Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer.

Myoferlin is a multiple C2-domain-containing protein that regulates membrane repair, tyrosine kinase receptor function and endocytosis in myoblasts and endothelial cells. Recently it has been reported as overexpressed in several cancers and shown to contribute to proliferation, migration and invasion of cancer cells. We have previously demonstrated that myoferlin regulates epidermal growth factor receptor activity in breast cancer. In the current study, we report a consistent overexpression of myoferlin in triple-negative breast cancer cells (TNBC) over cells originating from other breast cancer subtypes. Using a combination of proteomics, metabolomics and electron microscopy, we demonstrate that myoferlin depletion results in marked alteration of endosomal system and metabolism. Mechanistically, myoferlin depletion caused impaired vesicle traffic that led to a misbalance of saturated/unsaturated fatty acids. This provoked mitochondrial dysfunction in TNBC cells. As a consequence of the major metabolic stress, TNBC cells rapidly triggered AMP activated protein kinase-mediated metabolic reprogramming to glycolysis. This reduced their ability to balance between oxidative phosphorylation and glycolysis, rendering TNBC cells metabolically inflexible, and more sensitive to metabolic drug targeting in vitro. In line with this, our in vivo findings demonstrated a significantly reduced capacity of myoferlin-deficient TNBC cells to metastasise to lungs. The significance of this observation was further supported by clinical data, showing that TNBC patients whose tumors overexpress myoferlin have worst distant metastasis-free and overall survivals. This novel insight into myoferlin function establishes an important link between vesicle traffic, cancer metabolism and progression, offering new diagnostic and therapeutic concepts to develop treatments for TNBC patients.

Mucolytic Agents Can Enhance HER2 Receptor Accessibility for [(89)Zr]Trastuzumab, Improving HER2 Imaging in a Mucin-Overexpressing Breast Cancer Xenograft Mouse Model.

PURPOSE: Binding of trastuzumab to HER2 receptors can be impaired by steric hindrance caused by mucin MUC4. As mucolytic drugs can breakdown disulfide bonds of mucoproteins, we checked if this approach could positively affect zirconium-89-labeled trastuzumab ([(89)Zr]T) binding/uptake. PROCEDURES: The effect of N-acetylcysteine (NAC) and MUC4 knockdown/stimulation on [(89)Zr]T binding/uptake were evaluated in MCF7(HER2-), BT474 and SKBr3(HER2+/MUC4-), and JIMT1(HER2+/MUC4+) cell lines. The results were then validated in SKBR3 and JIMT1 tumor-bearing nude mice with a microPET-CT and ex vivo analysis. RESULTS: Significant increases in [(89)Zr]T binding/uptake were observed in JIMT1 cells following MUC4 knockdown (62.4 ± 6.5%) and exposure to NAC (62.8 ± 19.4%). Compared to controls, mice treated with NAC showed a significant increase in [(89)Zr]T uptake in MUC4 tumors on microPET-CT (SUVmean (18.3 ± 4.7%), SUVmax (41.7 ± 8.4%)) and individual organ counting (37.3 ± 18.3%). In contrast, no significant differences were observed in SKBr3. CONCLUSION: NAC can enhance [(89)Zr]T accumulation and improve the HER2 imaging of MUC4-overexpressing tumors. The potential positive impact on trastuzumab-based treatment deserves further investigation.

Non-Gaussian space-variant resolution modelling for list-mode reconstruction.

Partial volume effect is an important source of bias in PET images that can be lowered by accounting for the point spread function (PSF) of the scanner. We measured such a PSF in various points of a clinical PET scanner and modelled it as a product of matrices acting in image space, taking the asymmetrical, shift-varying and non-Gaussian character of the PSF into account (AMP modelling), and we integrated this accurate image space modelling into a conventional list-mode OSEM algorithm (EM-AMP reconstruction). We showed on the one hand that when a sufficiently high number of iterations are considered, the AMP modelling lead to better recovery coefficients at reduced background noise compared to reconstruction where no or only partial resolution modelling is performed, and on the other hand that for a small number of iterations, a Gaussian modelling gave the best recovery coefficients. Moreover, we have demonstrated that a deconvolution based on the AMP system response model leads to the same recovery coefficients as the corresponding EM-AMP reconstruction, but at the expense of an increased background noise.

Observation of resonance soliton trapping due to a photoinduced gap in wave number.

We investigate the nonlinear propagation of two forward propagating modes coupled by a resonant traveling-wave grating, which is photoinduced by illuminating an optical fiber with a beat signal. This interaction, representative of systems whose dispersion relation K=K(Omega) exhibits a gap in momentum K, shows evidence of localization mediated by resonance solitons. The signature of a still (in the grating frame) soliton is grating-induced cancellation of modal group-velocity mismatch.

Experimental demonstration of the Fermi-Pasta-Ulam recurrence in a modulationally unstable optical wave.

Through a detailed spectral analysis of the propagation of square-shaped laser pulses in optical fibers, we provide the experimental demonstration of the Fermi-Pasta-Ulam recurrence phenomenon in modulationally unstable optical waves ruled by the nonlinear Schrödinger equation.