Response to Comment on “Tumor-initiating cells establish an IL-33–TGF-β niche signaling loop to promote cancer progression”

Abstract

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.

Ras drives malignancy through stem cell crosstalk with the microenvironment

“…Overall, when coupled with the enhanced proximity of Lepr reporter activity to blood vessels in SCC-CSCs (Extended Data Fig. 7d ), our results provide compelling support for a model in which increased angiogenesis at the invasive SCC front endows the tumour microenvironment with an ample supply of leptin, while perivascular-associated immune and other stromal cells 6 , 19 provide the TGFβ necessary to induce Lepr expression in CSCs.…”

“…The list also included Krt8, Krt18, Mmp14 and Mmp1a, which are implicated in basement membrane remodelling, cytoskeletal dynamics and/or migration/metastasis. Genes encoding angiogenic factors also remained on this list, consistent with active TGFβ emanating from perivascular immune and other stromal cells near invasive fronts 6,19 .…”

“…On the basis of serial transplantations, tumour-initiating CSCs from mouse SCCs are enriched for integrins and reside at tumour-stromal interfaces 22 , 23 . In tumours displaying a mixed phenotype, basal progenitors undergoing TGFβ signalling are enriched for CSCs with increased resistance to chemotherapy and immunotherapy, and the loss of TGFβ signalling reverts tumours to a benign state 5 , 6 , 19 .…”

“…Increasing evidence has highlighted extrinsic perturbations-for example, inflammation, metabolism and wounding-in preconditioning tissues to heightened cancer vulnerabilities 6,[14][15][16][17][18][19] . It is less clear whether and how in healthy tissues an oncogenic mutation in a stem cell can intrinsically stimulate environmental changes that may lessen the need for multi-step mutagenesis.…”