Development and Validation of Four Different Methods to Improve MRI-CEST Tumor pH Mapping in Presence of Fat.

CEST-MRI is an emerging imaging technique suitable for various in vivo applications, including the quantification of tumor acidosis. Traditionally, CEST contrast is calculated by asymmetry analysis, but the presence of fat signals leads to wrong contrast quantification and hence to inaccurate pH measurements. In this study, we investigated four post-processing approaches to overcome fat signal influences and enable correct CEST contrast calculations and tumor pH measurements using iopamidol. The proposed methods involve replacing the Z-spectrum region affected by fat peaks by (i) using a linear interpolation of the fat frequencies, (ii) applying water pool Lorentzian fitting, (iii) considering only the positive part of the Z-spectrum, or (iv) calculating a correction factor for the ratiometric value. In vitro and in vivo studies demonstrated the possibility of using these approaches to calculate CEST contrast and then to measure tumor pH, even in the presence of moderate to high fat fraction values. However, only the method based on the water pool Lorentzian fitting produced highly accurate results in terms of pH measurement in tumor-bearing mice with low and high fat contents.

FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.