Abstract 1996: CXCL12 drives selective expansion of AKT-induced quiescent, pre-neoplastic breast cells
Authors: Masoud Zahra S. , Kim Lisa , Weigel Kelsey J. , Champion Matthew M. , Schafer Zachary T. , Leung Cheuk 
Published: July 2017

A critical stage of premalignant development in breast tumorigenesis is the emergence of preneoplastic cells that carry key oncogenic drivers yet remain quiescent. Preneoplastic cells maintain a state of quiescence, but may be triggered to proliferate through largely unknown factors. Expansion of these cells is key to driving clonal evolution, which is evident in early lesions and tissue fields surrounding tumors. Although preneoplastic development is determinant to successful evolution and formation of tumor growth, the cellular mechanisms controlling preneoplastic development is unclear. Our limited mechanistic understanding of quiescent, preneoplastic cell outgrowth highlights a major knowledge gap in the early control of tumor development. Advancements in detecting molecular changes in precancerous lesions have provided opportunities for devising early intervention strategies. Aberrant AKT activation has emerged as a founding oncogenic alteration in preneoplastic cells. While molecular changes predispose these cells to develop tumors and presumably favors their selection during early tumor development, how these alterations contribute to the cellular control of quiescent preneoplastic cells remains unknown. A major barrier to studying quiescent preneoplastic cells is the lack of physiologically relevant experimental models. Here, we utilized a novel quiescent, preneoplastic cell model that reconstructs the molecular and cellular contexts of preneoplastic breast tissue. We combined a three-dimensional (3D) organotypic cell culture on reconstituted basement membrane with cells that can be induced to activate defined oncogenic pathways. Using this model, we investigated the contribution of aberrant AKT activation in preneoplastic breast tumor development. We found that aberrant AKT signaling in quiescent, preneoplastic mammary cells does not stimulate cells to proliferate under normal conditions, but confers cell sensitivity to stroma-derived CXCL12 through upregulating the receptor CXCR4. Using heterotypic co-culture to recapitulate a tumor-promoting environment and quantitative proteomic analysis, we found that stromal-derived chemokine CXCL12 selectively promotes expansion of preneoplastic cells with hyperactivated AKT signaling. Mechanistically, we showed that AKT signaling induces the expression of the chemokine’s receptor, CXCR4, which confers the selective sensitivity to CXCL12. This CXCL12-CXCR4 axis serves as an alternate mitogenic signal through PKA and ERK to drive the downregulation of CDKN1C and promote cell proliferation in AKT-induced preneoplastic cells. Our studies uncovered a distinct role of AKT signaling in promoting preneoplastic development. Furthermore, our studies suggest a model of preneoplastic clonal expansion where oncogene signaling confers quiescent preneoplastic cell sensitivity to alternate mitogenic stimuli in a permissive tissue microenvironment.

Citation Format: Zahra S. Masoud, Lisa Kim, Kelsey J. Weigel, Matthew M. Champion, Zachary T. Schafer, Cheuk Leung. CXCL12 drives selective expansion of AKT-induced quiescent, pre-neoplastic breast cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1996. doi:10.1158/1538-7445.AM2017-1996