Shiv K Singh & Lab
@ShivKSingh6
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Our research focuses on the spatial heterogeneity and plasticity of tumor cells within the immune microenvironment of pancreatic tumors @yourUMG @uniGoettigen
Göttingen, Germany
Joined December 2018
📢 Happy to share our new study in @ScienceAdvances 🔥 🚨 We explore why pancreatic cancer cells survive after eliminating oncogenic missense TP53 (misp53) mutants, and how they continue to grow despite clinical therapies💊 🧵1/11 👉 https://t.co/8InEQ7IuEN
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New @Nature paper from Axel Behrens SPP1 is required for maintaining mesenchymal cell fate in #PancreaticCancer
https://t.co/zpwlhNvIV6 “mesenchymal and epithelial PDAC cell fates are determined by the reciprocal paracrine regulation of the soluble factors GREM1 and SPP1”
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#OpenAccess in @AnnualReviews Road Map to Defeat #PancreaticCancer By Paige Ferguson and David Tuveson @CSHL
https://t.co/0F6vy4OMV9
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PASS-01:ph II mFFX v GnP;#PDAC denovo met ds; excl gBRCA/PALB2 ➡️no clinically sig diff GnP v mFFX ➡️basal-like poor OS-mPFS on mFFX 3 mths ➡️54% receive 2nd line; mOS<6mths ➡️PDOs/ctDNA to come @AmberHabowski 1st-line biomarkers essential-RAS &🤞subtype https://t.co/bZ1TCzTYiK
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Proud to have contributed to this new work in Science Advances! Congrats to @ShivKSingh6 and team for revealing how TP53 missense mutations fuel plasticity & resistance in PDAC, highlighting the need for combined therapies.🔗
science.org
Misp53 mutant specificity affects tumor plasticity and therapy response in PDAC.
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🧵11/ Huge thank you to @dfg_public, @kfo_5002, and @Krebshilfe_Bonn, with significant support from @SanderStiftung and the Fritz-Thyssen Stiftung!!
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🧵10/ We also greatly appreciate our collaborators and especially to @NelsonDusetti for his timely support and contributions!
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..and our fantastic lab team for their strong support throughout this journey. Special thanks to @frederikepenz, @rebeccadiya, and @LukasKlein01 !
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🧵9/👏 huge shoutout to @UrbachLaura for her incredible work on this study, —what an incredible accomplishment after four years of her PhD journey! A big thank you to Lena Wieland for her fantastic support with her master’s thesis and during the revision process.....
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🧵8/ thus, using a combination of Palbociclib + Trametinib(MAPK/ERK inhibitor), not only counteracts Palbociclib adaptation but also effectively overcomes misp53R273H/C-driven plasticity
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🧵7/ 🔬Our combined multiplex IF/IHC imaging revealed the spatial distribution and mutual exclusivity patterns of p-ERK and misp53R273H hotspot regions in neoplastic cells within misp53 knockdown orthotopic tumors
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🧵6/ We suggest that a compensatory mechanism has emerged: These observations indicate that Palbo, or p53 loss, leads to increased p-ERK and a reduction in misp53 levels, suggesting that the MAPK/ERK pathway compensates to promote cell cycle progression in the absence of misp53
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🧵5/ Our findings show that misp53 is linked to cell cycle plasticity. 💡we were surprised to find that CDK4/6 cell cycle inhibitor 'Palbociclib' reduces misp53R273H levels. However, in PDAC cells treated with Palbociclib did not effectively slow down cell growth
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🧬2️⃣it blocks E2F4-mediated cell cycle repression function together with DREAM family proteins, allow cell cycle progression and induction of cell cycle genes! Loss of misp53R273H/C facilitated E2F4 binding to the promoters of E2F1, RBL1, and PCNA
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🧵4/ 🧬What is the mechanism of misp53-mediated cell cycle regulation and plasticity? Misp53R273H/C fuels the cell cycle in two ways: 🧬1️⃣it sequesters active Rb (pRb) from E2F1 promoters, facilitating cell cycle progression and promoting PDAC growth
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🧵3/ Loss of misp53R273H reduced tumor burden, liver metastases & improved survival in orthotopic PDAC models
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🧵2/ We found that misp53R273H/C, unlike misp53R248W/Q, drives enhanced cell cycle plasticity by transcriptionally regulating the E2F/G2M pathways, resulting in aggressive PDAC growth
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🧵1/ We investigate how two misp53 mutants (misp53R273H/C vs. misp53R248W/Q) affect tumor plasticity and therapeutic vulnerabilities in PDAC
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I am thrilled to share with the world a new preprint, spearheaded by the truly amazing Jose Reyes in partnership with @LoweLabMSKCC. Focused on the benign to malignant transition in PDAC, uncovering roles of plasticity, tissue remodeling and P53 ->
biorxiv.org
The transition from benign to malignant growth is a pivotal yet poorly understood step in cancer progression that marks the shift from a pathologically inert condition to a clinically lethal disease....
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Congratulations to @IamLinghua @GuangshengPei @jiminmin_v and all our exceptional collaborators at @MDAndersonNews & beyond for today's study in @Nature on spatial mapping of transcriptomic plasticity in metastatic #PancreaticCancer The full text link is
Thrilled to share our latest study just out in @Nature 😄A major milestone in our collaboration with @Aiims1742 Led by brilliant @GuangshengPei @jiminmin_v @MDAndersonNews
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