Although Stat3 is a recognised driver of inflammation-associated cancers, including those of the stomach, and is associated with increased expression of Myc (Ernst et al., Seminar Immunol 2014), no Stat3-specific therapeutics are available in the clinic. On the other hand, Myc is a non-redundant transcriptional effector of multiple oncogenic signalling pathways. However, the extent by which Myc also plays a non-redundant role in the progression of intestinal-type gastric cancers driven by excessive cytokine-dependent Stat3 activity remains unknown.

We used the Gp130F/F mouse strain as a clinically relevant model of spontaneously occurring inflammation-associated gastric cancer owing to excessive Gp130 cytokine family-dependent activation of Stat3 (Eissmann et al., Nature Comms 2019). We ablated Myc in tumour-bearing compound mutant Gp130F/F;Myc(flox) mice, which also harboured a tamoxifen-inducible Cre under the transcriptional control of either the Tff1 or the gpA33 locus to limit recombinase activity to the gastric epithelium (Thiem et al, Cancer Res 2016; Stuart et al, Mol Cancer Ther 2014). We used RNAseq analysis and compared transcriptomes between unaffected stomachs in wild-type mice with transcriptomes of Myc-proficient and of Myc-deleted gastric tumours collected from Gp130F/F;myc(flox) mice.

We demonstrate that conditional Myc ablation in Tff1-expressing foveolar, mitotic and mucous cells, or in gpA33-expressing enterocytes of established gastric tumours, markedly attenuated tumour growth in Gp130F/F;myc(flox) mice, where cancers occur in response to excessive interleukin (IL)11-dependent Stat3 activity. Likewise, Myc inhibition using the Brd4-antagonist iBET-151 reduced the number of Ki67+ proliferating tumour cells and conferred therapeutic benefits to tumour-bearing Gp130F/F mice. Meanwhile, the converse transgenic over-expression of Myc alone in Tff1-positive cells was sufficient to induce tumours in wild-type mice. Transcriptomic analysis revealed that Myc depletion in Tff1-expressing cells reduced expression of genes involved in cell proliferation and metabolism, and enhanced interferon responses in Tff1-negative cells of the tumour microenvironment. Contrasting these Myc-dependent responses, Stat3 promoted metaplastic transformation as well as engagement of IL11 and other cytokine pathways independently of Myc.

Our observations suggest that partitioning of Stat3 responses into their Myc dependencies informs about the suitability of emerging Myc-antagonists to control Stat3-driven tumors that lack current clinical alternatives to specifically inhibit Stat3.