Oncogenic KRAS Promotes Extracellular DNA Clearance to Drive Immunosuppression in Colorectal Cancer.

Abstract

Cellular turnover and death result in shedding of DNA into the extracellular space. In the context of cancer, the constant turnover of cancer cells leads to the release of tumor-derived DNA (tDNA) into the circulation. Circulating tDNA (ctDNA) provides molecular insights into the genetic alterations present within cancer cells, which has been exploited to noninvasively detect and monitor tumors. In addition to its utility in cancer monitoring, tDNA has also been implicated in the formation of neutrophil extracellular traps that can promote oncogenesis and metastasis. Despite the appreciation that tDNA/ctDNA can affect the tumor microenvironment (TME) to shape cancer progression and its promise in liquid biopsy applications, the mechanisms that control tDNA accumulation in the TME and the functional impacts of tDNA remain lacking. In this issue of Cancer Research, Cao and colleagues identify a role for mutant KRAS in reducing colorectal tDNA through upregulation of CD9, which remodels membrane tension to promote endocytosis. Knockdown of CD9 increases extracellular tDNA and reprograms tumor-associated macrophages to sensitize tumors to PD-1 blockade. Together, these studies identify novel roles for mutant KRAS in tDNA turnover and tDNA in immune evasion. See related article by Cao et al., p. 3394.