bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S7 from Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy
Authors: Chand Dhan , Savitsky David A. , Krishnan Shanmugarajan , Mednick Gabriel , Delepine Chloe , Garcia-Broncano Pilar , Soh Kah Teong , Wu Wei , Wilkens Margaret K. , Udartseva Olga , Vincent Sylvia , Joshi Bishnu , Keith Justin G. , Manrique Mariana , Marques Marilyn , Tanne Antoine , Levey Daniel L. , Han Haiyong , Ng Serina , Ridpath Jackson , Huber Olivia , Morin Benjamin , Galand Claire , Bourdelais Sean , Gombos Randi B. , Ward Rebecca , Qin Yu , Waight Jeremy D. , Costa Matthew R. , Sebastian-Yague Alvaro , Rudqvist Nils-Petter , Pupecka-Swider Malgorzata , Venkatraman Vignesh , Slee Andrew , Patel Jaymin M. , Grossman Joseph E. , Wilson Nicholas S. , Von Hoff Daniel D. , Stebbing Justin , Curiel Tyler J. , Buell Jennifer S. , O’Day Steven J. , Stein Robert B.
Published: December 2024

This dataset provides detailed information on the binding characteristics and functional properties of botensilimab. This comprehensive dataset demonstrates botensilimab's high affinity and selectivity for CTLA-4, its ability to effectively block CTLA-4 interactions with its ligands comparable to that of the parental IgG1 anti-CTLA-4 antibody. Importantly, this data further supports that the superior functional attributes of botensilimab are due to the Fc-engineered region and not the variable region of the antibody.
Figure S5 from RNA Shielding of p65 Is Required to Potentiate Oncogenic Inflammation in TET2-Mutated Clonal Hematopoiesis
Authors: Ben-Crentsil Nana Adjoa , Mohammed Ismail Wazim , Balasis Maria E. , Newman Hannah , Quintana Ariel , Binder Moritz , Kruer Traci , Neupane Surendra , Ferrall-Fairbanks Meghan C. , Fernandez Jenna , Lasho Terra L. , Finke Christy M. , Ibrahim Mohammed L. , McGraw Kathy L. , Wysota Michael , Aldrich Amy L. , Ryder Christopher B. , Letson Christopher T. , Traina Joshua , McLemore Amy F. , Droin Nathalie , Shastri Aditi , Yun Seongseok , Solary Eric , Sallman David A. , Beg Amer A. , Ma Li , Gaspar-Maia Alexandre , Patnaik Mrinal M. , Padron Eric
Published: December 2024

Contains data showing Malat1 depletion has no effect on myelopoiesis or self-renewal
Supplementary Figure S5 from Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy
Authors: Chand Dhan , Savitsky David A. , Krishnan Shanmugarajan , Mednick Gabriel , Delepine Chloe , Garcia-Broncano Pilar , Soh Kah Teong , Wu Wei , Wilkens Margaret K. , Udartseva Olga , Vincent Sylvia , Joshi Bishnu , Keith Justin G. , Manrique Mariana , Marques Marilyn , Tanne Antoine , Levey Daniel L. , Han Haiyong , Ng Serina , Ridpath Jackson , Huber Olivia , Morin Benjamin , Galand Claire , Bourdelais Sean , Gombos Randi B. , Ward Rebecca , Qin Yu , Waight Jeremy D. , Costa Matthew R. , Sebastian-Yague Alvaro , Rudqvist Nils-Petter , Pupecka-Swider Malgorzata , Venkatraman Vignesh , Slee Andrew , Patel Jaymin M. , Grossman Joseph E. , Wilson Nicholas S. , Von Hoff Daniel D. , Stebbing Justin , Curiel Tyler J. , Buell Jennifer S. , O’Day Steven J. , Stein Robert B.
Published: December 2024

