The Sarosiek Lab @HarvardChanSPH studies the regulation of #apoptosis in human development and diseases.
Boston, MA
Based in United States
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➡️Join our upcoming BCDI discussions on #celldeath as a modulator of intestinal inflammation from Pedro Saavedra @Northeastern and blocking ferroptosis to prevent pancreatitis from Zhe Cao from @HarvardChanSPH!
Monday January 5th at 3PM @harvardmed. BostonCellDeath.org
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➡️Join our upcoming BCDI discussions on the role of ferroptosis in autism led by Sundari Chetty @harvardstemcell and targeting apoptosis to overcome cancer chemoresistance led by Xingping Qin @HarvardChanSPH
Monday December 1st at 3PM @harvardmed Quad. BostonCellDeath.org
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➡️Join our next BCDI meeting for exciting discussions on immune-competent organoid brain tumor models from Xin Tang @BostonChildrens and immune suppression in ovarian tumorigenesis from @TanjinaKader @harvardmed! Monday Sept 8th at 3PM @ Harvard Med Quad. BostonCellDeath.org
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➡️Join our next BCDI meeting for exciting discussions on programmed cell removal from @mounicav07 @broadinstitute and NK-mediated targeting of tumor cells from @MichalSheffer @DanaFarber! Monday April 7th at 3PM on the Harvard Med Quad. BostonCellDeath.org
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➡️Join our next BCDI meeting for exciting discussions on Regulatory T Cell fate from Xudong Li @tufts and modulation of Gasdermin D function in pyroptosis from lab of Hongbo Luo @BostonChildrens! Monday March 3rd at 3PM on the Harvard Med Quad. BostonCellDeath.org
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➡️Join our next BCDI meeting for not-to-be-missed discussions on pericyte cell survival for capillary integrity from @KeYuan_BCH and preventing #ferroptosis in hematopoietic stem cells from @bloodgenes lab. Monday Feb 3rd at 3PM on the Harvard Med Quad. BostonCellDeath.org
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➡️Join our next BCDI meeting for not-to-be-missed discussions on harnessing GSDMD-mediated cell death in cancer immunotherapy from @WuLabHarvard and neutrophil-derived vesicles from Hongbo Lou's lab. Monday Jan 6th at 3PM on the Harvard Med Quad. BostonCellDeath.org
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➡️Join our next BCDI meeting for exciting discussions on mechanisms of immune suppression in breast cancer from @shimada_kenichi and modulation of epithelial cell death by Shigella from lab of @Cammie_Lesser. Monday Nov 4th at 3PM on the Harvard Med Quad. BostonCellDeath.org
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➡️Join our next BCDI meeting for exciting discussions on targeting cell death for radiation therapy (@HenningWillers from @MGHCancerCenter) and breast cancer metastasis (lab of @JudithAgudo1 from @DanaFarber)! Monday Oct 7th at 3PM on the Harvard Med Quad. BostonCellDeath.org
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➡️Join us October 11th at the JBL Symposium to hear from leaders in radiation oncology and AI in medicine including
@HugoAerts (@harvardmed)
@DrRebeccaHowel1 (@MDAndersonNews)
@DemariaLab_WCM (@WeillCornell) &
@HenningWillers (@MGHCancerCenter)!
Info: hsph.harvard.edu/jbl-center/…
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➡️Join us at the next BCDI meeting on Monday Sept 9th at 3PM on the Harvard Med Quad (Goldenson 122) for an exciting discussion with Reginald McNulty from @UCIrvine on using novel approaches to target the NLRP3 inflammasome. More info: BostonCellDeath.org
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➡️Join us at the next BCDI meeting on FRIDAY July 26th at 3PM on the Harvard Med Quad (Goldenson 122) for an exciting presentation and discussion with Stephen Tait (@MitosRUs) on targeting mitochondria to engage immunogenic cell death. More info: BostonCellDeath.org
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➡️Join our next BCDI meeting for exciting discussions on cell death in hair follicles (Ya-Chieh Hsu's lab @HarvardUniv) and Shigella infections (@MGoldbergLab)! Monday July 1st at 3PM on the Harvard Med Quad. BostonCellDeath.org
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➡️Join our next BCDI meeting for exciting discussions with Peter Tsvetkov (@BIDMChealth) on cuproptosis (copper-dependent cell death) and Hannah Schwartz (@Merck) on classifying modes of cell death! Monday June 3rd at 3PM on the Harvard Med Quad. BostonCellDeath.org
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➡️Join our next BCDI meeting for exciting discussions with @TashbibK from @alex_toker lab on metabolic cell death and @camfraser13 from @CellDeathLab on protecting platelets from BCL-XL inhibitors! Monday April 1st at 3PM on the Harvard Med Quad. BostonCellDeath.org
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➡️Join our next BCDI meeting for exciting discussions with @marioepalmma from @j_ubellacker lab on #ferroptosis in melanoma metastasis and @tristramryan from @Lo_Zanzi lab on #pyroptosis in immunothrombosis! Monday March 4th at 3PM on the Harvard Med Quad. BostonCellDeath.org
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➡️Join us at the next BCDI meeting for exciting discussions with @NamgyuLee1 on #ferroptosis suppression and Michael Xifaras from @leonard_zon lab @BostonChildrens on melanoma tumorigenesis! Monday Feb 5th at 3PM on the Harvard Med Quad (Goldenson 122). BostonCellDeath.org
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➡️Join us at the next BCDI meeting for exciting discussions with @KojinTx founder @VasanthiViswa on drugging #ferroptosis and @mgentili_ from @broadinstitute connecting STING with cell death. Monday Dec 4th at 3PM on the Harvard Med Quad (Goldenson 122). BostonCellDeath.org
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➡️Join us at the next BCDI meeting on Thursday Nov 2nd at 3PM on the Harvard Med Quad (Goldenson 122) for a presentation and discussion with Andreas Villunger @villunger on inflammatory cell death featuring the PIDDosome. More info: BostonCellDeath.org
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Join us October 27th at the JBL Symposium to learn from leaders in neuroscience and radiation oncology including:
Helen Shih from @MGHCancerCenter
@HerveyJumper from @UCSFHospitals
Scott Floyd from @DukeRadOnc
@KristinRedmond2 from @HopkinsMedicine
Info: hsph.harvard.edu/jbl-center/…
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Finished off the @AlexsLemonade Million Miles challenge by running a half marathon with friends to get those final miles. Amazing month, amazing cause. Congrats @AlexsLemonade for reaching the million miles goal this year!
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➡️Join us at the next BCDI meeting on Monday Oct 2nd at 3PM on the Harvard Med Quad (Goldenson 122) for exciting discussions with @chendi on inducing apoptosis in NSCLC and @nabel on identifying novel therapy targets in thymic epithelial tumors. More info: BostonCellDeath.org
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➡️Join us at the next BCDI meeting on Monday Sept 11th at 3PM on the Harvard Med Quad (Goldenson 122) for exciting discussions led by @TheLeeLab on cell death in response to transcription blockade and @OylerYanivLab on cell death in infections. More info: BostonCellDeath.org
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➡️We're excited to welcome Marcus Conrad at our next Boston Cell Death Initiative meeting! Marcus will discuss his research on targeting ferroptosis for disease therapy on Friday, August 4th at 3PM on the Harvard Med Quad (TMEC 250). More info: BostonCellDeath.org
ALT This month’s discussion: Targeting ferroptosis as a therapeutic vulnerability of disease Marcus Conrad, PhD Helmholtz Zentrum München
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➡️The next Boston Cell Death Initiative meeting is Monday June 5th at 3PM on the Harvard Med Quad (TMEC 250). Discussions from @JudithAgudo1 on cancer cell escape from immune cell killing and Daniel from @Lo_Zanzi on pyroptosis in gut injury. More info: BostonCellDeath.org
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➡️The next meeting of the Boston Cell Death Initiative is on Monday May 1st at 3PM on the Harvard Med Quad (TMEC 250). Join us to discuss FAS-mediated apoptosis and dietary lipids affecting cell fate in gliomas. Get more info and join our mailing list at BostonCellDeath.org
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➡️The next meeting of the Boston Cell Death Initiative is Monday April 3rd at 4PM on the Harvard Med Quad (TMEC 250). Join us to discuss gasdermin D pore formation and #pyroptosis driving inflammation in #COVID19. Get more info and join our mailing list at BostonCellDeath.org
ALT Boston Cell Death Initiative meeting for April 3rd.
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The Boston Cell Death Initiative is excited to re-launch our seminars after a COVID hiatus. Join us for #ferroptosis & #pyroptosis talks from Whitney Henry (@weinberglab @WhiteheadInst @MIT) & @dylanvneel (@IsaacChiuLab @harvardmed) on March 6th at 4PM. hsph.harvard.edu/cell-death-…
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We're looking for a hard working and ambitious postdoc to join our lab studying cell death in cancer, development, toxicology, neurodegeneration and beyond! We strive to maintain a diverse, inclusive and collaborative work environment.
Apply now at sarosieklab.org!
