AbstractERBB4 is commonly over-expressed in human CRC, however the utility of ERBB4 as a target for colorectal cancer (CRC) therapeutics is largely unexplored. Our group recently identified a molecular subtype of CRC that arises independent of EGFR and displays a more aggressive growth phenotype than those dependent on EGFR. The robust growth phenotype of EGFR-independent tumors can be in part attributed to upregulation of IL10 signaling. In addition, EGFR-independent tumors display a significant upregulation of Erbb2 and Erbb4 transcripts in both spontaneous and sporadic CRC mouse models, perhaps compensating for the loss of EGFR. To investigate the importance of other ERBB receptors in EGFR-independent CRC tumor progression, we ablated Erbb4 to interrogate its influence on tumor development in vivo using a conditional allele of Erbb4tm1Fej (Erbb4f). ERBB4-deficient ApcMin/+ mice (ApcMin/+, ErbB4f/f, Tg(Vil1-Cre)) were established and used to show that ERBB4 ablation in the intestinal epithelia results in a significant decrease in the number of intestinal and colon tumors. Polyps lacking ERBB4 were also significantly reduced size, contrary to what is observed with loss of EGFR. We also recently developed ERBB2-deficient ApcMin/+ mice, and preliminary results suggest that Erbb2 ablation also results in a decrease in intestinal and colon tumor number and size. Consistent with data from EGFR-independent tumors, transcriptomic analysis of ERBB4-deficient intestinal tumors predicted down-regulation of IL10 signaling, which was validated through Il10 and Socs3 qPCR. To complement our findings, the observed down-regulation of Il10 and Socs3 at the transcript level corresponded with a significant decrease in IL10 levels in the serum of mice harboring ERBB4 deficient tumors when compared to mice without tumors. Furthermore, we found that transcript levels of Erbb4 significantly decreased after anti-IL10 treatment of EGFR-independent tumors in vivo. This illustrates a possible negative feedback loop whereby neutralizing IL10 also leads to a reduction of Erbb4 expression, further reducing IL10 signaling. Taken together, the data suggest that the absence of EGFR triggers Erbb4 upregulation, implicating an important role for ERBB4 in EGFR-independent colon tumor growth. These results suggest that therapeutic targeting of ERBB4 may lead to a reduction in IL10 signaling and reduced intestinal polyp multiplicity and size in EGFR-independent tumors and inform the development of novel approaches to treat CRC that exhibit aberrant expression of EGFR and ERBB4.Citation Format: Michael P. McGill, Carolina Mantilla Rojas, David W. Threadgill. ERBB4 mediates IL10-induced growth of EGFR-independent colon tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 819.
