bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S2 from A Carbonic Anhydrase IX/SLC1A5 axis regulates glutamine metabolism dependent ferroptosis in hypoxic tumor cells
Authors: Venkateswaran Geetha , McDonald Paul C. , Chafe Shawn C. , Brown Wells S. , Gerbec Zachary J. , Awrey Shannon J. , Parker Seth J. , Dedhar Shoukat
Published: September 2024

Supplementary Figure S2 shows that CAIX catalytic activity and the CAIX intracellular domain regulate Gln uptake by hypoxic cancer cells.
Supplementary Table S2 from MTX-13, a novel PTK7-directed antibody-drug conjugate with widened therapeutic index shows sustained tumor regressions for a broader spectrum of PTK7-positive tumors
Authors: Kong Chao , Pu Junyi , Zhao Qianqian , Weng Weining , Ma Linjie , Qian Yu , Hu Wenhao , Meng Xun , Meng Tao
Published: September 2024

Supplementary Table S2 shows the pharmacokinetic parameters of MTX-13(ADC, total antibody, free payload) for each dose
Supplementary Fig.S9 from MTX-13, a novel PTK7-directed antibody-drug conjugate with widened therapeutic index shows sustained tumor regressions for a broader spectrum of PTK7-positive tumors
Authors: Kong Chao , Pu Junyi , Zhao Qianqian , Weng Weining , Ma Linjie , Qian Yu , Hu Wenhao , Meng Xun , Meng Tao
Published: September 2024

Supplementary Fig.S9 shows hematology and serum chemistry of MTX-13 in monkey
Supplementary Fig.S4 from MTX-13, a novel PTK7-directed antibody-drug conjugate with widened therapeutic index shows sustained tumor regressions for a broader spectrum of PTK7-positive tumors
Authors: Kong Chao , Pu Junyi , Zhao Qianqian , Weng Weining , Ma Linjie , Qian Yu , Hu Wenhao , Meng Xun , Meng Tao
Published: September 2024

Supplementary Fig.S4 shows MTX-13 cellular dynamics and bystander killing effect
Figure S4 from T cell-intrinsic immunomodulatory effects of TAK-981 (subasumstat), a SUMO-activating enzyme inhibitor, in chronic lymphocytic leukemia
Authors: Lam Vi , Roleder Carly , Liu Tingting , Bruss Nur , Best Scott , Wang Xiaoguang , Phillips Tycel , Shouse Geoffrey , Berger Allison J. , Alinari Lapo , Wang Lili , Siddiqi Tanya , Pennock Nathan D. , Danilov Alexey V.
Published: September 2024

Figure S4 shows 1x104 A20 lymphoma cells were treated with the indicated doses of TAK-981 for 48 hours.
Supplementary Figure S1 from Safety and Tolerability of a Novel Anti-HER2 Antibody-Drug Conjugate (PF-06804103) in Patients With HER2-Expressing Solid Tumors: A Phase 1 Dose Escalation Study
Authors: Meric-Bernstam Funda , Calvo Emiliano , Lee Keun Seok , Moreno Victor , Park Yeon Hee , Rha Sun Young , Chalasani Pavani , Zhong Wei , Zhou Li , Pirie-Shepherd Steven , Leung Abraham CF. , Curigliano Giuseppe
Published: September 2024

Supplementary Figure S1 shows the study design.
Figure S5 from Intratumoral interleukin-15 improves efficacy of near-infrared photoimmunotherapy
Authors: Fukushima Hiroshi , Furusawa Aki , Kato Takuya , Wakiyama Hiroaki , Takao Seiichiro , Okuyama Shuhei , Choyke Peter L. , Kobayashi Hisataka
Published: September 2024

Supplementary Fig. S5. In vitro CD44-targeted NIR-PIT in hIL-15-MC38 or parental MC38 cells.
Figure S3 from Intratumoral interleukin-15 improves efficacy of near-infrared photoimmunotherapy
Authors: Fukushima Hiroshi , Furusawa Aki , Kato Takuya , Wakiyama Hiroaki , Takao Seiichiro , Okuyama Shuhei , Choyke Peter L. , Kobayashi Hisataka
Published: September 2024

Supplementary Fig. S3. Immunohistochemical evaluation of Ki-67 positive cancer cells in hIL-15-MC38 or parental MC38 tumors.
Figure S11 from Intratumoral interleukin-15 improves efficacy of near-infrared photoimmunotherapy
Authors: Fukushima Hiroshi , Furusawa Aki , Kato Takuya , Wakiyama Hiroaki , Takao Seiichiro , Okuyama Shuhei , Choyke Peter L. , Kobayashi Hisataka
Published: September 2024

Supplementary Fig. S11. In vitro CD44-targeted NIR-PIT in Pan02-luc cells.
Figure S10 from Intratumoral interleukin-15 improves efficacy of near-infrared photoimmunotherapy
Authors: Fukushima Hiroshi , Furusawa Aki , Kato Takuya , Wakiyama Hiroaki , Takao Seiichiro , Okuyama Shuhei , Choyke Peter L. , Kobayashi Hisataka
Published: September 2024

Supplementary Fig. S10. Immunohistochemical evaluation of immune cell infiltration in MC38 and Pan02-luc tumors.
Supplementary Figure S7 from Efficacy and safety of glycosphingolipid SSEA-4 targeting CAR-T cells
in an ovarian carcinoma model
Authors: Monzo Hector J. , Kalander Kerttu , Hyytiäinen Marko M. , Elbasani Endrit , Wall Johanna , Moyano-Galceran Lidia , Tanjore Ramanathan Jayendrakishore , Jukonen Joonas J.J. , Laakkonen Pirjo , Ristimäki Ari , Carlson Joseph W. , Lehti Kaisa , Salehi Sahar , Puolakkainen Pauli , Haglund Caj , Seppänen Hanna , Leppä Sirpa , Ojala Päivi M.
Published: September 2024

