Myc heals all (tumor) wounds

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Science Translational Medicine  13 Dec 2017:
Vol. 9, Issue 420, eaar4434
DOI: 10.1126/scitranslmed.aar4434


The activation of Myc in Ras-driven lung adenomas causes profound immune/stromal remodeling to support tumor growth.

In the world of cancer biology, no two oncogenes elicit more interest, research effort, and even raw emotion than Myc and Ras. The activation of one or both of these quintessential oncogenes is found in a majority of solid tumors and is responsible for carrying out a variety of cancer-defining tasks. These include driving mitogenic signaling, biosynthesis and proliferation, migration, invasion and metastasis, as well as angiogenesis and suppression of apoptosis. Importantly, these oncogenes have been previously shown to cooperate by driving cell cycle proteins and attenuating each other’s few drawbacks (Ras suppresses Myc-driven apoptosis while Myc prevents Ras-driven senescence). They are, essentially, a perfect pair, and it’s no surprise that they are frequently activated in the same tumors.

In a thought-provoking study from Gerard Evan’s group, a critical benefit of the cooperation between Myc and Ras has been discovered: an active reprogramming of a tumor’s microenvironment to suppress immune surveillance. The key findings are based on the use of a switchable Myc mouse model to explore short- and long-term effects of Myc deregulation in Ras-driven lung adenomas. Kortlever et al. reported that, within 24 hours of Myc activation, the chemokine CCL9 was detected in lung tissue and drove the recruitment of proangiogenic macrophages. In addition, an increase in interleukin-23 (IL-23) secretion directly caused the expulsion of tumor-killing natural killer cells. These two factors profoundly facilitated tumor growth and, remarkably, blocking them was effective at controlling the tumor. This study showed that the stromal changes that occur upon Myc activation mimic those seen during typical wound healing; there is initial clearance of damaged cells and debris by recruited macrophages followed by immunosuppression during tissue regeneration, in which Myc is in this case orchestrating the regenerative healing of a wound (tumor) to the detriment of the host. Although this is not an entirely new concept, the work done here does demonstrate oncogene-driven dysregulation of physiological processes for a cancer cell’s benefit and the potential for modulating this process therapeutically.

Several key questions remain, yet none seem as important as understanding how Myc deregulation directly modulates CCL9 and IL-23 secretion. It is likely that the mechanism is related to the underlying Ras signaling and enabled by Myc expression, but this requires further exploration. In addition, although blocking CCL9 and IL-23 was effective at controlling tumor growth in this cooperative model, it is unclear whether inhibiting these factors in human tumors could become an effective treatment. Regardless, these important views into Myc and Ras biology will be vital to ongoing efforts to understand these infamous oncogenes and target them therapeutically.

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