Targeting the cross-talk between tumor-initiating cells (TICs) and the niche microenvironment is an attractive avenue for cancer therapy. We show here, using a mouse model of squamous cell carcinoma, that TICs play a crucial role in creating a niche microenvironment that is required for tumor progression and drug resistance. Antioxidant activity in TICs, mediated by the transcription factor NRF2, facilitates the release of a nuclear cytokine, interleukin-33 (IL-33). This cytokine promotes differentiation of macrophages that express the high-affinity immunoglobulin E receptor FcεRIα and are in close proximity to TICs. In turn, these IL-33–responding FcεRIα+ macrophages send paracrine transforming growth factor β (TGF-β) signals to TICs, inducing invasive and drug-resistant properties and further upregulating IL-33 expression. This TIC-driven, IL-33–TGF-β feedforward loop could potentially be exploited for cancer treatment.

ADAP1, a GTPase-activating protein (GAP) for the small GTPase ARF6, is a strong predictor of poor survival in early-stage squamous cell carcinoma patients and a critical mediator of TGF-β-induced invasive cell migration by facilitating basement membrane breakdown.

Kamphuis et al. argue that macrophages accumulated in the proximity of tumor-initiating cells do not express the high-affinity immunoglobulin E receptor FcεRIα. Although we cannot exclude the possibility of nonspecific binding of anti-FcεRIα antibody (clone MAR-1), we provide evidence that macrophages in squamous cell carcinomas express FcεRIα and that IL-33 induces FcεRIα expression in bone marrow cell–derived macrophages.

5 control, zebrafish, hdac1, cyclin dependent kinase inhibitors 6 7 Abstract 23 Objective and approaches: Aberrantly proliferating cells are linked to a number of diseases 24 including cancers and developmental defects.To determine the extent to which local extrinsic 25 signals contribute to or ameliorate mutant cell behaviors, we examined survival and differentiation 26 of mutant cells in wild-type retinal environments by generating chimeric zebrafish embryos 27 comprised of unlabeled host cells and GFP-labeled neural progenitor donor cells. In addition, we 28 examined the fate of retinal progenitor cells when cdkn1c, a cyclin dependent kinase inhibitor, 29 was induced in clones within wild-type and hdac1 mutant retinae. 30Results: We found that seven of the ten mutants examined exhibited apoptosis when grafted into 31 wild-type tissue, with cells from two slowly cycling mutants, elys and emi1, noticeably 32 differentiating in a wild-type environment. Observations of the one hyperproliferative mutant, 33 hdac1, revealed that these mutant cells did not appear to die or differentiate but instead survived 34 and formed tumor-like rosettes in a wild-type environment. Ectopic expression of cdkn1c was 35 unable to force cell cycle exit and differentiation of the majority of hdac1 mutant cells. 36Conclusions: Together, these results suggest that although a wild-type environment rarely 37 encourages cell cycle exit and differentiation of neural progenitors with cell cycle defects, wild-38 type survival signals may enable hyperproliferative progenitor cells to persist instead of die.

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