Supplementary Figure S7. T cell detection in mouse tissues after the long-term survival study. Indicated tissues were stained with HOECHST 33342 for nuclei (blue), anti-EGFR to detect CAR-T cells (middle panel; green) and anti-CD3 for T cells (right panel, white). Left panel shows a merged image of all three channels. Arrows highlight CAR-T and CD3 positive cells, while arrowheads highlight erythrocytes with an intense background staining.
Supplementary Figure S6 from Efficacy and safety of glycosphingolipid SSEA-4 targeting CAR-T cells
in an ovarian carcinoma model
Authors: Monzo Hector J. , Kalander Kerttu , Hyytiäinen Marko M. , Elbasani Endrit , Wall Johanna , Moyano-Galceran Lidia , Tanjore Ramanathan Jayendrakishore , Jukonen Joonas J.J. , Laakkonen Pirjo , Ristimäki Ari , Carlson Joseph W. , Lehti Kaisa , Salehi Sahar , Puolakkainen Pauli , Haglund Caj , Seppänen Hanna , Leppä Sirpa , Ojala Päivi M.
Published: September 2024

Supplementary Figure S6. Expression of SSEA-4 in normal mouse tissues. Immunofluorescence detection of SSEA-4 (green) in the indicated tissues of healthy 10 weeks old (C57BL/6) mouse using anti-SSEA-4 antibody.
Supplementary Figure S5 from Efficacy and safety of glycosphingolipid SSEA-4 targeting CAR-T cells
in an ovarian carcinoma model
Authors: Monzo Hector J. , Kalander Kerttu , Hyytiäinen Marko M. , Elbasani Endrit , Wall Johanna , Moyano-Galceran Lidia , Tanjore Ramanathan Jayendrakishore , Jukonen Joonas J.J. , Laakkonen Pirjo , Ristimäki Ari , Carlson Joseph W. , Lehti Kaisa , Salehi Sahar , Puolakkainen Pauli , Haglund Caj , Seppänen Hanna , Leppä Sirpa , Ojala Päivi M.
Published: September 2024

Supplementary Figure S5. Weight monitoring during the long-term in vivo study. Mice treated with 2M CAR-T dose showed pronounced weight loss and health deterioration at earlier time points than mice treated with 1M CAR-T dose. PBS, tumor-free CAR/NT-T 1M, and NT-T groups did not show weight loss and remained healthy during the duration of the experiment. Unless otherwise indicated, mice groups are tumor-bearing. (M=1x106).
Supplementary Figure S4 from Efficacy and safety of glycosphingolipid SSEA-4 targeting CAR-T cells
in an ovarian carcinoma model
Authors: Monzo Hector J. , Kalander Kerttu , Hyytiäinen Marko M. , Elbasani Endrit , Wall Johanna , Moyano-Galceran Lidia , Tanjore Ramanathan Jayendrakishore , Jukonen Joonas J.J. , Laakkonen Pirjo , Ristimäki Ari , Carlson Joseph W. , Lehti Kaisa , Salehi Sahar , Puolakkainen Pauli , Haglund Caj , Seppänen Hanna , Leppä Sirpa , Ojala Päivi M.
Published: September 2024

Supplementary Figure S4. Anti-tumor response and survival in the long-term in vivo study. A. Treatment groups and used T cell doses. B. Representative BLI images of mice treated with PBS, 1M, and 2M NT or CAR-T cells doses at the indicated time points (days; d). (M=1x106). *Asterisks indicate mice sacrificed due to toxicities.
Table S3 from Use of Payload Binding Selectivity Enhancers to Improve Therapeutic Index of Maytansinoid-Antibody-Drug Conjugates
Authors: Nguyen Toan Duc. , Bordeau Brandon M. , Balthasar Joseph P.
Published: September 2024

Supplemental table 3: Anti-DM4 sdAb, Effects on DM4 / DM4-ADC cytotoxicity and binding data
Table S2 from Use of Payload Binding Selectivity Enhancers to Improve Therapeutic Index of Maytansinoid-Antibody-Drug Conjugates
Authors: Nguyen Toan Duc. , Bordeau Brandon M. , Balthasar Joseph P.
Published: September 2024

Supplemental table 2: CD123 cell expression data
Table S1 from Use of Payload Binding Selectivity Enhancers to Improve Therapeutic Index of Maytansinoid-Antibody-Drug Conjugates
Authors: Nguyen Toan Duc. , Bordeau Brandon M. , Balthasar Joseph P.
Published: September 2024

Supplemental table 1: model parameters
Figure S3 from Use of Payload Binding Selectivity Enhancers to Improve Therapeutic Index of Maytansinoid-Antibody-Drug Conjugates
Authors: Nguyen Toan Duc. , Bordeau Brandon M. , Balthasar Joseph P.
Published: September 2024

ADC and mAb binding data
Supplementary Fig. S2 from Preclinical development of brain permeable ERβ agonist for the treatment of glioblastoma
Authors: Pratap Uday P. , Tidwell Michael , Balinda Henriette U. , Clanton Nicholas A. , Yang Xue , Viswanadhapalli Suryavathi , Sareddy Gangadhara R. , Liang Dong , Xie Huan , Chen Yidong , Lai Zhao , Tekmal Rajeshwar R. , McHardy Stanton F. , Brenner Andrew J. , Vadlamudi Ratna K.
Published: September 2024

Supplementary Fig.S2 shows data shows specificity of CIDD-0149897 using ER beta KO cells.
Table S4 from Co-targeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells
Authors: Hardin Haley M. , Dinh Christine T. , Huegel Julianne , Petrilli Alejandra M. , Bracho Olena , Allaf Abdulrahman , Karajannis Matthias A. , Griswold Anthony J. , Ivan Michael E. , Morcos Jacques , Gultekin Sakir H. , Telischi Fred F. , Liu Xue Zhong , Fernandez-Valle Cristina
Published: September 2024

Supplemental Table 4. NF2 mutation status of VS tumors.
Table S3 from Co-targeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells
Authors: Hardin Haley M. , Dinh Christine T. , Huegel Julianne , Petrilli Alejandra M. , Bracho Olena , Allaf Abdulrahman , Karajannis Matthias A. , Griswold Anthony J. , Ivan Michael E. , Morcos Jacques , Gultekin Sakir H. , Telischi Fred F. , Liu Xue Zhong , Fernandez-Valle Cristina
Published: September 2024

Supplemental Table 3. Efficacy of Drug Combinations in Additional Cell Lines.
Figure S1 from Co-targeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells
Authors: Hardin Haley M. , Dinh Christine T. , Huegel Julianne , Petrilli Alejandra M. , Bracho Olena , Allaf Abdulrahman , Karajannis Matthias A. , Griswold Anthony J. , Ivan Michael E. , Morcos Jacques , Gultekin Sakir H. , Telischi Fred F. , Liu Xue Zhong , Fernandez-Valle Cristina
Published: September 2024

Supplemental Figure 1. HS01 western blots for dasatinib target and necroptosis markers.
Table S1 from Targeted Investigational Oncology Agents (IOA) in the NCI60: A Phenotypic Systems-Based Resource
Authors: Morris Joel , Kunkel Mark W. , White Stephen L. , Wishka Donn G. , Lopez Omar D. , Bowles Lori , Sellers Brady Penny , Ramsey Patricia , Grams Julie , Rohrer Tiffany , Martin Karen , Dexheimer Thomas S. , Coussens Nathan P. , Evans David , Risbood Prabhakar , Sonkin Dmitriy , Williams John D. , Polley Eric C. , Collins Jerry M. , Doroshow James H. , Teicher Beverly A.
Published: September 2024

Table of GI50 data
Supplementary Figures 1 and 2 from Targeted Investigational Oncology Agents (IOA) in the NCI60: A Phenotypic Systems-Based Resource
Authors: Morris Joel , Kunkel Mark W. , White Stephen L. , Wishka Donn G. , Lopez Omar D. , Bowles Lori , Sellers Brady Penny , Ramsey Patricia , Grams Julie , Rohrer Tiffany , Martin Karen , Dexheimer Thomas S. , Coussens Nathan P. , Evans David , Risbood Prabhakar , Sonkin Dmitriy , Williams John D. , Polley Eric C. , Collins Jerry M. , Doroshow James H. , Teicher Beverly A.
Published: September 2024

Figures S1 and S2
Supplementary Data from Targeted Nanofitin-drug conjugates achieve efficient tumor delivery and therapeutic effect in an EGFR-positive mouse xenograft model
Authors: Huet Simon , Zeisser Labouebe Magali , Castro Rute , Jacquot Perrine , Pedrault Jessy , Viollet Sébastien , Van Simaeys Gaetan , Doumont Gilles , Larbanoix Lionel , Zindy Egor , Cunha António E. , Scapozza Leonardo , Cinier Mathieu
Published: September 2024

Figures S1 to S5
Figure S6 from Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule Inhibitor
Authors: Moure Casey J. , Vara Brandon , Cheng Mangeng M. , Sondey Christopher , Muise Eric , Park Eunsil , Vela Ramirez Julia Eulalia , Su Dan , D’Souza Shanti , Yan Qingyun , Yeung Charles S. , Zhang Minjia , Mansueto My Sam , Linn Doug , Buchanan Mark , Foti Robert , DiMauro Erin , Long Brian , Simov Vladimir , Barry Evan R.
Published: September 2024

Characterization of HGF impact on MRK-A activity.
Figure S4 from Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule Inhibitor
Authors: Moure Casey J. , Vara Brandon , Cheng Mangeng M. , Sondey Christopher , Muise Eric , Park Eunsil , Vela Ramirez Julia Eulalia , Su Dan , D’Souza Shanti , Yan Qingyun , Yeung Charles S. , Zhang Minjia , Mansueto My Sam , Linn Doug , Buchanan Mark , Foti Robert , DiMauro Erin , Long Brian , Simov Vladimir , Barry Evan R.
Published: September 2024

MRK-A combination with immune checkpoint blockade.
Data from Small molecule mediated stabilization of PP2A modulates the Homologous Recombination pathway and potentiates DNA damage-induced cell death.
Authors: Avelar Rita A. , Armstrong Amy J. , Carvette Gracie , Gupta Riya , Puleo Noah , Colina Jose A. , Joseph Peronne , Sobeck Alexander M. , O'Connor Caitlin M. , Raines Brynne , Gandhi Agharnan , Dziubinski Michele L. , Ma Daniel S. , Resnick Kimberly , Singh Sareena , Zanotti Kristine , Nagel Christa , Waggoner Steven , Thomas Dafydd G. , Skala Stephanie L. , Zhang Junran , Narla Goutham , DiFeo Analisa
Published: September 2024

Abstract
High-Grade Serous Carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP-inhibitors (PARPi) have become the mainstay of HGSC targeted therapy, given that these tumors are driven by a high degree of genomic instability and Homologous Recombination (HR) defects. Nonetheless, ~30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a Small Molecule Activator of Protein Phosphatase 2A (PP2A) (SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in Patient-Derived HGSC cells and Xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56,B56 and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlate with worse overall patient survival. We show that SMAP-061 stabilization of PP2A inhibits the homologous recombination (HR) output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient cells and in PDX models. Our studies identifies PP2A as a novel regulator of HR and indicates PP2A modulators as a therapeutic therapy for HGSC. In sum, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi-resistance driven by BRCA1/2 mutation reversions.
Data from Selective inhibition of ATM-dependent double-strand break repair and checkpoint control synergistically enhances the efficacy of ATR inhibitors
Authors: Turchick Audrey , Zimmermann Astrid , Chiu Li-Ya , Dahmen Heike , Elenbaas Brian , Zenke Frank T. , Blaukat Andree , Vassilev Lyubomir T.
Published: September 2024

Abstract
Ataxia Telangiectasia and Rad3-Related Protein (ATR) kinase regulates a key cell regulatory node for maintaining genomic integrity by preventing replication fork collapse. ATR inhibition has been shown to increase replication stress resulting in DNA double strand breaks (DSBs) and cancer cell death, and several inhibitors are under clinical investigation for cancer therapy. However, activation of cell cycle checkpoints controlled by Ataxia Telangiectasia Mutated (ATM) kinase could minimize the lethal consequences of ATR inhibition and protect cancer cells. Here, we investigate ATR-ATM functional relationship and potential therapeutic implications. In cancer cells with functional ATM and p53 signaling, selective suppression of ATR catalytic activity by M6620 induced G1 phase arrest to prevent S-phase entry with unrepaired DSBs. The selective ATM inhibitors, M3541 and M4076, suppressed both ATM-dependent cell cycle checkpoints and DSB repair, lowered the p53 protective barrier and extended the life of ATR inhibitor induced DSBs. Combination treatment amplified the fraction of cells with structural chromosomal defects and enhanced cancer cell death. ATM inhibitor synergistically potentiated the ATR inhibitor efficacy in cancer cells in vitro and increased ATR inhibitor efficacy in vivo at doses that did not show overt toxicities. Further, a combination study in 26 patient-derived xenograft models of triple negative breast cancer with the newer generation ATR inhibitor M4344 and ATM inhibitor M4076 demonstrated substantial improvement in efficacy and survival compared to single-agent M4344, suggesting a novel and potentially broad combination approach to cancer therapy.
Data from Schlafen 11 (SLFN11) kills cancer cells undergoing unscheduled re-replication
Authors: Murai Junko , Ceribelli Michele , Fu Haiqing , Redon Christophe E. , Jo Ukhyun , Murai Yasuhisa , Aladjem Mirit I. , Thomas Craig J. , Pommier Yves
Published: September 2024