This dataset presents the pharmacokinetic (PK) profile of mouse Fc-enhanced anti-CTLA-4 antibody versus the parental anti-CTLA-4 antibody. The PK profile is important for interpreting the efficacy data, and further supports the conclusion that the enhanced anti-tumor effects are likely due to the engineered Fc-mediated functions rather than altered drug exposure or persistence in the body.
Supplementary Figure S2 from Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy
Authors: Chand Dhan , Savitsky David A. , Krishnan Shanmugarajan , Mednick Gabriel , Delepine Chloe , Garcia-Broncano Pilar , Soh Kah Teong , Wu Wei , Wilkens Margaret K. , Udartseva Olga , Vincent Sylvia , Joshi Bishnu , Keith Justin G. , Manrique Mariana , Marques Marilyn , Tanne Antoine , Levey Daniel L. , Han Haiyong , Ng Serina , Ridpath Jackson , Huber Olivia , Morin Benjamin , Galand Claire , Bourdelais Sean , Gombos Randi B. , Ward Rebecca , Qin Yu , Waight Jeremy D. , Costa Matthew R. , Sebastian-Yague Alvaro , Rudqvist Nils-Petter , Pupecka-Swider Malgorzata , Venkatraman Vignesh , Slee Andrew , Patel Jaymin M. , Grossman Joseph E. , Wilson Nicholas S. , Von Hoff Daniel D. , Stebbing Justin , Curiel Tyler J. , Buell Jennifer S. , O’Day Steven J. , Stein Robert B.
Published: December 2024

This dataset presents comparative results demonstrating the enhanced efficacy of Fc-enhanced anti-CTLA-4 versus the parental anti-CTLA-4 antibody in various tumor-bearing mouse models. Data from multiple tumor-bearing mouse models, strengthens the generalizability of the findings across different tumor types. The individual mouse data allows for a detailed view of treatment responses, including, variability within treatment groups, timing and rate of tumor growth or regression and potential identification of exceptional responders or non-responders.
Supplementary Figure S16 from Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy
Authors: Chand Dhan , Savitsky David A. , Krishnan Shanmugarajan , Mednick Gabriel , Delepine Chloe , Garcia-Broncano Pilar , Soh Kah Teong , Wu Wei , Wilkens Margaret K. , Udartseva Olga , Vincent Sylvia , Joshi Bishnu , Keith Justin G. , Manrique Mariana , Marques Marilyn , Tanne Antoine , Levey Daniel L. , Han Haiyong , Ng Serina , Ridpath Jackson , Huber Olivia , Morin Benjamin , Galand Claire , Bourdelais Sean , Gombos Randi B. , Ward Rebecca , Qin Yu , Waight Jeremy D. , Costa Matthew R. , Sebastian-Yague Alvaro , Rudqvist Nils-Petter , Pupecka-Swider Malgorzata , Venkatraman Vignesh , Slee Andrew , Patel Jaymin M. , Grossman Joseph E. , Wilson Nicholas S. , Von Hoff Daniel D. , Stebbing Justin , Curiel Tyler J. , Buell Jennifer S. , O’Day Steven J. , Stein Robert B.
Published: December 2024

This dataset examines the relationship between FCGR2A and FCGR3A gene expression and clinical response to anti-PD-1 or conventional anti-CTLA-4 therapies in patients with advanced melanoma. Analysis of multiple clinical trial datasets shows that response to these conventional immunotherapies is not associated with FCGR2A or FCGR3A expression levels. This contrasts with botensilimab's efficacy profile, supporting its unique Fc-dependent mechanism of action. The data further support that FCGR2A and FCGR3A expression could be predictive biomarkers of response to botensilimab, distinguishing it from conventional immunotherapies.
Supplementary Table S3 from MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer
Authors: Klingbeil Olaf , Skopelitis Damianos , Tonelli Claudia , Yoshimoto Toyoki , Alpsoy Aktan , Panepinto Maria C. , Minicozzi Francesca , Merrill Joseph R. , Cafiero Amanda M. , Aggarwal Disha , Russo Suzanne , Ha Taehoon , Demerdash Osama E. , Wee Tse-Luen , Spector David L. , Lyons Scott K. , Tuveson David A. , Cifani Paolo , Vakoc Christopher R.
Published: December 2024

Cancer cell line model information. Table of mutations and cancer driver of cell lines used in this study.
Key Resource Table from A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention
Authors: Yamaguchi Norihiro , Wu Y. Gloria , Ravetch Ethan , Takahashi Mai , Khan Abdul G. , Hayashi Akimasa , Mei Wenbin , Hsu Dennis , Umeda Shigeaki , de Stanchina Elisa , Lorenz Ivo C. , Iacobuzio-Donahue Christine A. , Tavazoie Sohail F.
Published: December 2024

key resource table with cat numbers
Figure S5 from A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention
Authors: Yamaguchi Norihiro , Wu Y. Gloria , Ravetch Ethan , Takahashi Mai , Khan Abdul G. , Hayashi Akimasa , Mei Wenbin , Hsu Dennis , Umeda Shigeaki , de Stanchina Elisa , Lorenz Ivo C. , Iacobuzio-Donahue Christine A. , Tavazoie Sohail F.
Published: December 2024

