Lung cancer is the leading cause of cancer deaths in the United States. New targeted therapies against the once-deemed undruggable oncogenic KRAS are changing current therapeutic paradigms. However, resistance to targeted KRAS inhibitors almost inevitably occurs; resistance can be driven by tumor cell–intrinsic changes or by changes in the microenvironment. Here, we utilized a genetically engineered mouse model of KRAS ^G12D -driven lung cancer that allows for inducible and reversible expression of the oncogene: activation of oncogenic KRAS ^G12D induces tumor growth; conversely, inactivation of KRAS ^G12D causes tumor regression. We showed that in addition to regulating cancer cell growth and survival, oncogenic KRAS regulated the transcriptional status of cancer-associated fibroblasts and macrophages in this model. Utilizing ex vivo approaches, we showed that secreted factors from cancer cells induced the expression of multiple cytokines in lung fibroblasts, and in turn drove expression of immunosuppressive factors, such as arginase 1, in macrophages. In summary, fibroblasts emerged as a key source of immune regulatory signals, and a potential therapeutic target for improving the efficacy of KRAS inhibitors in lung cancer.

MicroRNAs (miRNAs) are small non-coding RNAs with the crucial regulatory functions of gene expression at post-transcriptional level, detectable in cell and tissue extracts, and body fluids. For their stability in body fluids and accessibility to sampling, circulating miRNAs and changes of their concentration may represent suitable disease biomarkers, with diagnostic and prognostic relevance. A solid literature now describes the profiling of circulating miRNA signatures for several tumor types. Among body fluids, saliva accurately reflects systemic pathophysiological conditions, representing a promising diagnostic resource for the future of low-cost screening procedures for systemic diseases, including cancer. Here, we provide a review of literature about miRNAs as potential disease biomarkers with regard to ovarian cancer (OC), with an excursus about liquid biopsies, and saliva in particular. We also report on salivary miRNAs as biomarkers in oncological conditions other than OC, as well as on OC biomarkers other than miRNAs. While the clinical need for an effective tool for OC screening remains unmet, it would be advisable to combine within a single diagnostic platform, the tools for detecting patterns of both protein and miRNA biomarkers to provide the screening robustness that single molecular species separately were not able to provide so far.