Abstract
SLFN11 is an increasingly prominent predictive biomarker and a molecular sensor for a wide range of clinical drugs: topoisomerases, PARP and replication inhibitors, and platinum derivatives. To expand the spectrum of drugs and pathways targeting SLFN11, we ran a high-throughput screen (HTS) with 1,978 mechanistically-annotated, oncology-focused compounds in two isogenic pairs of SLFN11-proficient and -deficient cells (CCRF-CEM and K562). We identified 29 hit compounds that selectively kill SLFN11-proficient cells, including not only previously known DNA-targeting agents, but also the neddylation inhibitor Pevonedistat (MLN-4924) and the DNA polymerase alpha inhibitor AHPN/CD437, which both induced SLFN11 chromatin recruitment. By inactivating cullin-ring E3 ligases, Pevonedistat acts as an anticancer agent partly by inducing unscheduled re-replication through supra-physiological accumulation of CDT1, an essential factor for replication initiation. Unlike the known DNA-targeting agents and AHPN/CD437 that recruit SLFN11 onto chromatin in 4 hours, Pevonedistat recruited SLFN11 at late time points (24 hours). While Pevonedistat induced unscheduled re-replication in SLFN11-deficient cells after 24 hours, the re-replication was largely blocked in SLFN11-proficient cells. The positive correlation between sensitivity to Pevonedistat and SLFN11 expression was also observed in non-isogenic cancer cells in three independent cancer cell databases (NCI-60, CTRP: Cancer Therapeutics Response Portal and GDSC: Genomic of Drug Sensitivity in Cancer). The present study reveals that, in addition to sensing stressed replication, SLFN11 blocks unscheduled re-replication provoked by Pevonedistat, which augments the anti-cancer effect of Pevonedistat. It also suggests SLFN11 as a potential predictive biomarker for Pevonedistat in ongoing and future clinical trials.
Data from ABBV-184: A novel survivin-specific TCR/CD3 bispecific T cell engager is active against both solid tumor and hematological malignancies
Authors: Chervin Adam S. , Stone Jennifer D. , Konieczna Iwona , Calabrese Kelly M. , Wang Ningyan , Haribhai Dipica , Dong Feng , White Michael K. , Rodriguez Luis E. , Bukofzer Gail T. , Ellis Paul A. , Cosgrove Cormack , Hecquet Claudie , Clarin Jerry D. , Palma Joann P. , Reilly Edward B.
Published: September 2024

Abstract
CD3 bispecific T cell engagers (TCE), comprised of a tumor targeting domain linked to a CD3 binding domain, function by bridging target-positive tumors and CD3-expressing effector T cells enabling redirected T cell-mediated killing of tumor cells. Although the majority of CD3 bispecific molecules in clinical development incorporate tumor-targeting antibody-based binding domains, many tumor-associated antigens derive from intracellular proteins and are not accessible to targeting via antibody. Intracellular proteins processed into short peptide fragments and presented on the cell surface by major histocompatibility complex proteins (MHC) are recognized by T cell receptors (TCR) on the surface of T cells. Here we describe the generation and preclinical evaluation of ABBV-184, a novel TCR/anti-CD3 bispecific composed of a highly selective soluble TCR that binds a peptide derived from the oncogene survivin (BIRC5) bound to the Class I MHC allele human leukocyte antigen (HLA)-A*02:01 expressed on tumor cells, linked to a specific binder to the CD3 receptor on T cells. ABBV-184 drives an optimal distance between T cell and target cell thereby enabling sensitive recognition of low-density peptide/MHC targets. Consistent with the expression profile of survivin across a broad range of both hematological and solid tumors, treatment of AML and NSCLC cell lines with ABBV-184 results in T cell activation, proliferation, and potent redirected cytotoxicity of HLA-A2 positive target cell lines, both in vitro and in vivo, including patient-derived AML samples. These results indicate that ABBV-184 is an attractive clinical candidate for the treatment of patients with AML and NSCLC.
Data from S-531011, a novel anti-human CCR8 antibody, induces potent anti-tumor responses through depletion of tumor-infiltrating CCR8-expressing regulatory T cells
Authors: Nagira Yoji , Nagira Morio , Nagai Ryohei , Nogami Wataru , Hirata Michinari , Ueyama Azumi , Yoshida Tetsuya , Yoshikawa Mai , Shinonome Satomi , Yoshida Hiroshi , Haruna Miya , Miwa Hiroto , Chatani Natsumi , Ohkura Naganari , Wada Hisashi , Tanaka Hidekazu
Published: September 2024

Abstract
While regulatory T cells (Tregs) are inhibitory immune cells that are essential for maintaining immune homeostasis, Tregs that infiltrate tumor tissue promote tumor growth by suppressing anti-tumor immunity. Selective reduction of tumor-infiltrating Tregs is therefore expected to activate anti-tumor immunity without affecting immune homeostasis. We previously reported that selective Treg depletion targeted by a C-C motif chemokine receptor 8 (CCR8) resulted in induction of strong anti-tumor immunity without any obvious autoimmunity in mouse models. Thus, herein, we developed a novel humanized anti-CCR8 monoclonal antibody, S-531011, aimed as a cancer immunotherapy strategy for patients with cancer. S-531011 exclusively recognized human CCR8 among all chemokine receptors and showed potent antibody-dependent cell-mediated cytotoxicity activity toward CCR8+ cells and neutralization activity against CCR8-mediated signaling. We observed that S-531011 reduced tumor-infiltrating CCR8+ Tregs and induced potent anti-tumor activity in a tumor-bearing human-CCR8 knock-in mouse model. Moreover, combination therapy with S-531011 and anti-mouse programmed cell death 1 (PD-1) antibody strongly suppressed tumor growth compared to anti-PD-1 antibody alone with no observable adverse effects. S-531011 also depleted human tumor-infiltrating Tregs, but not Tregs derived from human peripheral blood mononuclear cells. These results suggest that S-531011 is a promising drug for inducing anti-tumor immunity without severe side effects in the clinical setting.
Data from Upregulation of Somatostatin Receptor Type 2 Improves 177Lu-DOTATATE Therapy in Receptor-Deficient Pancreatic Neuroendocrine Tumor Model
Authors: Sharma Rupali , Earla Bhargav , Baidoo Kwamena E. , Zeiger Martha A. , Madigan James P. , Escorcia Freddy E. , Sadowski Samira M.
Published: September 2024