suppl. Figure 5 showing AMIGO2 as a cell surface receptor for NPTX1 and a driver of PDAC metastasis
Figure S4 from A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention
Authors: Yamaguchi Norihiro , Wu Y. Gloria , Ravetch Ethan , Takahashi Mai , Khan Abdul G. , Hayashi Akimasa , Mei Wenbin , Hsu Dennis , Umeda Shigeaki , de Stanchina Elisa , Lorenz Ivo C. , Iacobuzio-Donahue Christine A. , Tavazoie Sohail F.
Published: December 2024

suppl. Figure 4 showing NPTX1 promotes cell growth under hypoxic conditions
Supplementary Figure S8 from MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer
Authors: Klingbeil Olaf , Skopelitis Damianos , Tonelli Claudia , Yoshimoto Toyoki , Alpsoy Aktan , Panepinto Maria C. , Minicozzi Francesca , Merrill Joseph R. , Cafiero Amanda M. , Aggarwal Disha , Russo Suzanne , Ha Taehoon , Demerdash Osama E. , Wee Tse-Luen , Spector David L. , Lyons Scott K. , Tuveson David A. , Cifani Paolo , Vakoc Christopher R.
Published: December 2024

A, Rescue experiment of MARK2+3dKO in Cas9+ YAPC cells following knockout of indicated genes. Data shown are the mean ± SD of %GFP+ (normalized to day 3 after infection). n=3-6. P values are calculated using a mixed effects model (considering the interaction of experimental groups over time) compared to Ctrl group and corrected with Bonferroni-Holm (BH). B, Western blot analysis of YAPC cells. C, Normalized relative luminescence units (RLU) from CellTiter-Glo viability measurements of Cas9+ YAPC-MARK2+3dKO + MARK2M129G cells following 5 days of combinational treatment of 1NM-PP1 and either +DMSO (0.1%), +500nM MST1/2 inhibitor (XMU-MP-1) or + 5µM LATS1/2 inhibitor (Lats-IN-1). Data are shown as mean ± SD. n=9 measurements from three biological replicates performed in triplicate. Four-parameter dose-response curves were plotted. D,E Competition-based fitness assays for Ctrl and knockout of essential gene CDK1 corresponding to rescue experiment shown in Fig. 5A, 5E. Data shown are the mean ± SD of %GFP+ (normalized to day 3 after infection). n=3-6.
Supplementary Figure S4 from MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer
Authors: Klingbeil Olaf , Skopelitis Damianos , Tonelli Claudia , Yoshimoto Toyoki , Alpsoy Aktan , Panepinto Maria C. , Minicozzi Francesca , Merrill Joseph R. , Cafiero Amanda M. , Aggarwal Disha , Russo Suzanne , Ha Taehoon , Demerdash Osama E. , Wee Tse-Luen , Spector David L. , Lyons Scott K. , Tuveson David A. , Cifani Paolo , Vakoc Christopher R.
Published: December 2024

A, Western blot analysis of Cas9+ YAPC cells. B, Representative immunofluorescence (IF) images of YAP and DAPI following MARK2+3dKO in A549 cancer cells. scale bar = 30 µm. C, Comparison of mean immunofluorescence signal of YAP across the cell (A549) following MARK2+3dKO. P value was calculated using a two-tailed parametric t-test with Welch’s correction. n= 234 for Ctrl and n=155 for MARK2+3dKO cells were quantified. Data are shown as box plots with whiskers (5-95 percentile). D-E, Western blot analysis of MARK2 or MARK3 specific in-cell phosphorylation of Hippo pathway components. Substrates were labeled as described in Fig. 3D, and phosphorylation was identified by staining with thiophosphate ester-specific antibodies. Data are representative of two independent experiments. F, Coomassie stain of affinity purified recombinant Strep-SUMO tagged MARK2 (rMARK2) purified from insect cells. G, Western blot analysis of purified HA-CDC25C following treatment of Lambda phosphatase (L-PP) and phosphorylation using rMARK2.
Supplementary Data MS from MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer
Authors: Klingbeil Olaf , Skopelitis Damianos , Tonelli Claudia , Yoshimoto Toyoki , Alpsoy Aktan , Panepinto Maria C. , Minicozzi Francesca , Merrill Joseph R. , Cafiero Amanda M. , Aggarwal Disha , Russo Suzanne , