Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance
Salvador Alonso, Daniela Hernandez, Yu-ting Chang, Christian B. Gocke, Megan McCray, Ravi Varadhan, William H. Matsui, Richard J. Jones, Gabriel Ghiaur
Salvador Alonso, Daniela Hernandez, Yu-ting Chang, Christian B. Gocke, Megan McCray, Ravi Varadhan, William H. Matsui, Richard J. Jones, Gabriel Ghiaur
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Research Article Oncology

Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance

Abstract

Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in bortezomib (BTZ) resistance. However, the mechanisms involved in these interactions are not completely understood. We previously showed that expression of CYP26 in BM stromal cells maintains a retinoic acid–low (RA-low) microenvironment that prevents the differentiation of normal and malignant hematopoietic cells. Since a low secretory B cell phenotype is associated with BTZ resistance in MM and retinoid signaling promotes plasma cell differentiation and Ig production, we investigated whether stromal expression of the cytochrome P450 monooxygenase CYP26 modulates BTZ sensitivity in the BM niche. CYP26-mediated inactivation of RA within the BM microenvironment prevented plasma cell differentiation and promoted a B cell–like, BTZ-resistant phenotype in human MM cells that were cocultured on BM stroma. Moreover, paracrine Hedgehog secretion by MM cells upregulated stromal CYP26 and further reinforced a protective microenvironment. These results suggest that crosstalk between Hedgehog and retinoid signaling modulates BTZ sensitivity in the BM niche. Targeting these pathological interactions holds promise for eliminating minimal residual disease in MM.

Authors

Salvador Alonso, Daniela Hernandez, Yu-ting Chang, Christian B. Gocke, Megan McCray, Ravi Varadhan, William H. Matsui, Richard J. Jones, Gabriel Ghiaur

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Figure 3

Effects of MM cells on the expression of CYP26A1 in BM stroma.

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Effects of MM cells on the expression of CYP26A1 in BM stroma. (A) Relat...
(A) Relative quantification of CYP26A1 mRNA in human BM mesenchymal cells incubated for 24 hours either in the absence (Ctrl) or presence (Coculture or Transwell) of MM cells (H929, MM1s, U266). Expression in untreated BM stroma (Ctrl) was arbitrarily set at 1. (B) Relative quantification of CYP26A1 mRNA in human BM mesenchymal cells treated for 24 hours with soluble factors secreted by MM cells (IL-1, IL-3, IL-6, TNF-α, and SHH). Expression in untreated BM stromal cells was set at 1. (C) Relative quantification of SHH mRNA in human BM stroma, MM cells lines (H929, MM1S, U266), and primary CD138+ MM cells from 3 different patient samples. Expression in BM stromal cells was set at 1. (D) Correlation between induction of CYP26A1 mRNA and induction of PTCH mRNA expression in human BM mesenchymal cells cocultured with the indicated MM cells. R and P values were calculated using Pearson’s correlation coefficient. (E) Relative quantification of CYP26A1 mRNA in mouse WT or Smo-KO BM stroma incubated for 24 hours in the absence (Ctrl) or presence (Coculture or Transwell) of MM cells (H292, MM1s, U266). Expression in untreated WT or Smo-KO stroma was arbitrarily set at 1 for the respective treated conditions. Data depicted in A–C and E represent the mean ± SEM of 3 independent experiments. *P ≤ 0.05 and **P ≤ 0.01, by unpaired, 2-tailed Student’s t test.