Join us in Belfast for two days of rigorous metabolic science, ECR-led talks and posters, and exciting opportunities for collaboration. The UK Cancer Metabolism Network is a young but fun and open community - do check out the meeting, registration open until 24th March!
π£ Weβre hiring 6 new Team Science postdocs!
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Congratulations Will Scott and team @mrc-lms.bsky.social on some fantastic work looking at how adipose tissue remodels in obesity and weight loss.
Seconded! Worth a look for anyone who wants to open a lab working on metabolic physiology and/or disease, or immunometabolism
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
Congrats to the drug transport and tumour metabolism group, headed by @louisefets.bsky.social for winning two awards!
#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...
Thank you Aakriti! π
Thank you Dimitris π
Thank you for all your help with single cell imaging approaches! A fab collaborator as ever β₯οΈ
Couldn't have done it without you!! β₯οΈ
Thanks Dylan!
Thank you Michalis β₯οΈ
Heterogeneity is rife in all tumours and weβre 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. Weβd love to hear any feedback!
By contrast, Olaparib isnβt a weak base so shouldnβt 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.
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
β¦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!
But how does this impact activity? We found that high-Rucaparib cells showed increased DNA damage (Ξ³H2AX) and reduced proliferation after treatment, suggesting the lysosomal drug pool isnβt βtrappedβ, but contributes to efficacyβ¦
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
In fact, the punctate distribution of rucaparib co-localised with lysosomes, and the content of lysosomes per cell was highly correlated to rucaparib content!
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 signaturesβ¦
β¦.and shows heterogenous accumulation even within cell line modelsβ a perfect tool to dig deeper.
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 fluorescentβ¦
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!
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
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!)
Weβre 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
Eeekkk HUGE congratulations @aakritijain.bsky.social and @robzonculab.bsky.social! π π π Such a cool story and very pleased to see it out!
π¨ Less than one week until the abstract deadline for the Mechanisms of Membrane Transport GRS!! π¨
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Apply by Feb 16th!
If you enjoy learning about novel insights into membrane transporters in beautiful places, this is the conference for you! π§ͺ
#STEMseminar
Fantastic time at the lab's first retreat with @Alexis_Barr lab - great to get away and have some time for team building and big picture thinking. Very proud of how open and engaged both teams were. Until next time!
