Abstract
Tumor stroma is a major contributor to the biological aggressiveness of cancer cells. Cancer cells induce activation of normal fibroblasts to carcinoma-associated fibroblasts (CAFs), which promote survival, proliferation, metastasis, and drug resistance of cancer cells. A better understanding of these interactions could lead to new, targeted therapies for cancers with limited treatment options, such as triple negative breast cancer (TNBC). To overcome limitations of standard monolayer cell cultures and xenograft models that lack tumor complexity and/or human stroma, we have developed a high throughput tumor spheroid technology utilizing a polymeric aqueous two-phase system to conveniently model interactions of CAFs and TNBC cells and quantify effects on signaling and drug resistance of cancer cells. We focused on signaling by chemokine CXCL12, a hallmark molecule secreted by CAFs, and receptor CXCR4, a driver of tumor progression and metastasis in TNBC. Using three-dimensional stromal-TNBC cells cultures, we demonstrate that CXCL12 – CXCR4 signaling significantly increases growth of TNBC cells and drug resistance through activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Despite resistance to standard chemotherapy, upregulation of MAPK and PI3K signaling sensitizes TNBC cells in co-culture spheroids to specific inhibitors of these kinase pathways. Furthermore, disrupting CXCL12 – CXCR4 signaling diminishes drug resistance of TNBC cells in co-culture spheroid models. This work illustrates the capability to identify mechanisms of drug resistance and overcome them using our engineered model of tumor-stromal interactions.
Highlights
Signaling between cancer cells and tumor stroma drives all stages of cancer initiation and progression [1,2,3,4]
We focused on signaling by chemokine CXCL12, a hallmark molecule secreted by carcinoma-associated fibroblasts (CAFs), and receptor CXCR4, a driver of tumor progression and metastasis in triple negative breast cancer (TNBC)
Using three-dimensional stromal-TNBC cells cultures, we demonstrate that CXCL12 – CXCR4 signaling significantly increases growth of TNBC cells and drug resistance through activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways
Summary
Signaling between cancer cells and tumor stroma drives all stages of cancer initiation and progression [1,2,3,4]. Our statistical analysis of the multivariate, temporally-dependent data resulting from all eight co-culture spheroid models showed that cell proliferation of the CXCR4+TNBC:CAFs model was significantly different from the seven other models across the six-day culture period (Figure 2B). We evaluated growth of cancer cells in co-culture spheroids of TNBC:HMF and TNBC:CAFs that lacked both elements of the signaling axis or CXCR4 receptor expression, respectively.
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