Dataset Information

TGF?R-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment.

ABSTRACT: Synthetic lethality triggered by PARP inhibitor (PARPi) yields promising therapeutic results. Unfortunately, tumor cells acquire PARPi resistance, which is usually associated with the restoration of homologous recombination, loss of PARP1 expression, and/or loss of DNA double-strand break (DSB) end resection regulation. Here, we identify a constitutive mechanism of resistance to PARPi. We report that the bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia cells to protect them against PARPi-mediated synthetic lethality. This effect depends on the hypoxia-induced overexpression of transforming growth factor beta receptor (TGF?R) kinase on malignant cells, which is activated by bone marrow stromal cells-derived transforming growth factor beta 1 (TGF-?1). Genetic and/or pharmacological targeting of the TGF-?1-TGF?R kinase axis results in the restoration of the sensitivity of malignant cells to PARPi in BMM and prolongs the survival of leukemia-bearing mice. Our finding may lead to the therapeutic application of the TGF?R inhibitor in patients receiving PARPis.

SUBMITTER: Le BV

PROVIDER: S-EPMC7578922 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment.

Le Bac Viet BV Podszywalow-Bartnicka Paulina P Maifrede Silvia S Sullivan-Reed Katherine K Nieborowska-Skorska Margaret M Golovine Konstantin K Yao Juo-Chin JC Nejati Reza R Cai Kathy Q KQ Caruso Lisa Beatrice LB Swatler Julian J Dabrowski Michal M Lian Zhaorui Z Valent Peter P Paietta Elisabeth M EM Levine Ross L RL Fernandez Hugo F HF Tallman Martin S MS Litzow Mark R MR Huang Jian J Challen Grant A GA Link Daniel D Tempera Italo I Wasik Mariusz A MA Piwocka Katarzyna K Skorski Tomasz T

Cell reports 20201001 1

Synthetic lethality triggered by PARP inhibitor (PARPi) yields promising therapeutic results. Unfortunately, tumor cells acquire PARPi resistance, which is usually associated with the restoration of homologous recombination, loss of PARP1 expression, and/or loss of DNA double-strand break (DSB) end resection regulation. Here, we identify a constitutive mechanism of resistance to PARPi. We report that the bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia cells to prot ...[more]

PMID: 33027668

Similar Datasets

Project description:BackgroundSyringomyelia is a cerebrospinal fluid (CSF) disorder resulted in separation of pain and temperature, dilation of central canal and formation of syrinx in central canal. It is unclear about mechanisms of the dilation and syrinx formation. We aimed to investigate roles of ependymal cells lining central canal on the dilation, trying to reduce syrinx formation in central canal.MethodsWe employed 78 Sprague-Dawley (SD) rats totally with syringomyelia to detect the contribution of ependymal cells to the dilation of central canal. Immunofluorescence was used to examine the activation of ependymal cells in 54 syringomyelia rat models. BrdU was used to indicate the proliferation of ependymal cells through intraperitoneal administration in 6 syringomyelia rat models. 18 rats with syringomyelia were injected with SIS3, an inhibitor of TGFβR-Smad3, and rats injected with DMSO were used as control. Among the 18 rats, 12 rats were used for observation of syrinx following SIS3 or DMSO administration by using magnetic resonance imaging (MRI) on day 14 and day 30 under syringomyelia without decompression. All the data were expressed as mean ± standard deviation (mean ± SD). Differences between groups were compared using the two-tailed Student's t-test or ANOVA. Differences were considered significant when *p < 0.05.ResultsOur study showed the dilation and protrusions of central canal on day 5 and enlargement from day 14 after syringomyelia induction in rats with activation of ependymal cells lining central canal. Moreover, the ependymal cells contributed to protrusion formation possibly through migration along with central canal. Furthermore, suppression of TGFβR-Smad3 which was crucial for migration reversed the size of syrnix in central canal without treatment of decompression, suggesting TGFβR-Smad3 signal might be key for dilation of central canal and formation of syrinx.ConclusionsThe size of syrinx was decreased after SIS3 administration without decompression. Our study depicted the mechanisms of syrinx formation and suggested TGFβR-Smad3 signal might be key for dilation of central canal and formation of syrinx.

Dataset Information

TGF?R-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment.

Publications

TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets