Abstract IA10: Convergent control of cancer associated fibroblast activation and field cancerization by Notch/CSL and p53 signaling

Abstract

Abstract The vast majority of epithelial cancers is limited to in situ lesions that, for internal organs like breast, prostate or lung, can remain undetected for the whole life of an individual. The reason(s) why only a minor fraction of these lesions progresses into malignancy is not understood. Changes in tumor stroma are most frequently viewed as secondary to changes in the epithelium. However, recent evidence indicates that they may play a primary role. Such a possibility would help explain not only dormancy of most epithelial cancers, but also field cancerization, a condition of major clinical significance linked with multifocal and recurrent tumors and broader tissue changes beyond areas of tumor development that expand over time. Stromal fibroblast senescence has been linked to aging-associated cancer risk. However, density and proliferation of cancer associated fibroblasts (CAF) are frequently increased. In the mouse, deletion of the Notch effector CSL/RBP-Jκ in dermal fibroblasts is sufficient for CAF activation and ensuing multifocal keratinocyte tumors. We report that CSL silencing induces senescence of primary fibroblasts of both mouse and human origin, and from dermis, oral mucosa, breast and lung. CSL functions in these cells as direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is down-modulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas (SCC), while p53 expression and function is down-modulated only in the latter, with paracrine FGF signaling as likely culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effectors and promotes stromal and cancer cell expansion. The findings support a CAF activation/stromal co-evolution model under convergent CSL/p53 control. Citation Format: G. Paolo Dotto, G. Paolo Dotto. Convergent control of cancer associated fibroblast activation and field cancerization by Notch/CSL and p53 signaling. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA10.