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Finally, knocking out the apoptosis pathway in vascular endothelial cells lowered their apoptotic priming and protected them from targeted and cytotoxic chemotherapeutic drugs. We're now developing agents that can protect vasculature from cancer therapy-induced toxicities 10/n
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Sensitivity of vasculature to BH3 mimetics was also evident in vivo: MCL-1 inhibitor S63845 induced apoptosis in vascular endothelial cells more than parenchymal cells. Combining MCL-1 and BCL-XL inhibitors was highly toxic to vasculature while cardiomyocytes were resistant. 9/n
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We also tested endothelial cell (EC) sensitivity to BH3 mimetics and found that ECs are sensitive to single agent MCL-1 inhibition. Further, combining BH3 mimetics strongly enhanced EC death, especially when combining MCL-1 and BCL-XL inhibitors. 8/n
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Interestingly, those drugs that induced apoptosis in endothelial cells in vitro at clinically-relevant doses were also those that were associated with major cardiovascular toxicities such as myocardial ischemia and blood pressure dysregulation in the clinic. 7/n
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We compared endothelial and vascular smooth muscle cell sensitivity to a diverse array of anti-cancer agents and found them to be highly susceptible, frequently undergoing apoptosis at higher rates than fibroblasts or HeLa cancer cells. 6/n
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We generated vascular endothelial and smooth muscle cells from iPSCs and found them also to be primed for apoptosis. More primed, in fact, than fibroblasts and equivalent to HeLa cervical cancer cells. This suggests they may be vulnerable to apoptosis-inducing chemotherapies 5/n
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Comparing transcriptomes, we see that vascular endothelial cells exhibit similar expression patterns of BCL-2 family and apoptosis genes regardless of what tissue they reside in. This is evident even during embryogenesis - their divergent apoptosis regulation begins early! 4/n
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In agreement with the priming data, when we irradiate adult tissues, we find that CD31+ endothelial cells undergo apoptosis at much higher rates than parenchymal cells such as hepatocytes (GLUT2+), cardiomyocytes (cTnT+) or renal epithelial cells. 3/n
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We first measured apoptotic priming in healthy tissues across lifespan at the single cell level and found that although most of our healthy parenchymal cells lose their apoptotic sensitivity after adolescence, vascular endothelial cells remain primed for apoptosis. 2/n
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I'm excited to host colleague and friend Larry Boise from @WinshipAtEmory at the @DanaFarber Connect:Science seminar series next Tuesday at noon ET. Larry will present his pioneering work in myeloma therapeutics and functional precision medicine. Join us! dfhcc.harvard.edu/events/dfh…
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Nice work showing ralimetinib hits EGFR, Jason + team! It would be great to see how KO of MAPK14 affects sensitivity to ralimetinib in cells that are dependent on p38a but not EGFR such as SUPT1, RH4 + others (depmap data below). DLD1 & A375 don't seem to be p38a dependent at all
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Join us Friday from 11-2 ET for the JBL Symposium! This year we're featuring talks from key leaders in Alzheimer's Disease research including:
Dennis Selkoe @harvardmed
Keenan Walker @NIH
Vilhelm Bohr @NIH
Melinda Power @GWpublichealth
Info & Zoom link: hsph.harvard.edu/jbl-center/…
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Finally, we found that clonal plasma cells from t(11;14) positive AL amyloidosis patients were more sensitive to venetoclax than t(11;14) negative pts. However, we detected BCL-2 dependence in some specimens from the negative group, suggesting this biomarker isn't absolute. (9/n)
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We also ran mass spec analysis to compare the proteomes of AL amyloidosis (ALMC-1) versus isogenic multiple myeloma (ALMC-2) cells. We found potentially exploitable differences in pathways regulating proliferation and mitochondrial metabolism that we're following up on now. (8/n)
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We then established AL amyloidosis cell line xenografts to directly compare the efficacy of bortezomib versus venetoclax - we found that venetoclax produced deeper remissions than bortezomib and tripled median survival (7/n)
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BCL-2 inhibition with venetoclax also sensitized AL clonal plasma cells to other front line therapies including lenalidomide, pomalidomide and dexamethasone (6/n)
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Working with the ALMC-1 AL amyloidosis cell line provided by the @MayoClinic, we found that proteasome inhibition induces pro-apoptotic Noxa expression, which then inhibits MCL-1. Based on this, proteasome inhibitors promote AL cell apoptosis by indirectly inhibiting MCL-1 (5/n)
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...and found that the proteasome inhibitor bortezomib causes upregulation of the endogenous MCL-1 inhibitor Noxa, thus rendering further MCL-1 inhibition less effective. This was also seen directly in patients being treated with proteasome inhibitors. (4/n)
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Interestingly, the BCL-2 inhibitor ABT-199 (venetoclax) sensitized AL amyloidosis clonal plasma cells to the standard of care therapy bortezomib while MCL-1 did not. We looked into this... (3/n)
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We utilized complementary approaches to find that although there is some heterogeneity between patients, AL amyloidosis clonal plasma cells are typically primed for apoptosis and undergo cell death in response to BCL-2 or MCL-1 inhibition. (2/n)
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We're excited to share our report on apoptotic vulnerabilities in AL amyloidosis. We analyzed over 50 primary specimens from AL patients at @BU_Amyloidosis and find that clonal plasma cells are frequently dependent on BCL-2 or MCL-1 for survival. (1/n) nature.com/articles/s41467-0…
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