Discovery of Stromal Regulatory Networks that Suppress Ras-Sensitized Epithelial Cell Proliferation

Abstract

Mesodermal cells signal to neighboring epithelial cells to modulate their proliferation in both normal and disease states. We adapted a C. elegans organogenesis model to enable a genome-wide mesodermal-specific RNAi screen and discovered 39 factors in mesodermal cells that suppress the proliferation of adjacent ‘Ras pathway-sensitized’ epithelial cells. These candidates encode components of protein complexes and signaling pathways that converge on the control of chromatin dynamics, cytoplasmic polyadenylation and translation. Stromal fibroblast-specific deletion of candidate mouse orthologs of several candidates resulted in the hyperproliferation of mammary gland epithelium. Furthermore, a 33-gene signature of human orthologs was selectively enriched in the tumor stroma of breast cancer patients and depletion of these factors from normal human breast fibroblasts increased proliferation of co-cultured breast cancer cells. This cross-species approach identified unanticipated regulatory networks in mesodermal cells with growth suppressive function, exposing the conserved and selective nature of mesodermal-epithelial communication in development and cancer.

IL-6 augments IL-4-induced polarization of primary human macrophages through synergy of STAT3, STAT6 and BATF transcription factors

“…We investigated the relevance of our findings for human breast cancer by analyzing mRNA expression levels of BATF along with macrophage marker CD163 48 in breast tumor stroma using GEO2R analysis. Exploring publicly available breast cancer datasets for tumor stroma BATF expression, we found significantly increased BATF expression in tumor stroma compared to normal tissue stroma in ductal carcinoma in situ/ invasive ductal carcinoma (DCIS/IDC), 49 (Figure 7A, triple negative breast carcinoma (TNBC), 50 (Figure 7B, HER2+ breast carcinoma, 51 (Figure 7C, and invasive breast carcinoma ( Figure 7D), 52 The relative expression of TAM's genes (CD163) were also upregulated in tumor versus normal stroma. BATF expression was induced along with other IL−4/IL−6 target genes (CCL18, CCL8, CCL23, CD274, FCGR2B) in breast tumor versus normal tissue stroma ( Figure 7E.…”

Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer

“…Human recombinant proteins can be antigenic, but minimal host immune response to TAT-TLK1B instilled in salivary glands suggested its unlikely impact 10 . Breast cancer cells when co-cultured with fibroblasts depleted of TLK1 or TLK2 showed increased proliferation, 39 which suggested a pivotal role of TLKs in stromal signaling. Additionally, in murine embryonic stem cells, TLK1 downregulated expression of core pluripotency factors and promoted cell differentiation 40 .…”

TLK2 enhances aggressive phenotypes of glioblastoma cells through the activation of SRC signaling pathway

“…Additional factors within the tumor microenvironment may further regulate the role of TLK2 in glioblastoma in an endogenous setting, potentially complicating any interpretation of these in vitro finding. 20 Further research in autochthonous model systems not reliant on developed cell lines will shed further light on the true relevance of TLK2 to glioblastoma progression in vivo. Ultimately, this study suggests that inhibiting TLK2 may be a viable therapeutic strategy for combating glioblastoma in patients whose tumors exhibit high levels of TLK2 expression.…”