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Louise Fets @louisefets.bsky.social · Jul 10

Congratulations Will Scott and team @mrc-lms.bsky.social on some fantastic work looking at how adipose tissue remodels in obesity and weight loss.

MRC Laboratory of Medical Sciences @mrc-lms.bsky.social · Jul 9

A new study, published today in Nature, reveals the hidden benefits of weight loss on fat tissue.

A better understanding of how weight loss leads to health improvements at a molecular level could help inform the development of therapies for diseases such as type 2 diabetes in the future.

Study reveals the hidden benefits of weight loss on fat tissue

Scientists from the MRC Laboratory of Medical Sciences (LMS) and Imperial College London have produced the first detailed characterisation of the changes that weight loss causes in human fat tissue by...

lms.mrc.ac.uk

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Louise Fets @louisefets.bsky.social · Jul 7

Seconded! Worth a look for anyone who wants to open a lab working on metabolic physiology and/or disease, or immunometabolism

Alexis Barr @alexisbarr.bsky.social · Jul 7

We're recruiting junior team leaders @mrc-lms.bsky.social This time we're looking for those working in human metabolic disease.

It's a great place to start your lab. Fantastic colleagues, exciting science, world class facilities. Join us!

lms.mrc.ac.uk/work/vacanci...

Programme Leader Track - MRC Laboratory of Medical Sciences

We are recruiting Programme Leader Track positions focusing on 1) Metabolic Physiology using murine and/or human in vivo models and 2) Immunometabolism.

lms.mrc.ac.uk

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Reposted by Louise Fets

Vicki Metzis @vmetzis.bsky.social · Jun 27

Paper alert! I am really pleased to share the final version of the work led by Irène Amblard in the team on a regulatory switch controlling Cdx2 expression during posterior body development! #regulatorylogic #devbio @mrc-lms.bsky.social @imperialmed.bsky.social

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Reposted by Louise Fets

MRC Laboratory of Medical Sciences @mrc-lms.bsky.social · Jun 25

Congrats to the drug transport and tumour metabolism group, headed by @louisefets.bsky.social for winning two awards!

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Louise Fets @louisefets.bsky.social · Jun 25

#JobAlert! We have an opening for a postdoctoral scientist in #CancerMetabolism in my lab @mrc-lms.bsky.social. If you're interested in the role of metabolism in drug response and resistance in cancer, and would like to work in a fun and friendly team, check it out: lms.mrc.ac.uk/work/vacanci...

MRC Postdoctoral Research Scientist - MRC Laboratory of Medical Sciences

The MRC Laboratory of Medical Sciences (LMS) is a biomedical research institute where scientists and clinicians collaborate to advance the understanding of biology and its application to medicine. LMS...

lms.mrc.ac.uk

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Louise Fets @louisefets.bsky.social · Jun 14

Thank you Aakriti! 🙏

Louise Fets @louisefets.bsky.social · Jun 12

Thank you Dimitris 🙏

Louise Fets @louisefets.bsky.social · Jun 12

Thank you for all your help with single cell imaging approaches! A fab collaborator as ever ♥️

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Louise Fets @louisefets.bsky.social · Jun 12

Couldn't have done it without you!! ♥️

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Louise Fets @louisefets.bsky.social · Jun 12

Thanks Dylan!

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Louise Fets @louisefets.bsky.social · Jun 12

Thank you Michalis ♥️

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Louise Fets @louisefets.bsky.social · Jun 11

Heterogeneity is rife in all tumours and we’re excited to explore drug distribution with other drug/cancer combinations, and the implications for efficacy and resistance. Finally, a huge thank you to the Fets Lab members, all collaborators and of course the patients. We’d love to hear any feedback!

Louise Fets @louisefets.bsky.social · Jun 11

By contrast, Olaparib isn’t a weak base so shouldn’t accumulate in lysosomes. Sure enough, when we measured intracellular concentration of all three drugs, Olaparib was not displaced by increased lysosomal pH, but in accordance with our GeoMx data, both Niraparib and Rucaparib were.

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Louise Fets @louisefets.bsky.social · Jun 11

But why does Rucaparib accumulate in lysosomes to begin with? Rucaparib (and also niraparib!) are weak bases, becoming protonated and therefore more hydrophilic at the low lysosomal pH. This creates a gradient that favours more drug across the cell

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Louise Fets @louisefets.bsky.social · Jun 11

…and in fact, the more rucaparib can accumulate in the lysosomes, the higher the signal in the nuclear compartment, where it interacts with its target proteins PARP1 and PARP2!

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Louise Fets @louisefets.bsky.social · Jun 11

But how does this impact activity? We found that high-Rucaparib cells showed increased DNA damage (γH2AX) and reduced proliferation after treatment, suggesting the lysosomal drug pool isn’t ‘trapped’, but contributes to efficacy…

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Louise Fets @louisefets.bsky.social · Jun 11

Importantly, the more acidic the lysosome (modulated with V-ATPase inhibitors or activators), the more rucaparib accumulated within the cell, showing that this organelle really was a driver of intracellular rucaparib concentration

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Louise Fets @louisefets.bsky.social · Jun 11

In fact, the punctate distribution of rucaparib co-localised with lysosomes, and the content of lysosomes per cell was highly correlated to rucaparib content!

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Louise Fets @louisefets.bsky.social · Jun 11

As well as imaging, we could FACS sort cells that accumulate high rucaparib and compare to low drug cells. By doing this as early as one hour after treatment to minimise drug responses, we could better understand what was driving differential accumulation, which again revealed lysosomal signatures…

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Louise Fets @louisefets.bsky.social · Jun 11

….and shows heterogenous accumulation even within cell line models— a perfect tool to dig deeper.

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Louise Fets @louisefets.bsky.social · Jun 11

The PDE system is powerful, but takes 24h for the drugs to reach steady-state throughout, making it tricky to unravel the factors driving differential drug accumulation from concentration-dependent drug responses. BUT! Rucaparib is naturally fluorescent…

a light bulb is on a wooden table

ALT: a light bulb is on a wooden table

media.tenor.com

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Louise Fets @louisefets.bsky.social · Jun 11

Using GeoMx Spatial Transcriptomics on adjacent slices for rucaparib and niraparib-treated PDEs, we compared high and low drug regions. High drug regions were enriched in apoptotic signatures, and intriguingly, we also found an association with #lysosomal signatures!

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Louise Fets @louisefets.bsky.social · Jun 11

Dosing ex-vivo, we could image drug distribution independently of tumour vasculature, to explore cell-intrinsic differences in drug accumulation. Mass Spec Imaging, with expert tutelage of @zoehall-icl.bsky.social, revealed particularly striking heterogeneity in rucaparib and niraparib-treated PDEs

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Louise Fets @louisefets.bsky.social · Jun 11

We asked whether intra-tumour heterogeneity affects drug distribution, and if this impacts drug response. To answer this, Carmen set up a multimodal imaging pipeline using PARP inhibitor-dosed patient derived explants (PDEs) from HGSOC tumours (big thanks to Paula Cunnea&Christina Fotopoulou!)

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Louise Fets @louisefets.bsky.social · Jun 11

We’re excited to share a new pre-print from the lab! Led by Carmen Ramirez Moncayo and a fantastic collaboration with several groups from across @mrc-lms.bsky.social & @imperialcollegeldn.bsky.social. Interested in #OvarianCancer, #PARPinhibitors or #DrugDistribution? please read on! bit.ly/45lpekS

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