Abstract
Pancreatic neuroendocrine tumors (PNETs) express high levels of somatostatin receptor type 2 (SSTR2), a unique target for both tumor imaging and therapy. This surface expression is lost in metastatic high-grade PNETs, making patients ineligible for SSTR2-targeted 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT), and represents an unmet clinical need. Here, we aimed to restore SSTR2 expression through the reversal of inhibitory epigenetic gene silencing in order to improve tumor responsiveness to PRRT. We first assessed human SSTR2 promoter methylation and expression levels in 96 patient samples. We then used three NET cell lines (QGP-1, BON-1, GOT-1) with variable SSTR2 expression profiles for functional in vitro studies using histone deacetylase inhibitors (HDACis). Finally, the QGP-1 xenograft mouse model, with low basal SSTR2 expression, was used to assess the therapeutic efficacy of combined HDACi and 177Lu-DOTATATE therapies. We confirm that SSTR expression is decreased and correlates with SSTR2 promoter methylation in patients with high grade NETs. When exposed to HDACis, SSTR2 surface expression is increased in three NET cell lines in vitro. In an in vivo PNET xenograft model with low basal SSTR2 expression, our studies demonstrate significantly higher tumor uptake of SSTR2-targeted 177Lu-DOTATATE in animals pretreated with HDACis compared to controls. For the first time, we show that this higher tumor uptake results in significant anti-tumor response when compared to standard PRRT alone. These preclinical results provide a rationale for utilizing HDACi pretreatment to improve targeted radionuclide therapy in patients with SSTR2-negative, metastatic PNETs.
Data from Conditional dependency of LP-184 on prostaglandin reductase 1 is synthetic lethal in pancreatic cancers with DNA damage repair deficiencies
Authors: Restifo Diana , McDermott Joseph R. , Cvetkovic Dusica , Dos Santos Troy , Ogier Charline , Surumbayeva Aizhan , Handorf Elizabeth A. , Schimke Caleb , Ma Charlie , Cai Kathy Q. , Olszanski Anthony J. , Kathad Umesh , Bhatia Kishor , Sharma Panna , Kulkarni Aditya , Astsaturov Igor
Published: September 2024

Abstract
The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways.
Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared to DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1 and BRCA2. Depletion of PTGR1, however, completely abrogates the anti-tumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy.
Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184.
Figure S5 from UBE2C-mediated autophagy inhibition via ubiquitination of SIRT1 contributes to endometrial cancer progression
Authors: Zhao Rong , Liu Yan , Wang Ziwei , Zhang Jun , Zhang Wei , Zhou Xing , Tsedendorj Sevjid , Enkhtur Amarsanaa , Feng Dilu , Wang Hongbo
Published: September 2024

FigureS5
Supplementary Figure Legend from USP10 regulates ZEB1 ubiquitination and protein stability to inhibit ZEB1-mediated colorectal cancer metastasis
Authors: Sun Lei , Yu Jia , Guinney Justin , Qin Bo , Sinicrope Frank A.
Published: September 2024

Supplementary Figure 1 legend
Supplementary Figure 1 from Non-essential amino acid availability influences proteostasis and breast cancer cell survival during proteotoxic stress
Authors: Sannino Sara , Manuel Allison M. , Shang Chaowei , Wendell Stacy G. , Wipf Peter , Brodsky Jeffrey L.
Published: September 2024

S1. Amino acid modulation orchestrates apoptosis when proteostasis is compromised.
Supplementary Figures and Legends, Supplementary Tables from Downregulation of BASP1 promotes temozolomide resistance in gliomas via epigenetic activation of the FBXO32/NF-κB/MGMT axis
Authors: Liao Xinyi , Li Ziwen , Zheng Haiqing , Qian Wanying , Zhang Shuxia , Chen Suwen , Li Xincheng , Tang Miaoling , Xu Yingru , Yu Ruyuan , Li Man , Song Libing , Li Jun
Published: September 2024

S1. BASP1 downregulation is associated with poor prognosis in glioma patients.
S2. Low expression of BASP1 is associated with poor prognosis in CGGA dataset.
S3. Dysregulation of BASP1 alters chemoresistance of glioma cells to TMZ treatment in vitro.
S4. BASP1 dysregulation has no effect on the rate of glioma cell growth in vivo.
S5. Dysregulation of BASP1 alters chemoresistance to TMZ treatment in glioma cells in vivo.
S6. BASP1 silencing activates NF-κB signaling in glioma cells.
S7. FBXO32 expression correlates with NF-κB signaling.
S8. BXO32 expression positively correlates with MGMT expression.
S9. FBXO32 is associated with poor prognosis of glioma patients.
S10. WDR5/MLL upregulates FBXO32 epigenetically.
S11. Combined OICR-9429 sensitizes BASP1-silenced glioma cells to TMZ in vivo.
Supplementary Table S1. Clinicopathological characteristics of studied patients and BASP1 expression in gliomas.
Supplementary Table S2. Correlation between the clinicopathological features and expression.
Supplementary Table S3. Univariate and multivariate analysis of different prognostic parameters in glioma patients by Cox-regression analysis.
Supplementary Table S4. Primers and Oligonucleotides used in this study.
Supplementary Table 12 from Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P.
Published: September 2024

MYC Blood Enhancer Complex (BENC) Module Cooordinates in Hg38
Supplementary Fig. 11 from Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P.
Published: September 2024

Single cell ATAC-seq cell population dynamics in primary patient samples follow-ing treatment with dual FLT3/LSD1 inhibition.
Supplementary Figure 1 from EIF4A3 acts on the PI3K-AKT-ERK1/2-P70S6K pathway through FLOT1 to influence the development of lung adenocarcinoma
Authors: Yu Wenhao , Liang Jinghui , Fang Tao , Jiang Jin , Zhao Renchang , Li Rongyang , Han Jingyi , Tian Hui
Published: September 2024

EIF4A3 promotes the proliferation and migration of LUAD cells in vitro.
Figure S2 from Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis
Authors: Choi Jiahn , Zhang Xusheng , Li Wenge , Houston Michele , Peregrina Karina , Dubin Robert , Ye Kenny , Augenlicht Leonard
Published: September 2024

The western diet elevates and suppresses multiple pathways by 3 months, most persisting to 12 months, and reversible by switching to control diet.
Supplementary Figure 1 from Desmoglein 2 Functions As A Receptor for Fatty Acid Binding Protein 4 in Breast Cancer Epithelial Cells
Authors: Chen Dongmei , Wirth Keith M. , Kizy Scott , Muretta Joseph M. , Markowski Todd W. , Yong Peter , Sheka Adam , Abdelwahab Hisham , Hertzel Ann V. , Ikramuddin Sayeed , Yamamoto Masato , Bernlohr David A.
Published: September 2024

S1. DSC and DSG isoforms expressed in MCF-7 cells.
Supplementary Table 1 from Absence of either Ripk3 or Mlkl reduces incidence of hepatocellular carcinoma independent of liver fibrosis
Authors: Mohammed Sabira , Thadathil Nidheesh , Ohene-Marfo Phoebe , Tran Albert L. , Van Der Veldt Michael , Georgescu Constantin , Oh Sangphil , Nicklas Evan H. , Wang Dawei , Haritha Nair Hariprasad , Luo Wenyi , Janknecht Ralf , Miller Benjamin F. , Wren Jonathan D. , Freeman Willard M. , Deepa Sathyaseelan S.
Published: September 2024

List of Differentially Expressed Genes from RNA Seq analysis
Table S1 from Fibronectin contributes to a BRAF inhibitor-driven invasive phenotype in thyroid cancer through EGR1, which can be blocked by inhibition of ERK1/2.
Authors: Hicks Hannah M. , Pozdeyev Nikita , Sams Sharon B. , Pugazhenthi Umarani , Bales Elise S. , Hofmann Marie-Claude , McKenna Logan R. , Schweppe Rebecca E.
Published: September 2024

Table S1. Thyroid cancer cell lines and their sensitivity/resistance to BRAFi.
Supplementary Table S1 from Single-Cell Evolutionary Analysis Reveals Drivers of Plasticity and Mediators of Chemoresistance in Small Cell Lung Cancer
Authors: Wollenzien Hannah , Tecleab Yohannes Afeworki A. , Szczepaniak-Sloane Robert , Restaino Anthony , Kareta Michael S.
Published: September 2024

Description of samples in the autochthonous study
Supplementary Figure S1 from Identification of a ΔNp63-Dependent Basal-Like A Subtype-Specific Transcribed Enhancer Program (B-STEP) in Aggressive Pancreatic Ductal Adenocarcinoma
Authors: Wang Xin , Kutschat Ana P. , Aggrey-Fynn Joana , Hamdan Feda H. , Graham Rondell P. , Wixom Alexander Q. , Souto Yara , Ladigan-Badura Swetlana , Yonkus Jennifer A. , Abdelrahman Amro M. , Alva-Ruiz Roberto , Gaedcke Jochen , Strobel Philipp , Kosinsky Robyn Laura , Wegwitz Florian , Hermann Patrick , Truty Mark J. , Siveke Jens T. , Hahn Stephan A. , Hessmann Elisabeth , Johnsen Steven A. , Najafova Zeynab
Published: September 2024

Defining the basal-like A-specific enhancer landscape in PDAC
Supplementary Figure 3 from Oncostatin-M and OSM-Receptor feed-forward activation of MAPK induces separable stem-like and mesenchymal programs
Authors: Polak Kelsey L. , Tamagno Ilaria , Parameswaran Neetha , Smigiel Jacob , Chan E. Ricky , Yuan Xueer , Rios Brenda , Jackson Mark W.
Published: September 2024

S3. Generation of OSMR knock-out cells.
Supplementary Figure 2 from Oncostatin-M and OSM-Receptor feed-forward activation of MAPK induces separable stem-like and mesenchymal programs
Authors: Polak Kelsey L. , Tamagno Ilaria , Parameswaran Neetha , Smigiel Jacob , Chan E. Ricky , Yuan Xueer , Rios Brenda , Jackson Mark W.
Published: September 2024

S2. Kaplan Meier comparison of IL-6 family member receptors.
Supplementary Fig S3 from Chromatin-associated SIN3B protects cancer cells from genotoxic stress-induced apoptosis and dictates DNA damage repair pathway choice
Authors: Morales-Valencia Jorge , Petit Coralie , Calderon Alexander , Saini Siddharth , David Gregory
Published: September 2024

Cell cycle effect on DNA damage-induced apoptosis
Supplementary Fig S1 from Chromatin-associated SIN3B protects cancer cells from genotoxic stress-induced apoptosis and dictates DNA damage repair pathway choice
Authors: Morales-Valencia Jorge , Petit Coralie , Calderon Alexander , Saini Siddharth , David Gregory
Published: September 2024

SIN3B protects against DNA damage-induced apoptosis.
Supplementary Figure 9 from Targeting the ATF6-mediated ER stress response and autophagy blocks integrin-driven prostate cancer progression
Authors: Macke Amanda J. , Pachikov Artem N. , Divita Taylor E. , Morris Mary E. , LaGrange Chad A. , Holzapfel Melissa S. , Kubyshkin Anatoly V. , Zyablitskaya Evgeniya Y. , Makalish Tatiana P. , Eremenko Sergey N. , Qiu Haowen , Riethoven Jean-Jack M. , Hemstreet George P. , Petrosyan Armen
Published: September 2024

