, George Myers, Yuxiang Wang, Xuan Zhao, Suzanne Tomchuck, George Dubyak, Richard T. Lee, Bassam Estfan, Marc Shapiro, Suneel Kamath, Amr Mohamed, Stanley Ching-Cheng Huang, Alex Y. Huang, Ronald Conlon, Smitha Krishnamurthi, Jennifer Eads, Joseph E. Willis, Alok A. Khorana, David Bajor, Zhenghe Wang

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Figure 7

The combination of CB-839 and 5-FU induces NETs in syngeneic and GEM PIK3CA-mutant tumor models.

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The combination of CB-839 and 5-FU induces NETs in syngeneic and GEM PIK...
(A and B) CMT93 Pik3ca WT or E545 K mutant tumors were treated with indicated drugs, with growth curves shown in A for CMT93 Pik3ca WT and (B) for CMT93 Pik3ca E545K mutant. (5 mice/group). (C–E) The indicated tumors were stained with antibodies against MPO and H3cit. Representative images are shown in C. Quantifications shown in D and E (n = 15/group). (F and G) MC38 Pik3ca WT or mutant tumors with indicated treatment, growth curve shown in F for MC38 Pik3ca WT, G for MC38 PIK3CA mutant (5 mice/group). (H–J) The indicated tumors were stained with antibodies against MPO and H3cit. Representative images are shown in H. Quantifications shown in I and J (n = 15/group). (K) CDX2P-CreERT2 Apcfl/+ KrasLSL–G12D/+ Pik3caLSL–H1047R/+ mice were treated with tamoxifen and then treated with the indicated drug a week after tamoxifen treatment for 4 weeks. Kalplan-Meier curves of the mice are shown. A log-rank test was used to assess the statistical significance between the vehicle and the combination of CB-839 and 5-FU treatment groups. (L–N) CDX2P-CreERT2 Apcfl/+ KrasLSL–G12D/+ Pik3caLSL–H1047R/+ mice were treated with tamoxifen, and 4 weeks later, the mice were treated with the indicated drugs, and colon tumors were harvested and stained with antibodies against MPO and H3cit (3 mice/group). Representative images are shown in L. Quantifications of MPO are shown in M. Quantifications of H3cit are shown in N (n = 15/group). 2-way ANOVA (A, B, D–G, I and J) or 1-way ANOVA (N) was used for statistical analysis. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Scale bar: 50 μm.