Figure S9. (A) Left Panels: representative images of triple IHC staining of Na+/K+-ATPase (green), Integrin αv (red), and Gal-3 (brown) in the orthotopic tumor samples from the indicated group of mice; bars, 100 µm. Middle panel: IF of Golgi stained by GM130 in the prostate tumor foci; bars, 10 µm. White boxes indicate areas enlarged at the right. (B) Quantification of Golgi fragments per cell in tumor foci from samples in A; median ± SD. (C) ATF6 IF in the orthotopic tumor samples from the indicated group of mice; bars, 20 µm. Areas of mice prostate epithelium is highlighted by dotted lines. (D) Quantification of ATF6 IF intensity from samples in C; median ± SD. For all graphs: pairwise comparisons using Wilcoxon rank sum exact test, p-adjusted using Benjamini-Hochberg; ****p<0.0001, **p<0.01, and *p<0.05; n indicates the number of foci counted. (E) IF staining of the prostate tumor foci from the indicated group of mice to visualize Na+/K+-ATPase (magenta), Integrin αv (red), and Gal-3 (green); bars, 10 µm. (F, G) Quantification of IF intensity of Integrin αv (F) and Gal-3 (G) at the PM in samples from C; median ± SD.
Supplementary Figure 5 from Targeting the ATF6-mediated ER stress response and autophagy blocks integrin-driven prostate cancer progression
Authors: Macke Amanda J. , Pachikov Artem N. , Divita Taylor E. , Morris Mary E. , LaGrange Chad A. , Holzapfel Melissa S. , Kubyshkin Anatoly V. , Zyablitskaya Evgeniya Y. , Makalish Tatiana P. , Eremenko Sergey N. , Qiu Haowen , Riethoven Jean-Jack M. , Hemstreet George P. , Petrosyan Armen
Published: September 2024

Figure S5. (A, B) Representative EM images of PC-3 (A) and DU145 (B) cells. Note phagophore nucleation from Golgi (arrowheads) and autophagosomes localizing close to the Golgi (arrow). Orange boxes indicate the areas magnified at the right. (C) WIPI2 W-B of the Golgi fractions isolated from LNCaP, PC-3, and DU145 cells. Samples were normalized by GM130.
Supplementary Figure 3 from LncRNA-encoded Micropeptide ACLY‍-‍BP drives lipid deposition and cell proliferation in Clear Cell Renal Cell Carcinoma via maintenance of ACLY acetylation
Authors: Zhang Shenghua , Zhang Zheng , Liu Xiaolong , Deng Yibin , Zheng Jian , Deng Jieqiong , Wang Yirong , Guo Binbin , Li Fanrong , Chen Xiaoyue , Pan Yacheng , Wang Jieyu , Lu Jiachun , Wu Siqi , Guo Qiang , Zhou Yifeng
Published: September 2024

Related information to figure 2, figure 3, and figure 5
Supplementary Figure 5 from Hierarchical phosphorylation of HOXB13 by mTOR dictates its activity and oncogenic function in prostate cancer
Authors: Chen Yonghong , Dufour Catherine R. , Han Lingwei , Li Ting , Xia Hui , Giguere Vincent
Published: September 2024

Supplementary Figure 5. HOXB13 transcriptional activity depends on its phosphorylation status.
Supplementary Table 2 from TRIM50 inhibits gastric cancer progression by regulating the ubiquitination and nuclear translocation of JUP
Authors: Hu Jiajia , Huang Runjie , Liang Chengcai , Wang Yingnan , Wang Min , Chen Yanxing , Wu Chenyi , Zhang Jinling , Liu Zekun , Zhao Qi , Liu Zexian , Wang Feng , Yuan Shuqiang
Published: September 2024

The raw data of 1B.
Table S2 from FBXO24 suppresses breast cancer tumorigenesis by targeting LSD1 for Ubiquitination
Authors: Dong Bo , Song Xiang , Wang Xinzhao , Dai Tao , Wang Jianlin , Yu Zhiyong , Deng Jiong , Evers B. Mark , Wu Yadi
Published: September 2024

The sequence of primers for RT-qPCR and ChIP-qPCR.
Supplementary Figure 6 from Competing engagement of β-arrestin isoforms balances IGF1R/p53 signaling and controls melanoma cell chemotherapeutic responsiveness
Authors: Cismas Sonia , Pasca Sylvya , Crudden Caitrin , Troccoli Drakensjo Iara , Suleymanova Naida , Zhang Simin , Gebhard Benjamin , Song Dawei , Neo Shiyong , Shibano Takashi , Smith Terry J. , Calin George A. , Girnita Ada , Girnita Leonard
Published: September 2024

Effect of β-arrestin imbalance on response to dacarbazine (DTIC)
Data from EIF4A3 acts on the PI3K-AKT-ERK1/2-P70S6K pathway through FLOT1 to influence the development of lung adenocarcinoma
Authors: Yu Wenhao , Liang Jinghui , Fang Tao , Jiang Jin , Zhao Renchang , Li Rongyang , Han Jingyi , Tian Hui
Published: September 2024

Abstract
Lung adenocarcinoma (LUAD) is a major lung cancer subtype. In this study, we discovered that the eukaryotic translation initiation factor EIF4A3 expression was significantly higher in LUAD tissues, and that this higher expression was closely linked to a poor prognosis for LUAD. In addition, we demonstrated that the knockdown of EIF4A3 significantly inhibited the proliferation, invasion, and migration of LUAD cells in vitro and in vivo. The findings of mass spectrometry analysis revealed that EIF4A3 could interact with Flotillin-1 in lung adenocarcinoma cells and that EIF4A3 could positively regulate the expression of FLOT1 at the protein level. Meanwhile, transcriptome sequencing showed that EIF4A3 could influence the development of lung adenocarcinoma by affecting PI3K-AKT-ERK1/2-P70S6K and PI3K class III-mediated autophagy in the Apelin pathway. In addition, we confirmed that Flotillin-1 expression was upregulated in LUAD based on the existing literature, and knockdown of FLOT1 could inhibit the proliferation and migration of LUAD cells. And the knockdown of Flotillin-1 reversed the increase of cell proliferation and migration caused by EIF4A3 overexpression. Furthermore, we found that the activation of PI3K-AKT-ERK1/2-P70S6K signaling pathway and PI3K class III-mediated autophagy caused by EIF4A3 overexpression was rescued by the knockdown of FLOT1. In a word, we proved that EIF4A3 positively regulates the expression of FLOT1 and plays a pro-cancer role in LUAD.
Implications: Our study revealed the role of EIF4A3 in prognosis and tumor progression in LUAD, indicating that EIF4A3 could be employed as the molecular diagnostic and prognostic therapeutic target.
Data from MDM2 inhibition enhances immune checkpoint inhibitor efficacy by increasing IL-15 and MHC class II production
Authors: Langenbach Marlene , Giesler Sophie , Richtsfeld Stefan , da Costa-Pereira Sara , Rindlisbacher Lukas , Wertheimer Tobias , Braun Lukas M. , Andrieux Geoffroy , Duquesne Sandra , Pfeifer Dietmar , Woessner Nadine M. , Menssen Hans D. , Taromi Sanaz , Duyster Justus , Boerries Melanie , Brummer Tilman , Blazar Bruce R. , Minguet Susana , Turko Patrick , Levesque Mitchell P. , Becher Burkhard , Zeiser Robert
Published: September 2024

Abstract
The treatment of metastatic melanoma patients with immune checkpoint inhibitors (ICI) leads to impressive response rates but primary and secondary resistance to ICI reduce progression-free survival. Novel strategies that interfere with resistance mechanisms are key to further improve patient outcome during ICI therapy. P53 is often inactivated by mouse-double-minute-2 (MDM2), which may decrease immunogenicity of melanoma cells.
We analyzed primary patient-derived melanoma cell lines, performed bulk sequencing analysis of patient-derived melanoma samples and used melanoma mouse models to investigate the role of MDM2-inhibition for enhanced ICI therapy.
We found increased expression of IL-15 and MHC-II in murine melanoma cells upon p53 induction by MDM2-inhibition. MDM2-inhibitor induced MHC-II and IL-15-production, which was p53 dependent as p53 knockdown blocked the effect. Lack of IL-15-receptor in hematopoietic cells or IL-15 neutralization reduced the MDM2-inhibition/p53-induction mediated anti-tumor immunity. p53 induction by MDM2-inhibition caused anti-melanoma immune memory as T cells isolated from MDM2-inhibitor treated melanoma bearing mice exhibited anti-melanoma activity in secondary melanoma-bearing mice. In patient-derived melanoma cells p53 induction by MDM2-inhibition increased IL-15 and MHC-II. IL-15 and CIITA expression was associated with a more favorable prognosis in patients bearing WT but not TP53 mutated melanoma. Implications: MDM2-inhibition represents a novel strategy to enhance IL-15 and MHC-II-production, which disrupts the immunosuppressive tumor microenvironment. Based on our findings a clinical trial combining MDM2-inhibition with anti-PD-1 immunotherapy for metastatic melanoma is planned.
Data from Absence of either Ripk3 or Mlkl reduces incidence of hepatocellular carcinoma independent of liver fibrosis
Authors: Mohammed Sabira , Thadathil Nidheesh , Ohene-Marfo Phoebe , Tran Albert L. , Van Der Veldt Michael , Georgescu Constantin , Oh Sangphil , Nicklas Evan H. , Wang Dawei , Haritha Nair Hariprasad , Luo Wenyi , Janknecht Ralf , Miller Benjamin F. , Wren Jonathan D. , Freeman Willard M. , Deepa Sathyaseelan S.
Published: September 2024

Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the etiologies that contribute to hepatocellular carcinoma (HCC), and chronic inflammation is one of the proposed mediators of HCC. Since necroptosis is a cell death pathway that induces inflammation, we tested whether necroptosis-induced inflammation contributes to the progression of NAFLD to HCC in a mouse model of diet-induced HCC. Male and female wild-type (WT) mice and mouse models where necroptosis is blocked (Ripk3-/- or Mlkl-/- mice) were fed either a control diet or choline-deficient low-fat diet (CD-LFD) or CD-high fat diet (CD-HFD). Blocking necroptosis reduced markers of inflammation [proinflammatory cytokines (TNF, IL-6, and IL-1), F4/80+ve macrophages, CCR2+ve infiltrating monocytes], inflammation associated oncogenic pathways (JNK, PD-L1/PD-1, -catenin), and HCC in male mice. We demonstrate that hepatic necroptosis promotes recruitment and activation of liver macrophages leading to chronic inflammation, which in turn trigger oncogenic pathways leading to the progression of NAFLD to HCC in male mice. Whereas in female mice, blocking necroptosis reduced HCC independent of inflammation. Our data show a sex-specific difference in the development of inflammation, fibrosis and HCC in WT mice. However, blocking necroptosis reduced HCC in both males and females without altering liver fibrosis. Thus, our study suggests that necroptosis is a valid therapeutic target for NAFLD-mediated HCC.
Implications: Necroptosis is a major contributor to hepatic inflammation that drives the progression of NAFLD to HCC and therefore represents a valid target for NAFLD-mediated HCC.
Data from Single-Cell Evolutionary Analysis Reveals Drivers of Plasticity and Mediators of Chemoresistance in Small Cell Lung Cancer
Authors: Wollenzien Hannah , Tecleab Yohannes Afeworki A. , Szczepaniak-Sloane Robert , Restaino Anthony , Kareta Michael S.
Published: September 2024

Abstract
Small Cell Lung Cancer (SCLC) is often a heterogeneous tumor, where dynamic regulation of key transcription factors can drive multiple populations of phenotypically different cells which contribute differentially to tumor dynamics. This tumor is characterized by a very low 2-year survival rate, high rates of metastasis, and rapid acquisition of chemoresistance. The heterogeneous nature of this tumor makes it difficult to study and to treat, as it is not clear how or when this heterogeneity arises. Here we describe temporal, single-cell analysis of SCLC to investigate tumor initiation and chemoresistance in both SCLC xenografts and an autochthonous SCLC model. We identify an early population of tumor cells with high expression of AP-1 network genes that are critical for tumor growth. Furthermore, we have identified and validated the cancer testis antigens (CTAs) PAGE5 and GAGE2A as mediators of chemoresistance in human SCLC. CTAs have successfully been targeted in other tumor types and may be a promising avenue for targeted therapy in SCLC.

Implications: Understanding the evolutionary dynamics of SCLC can shed light on key mechanisms such as cellular plasticity, heterogeneity, and chemoresistance.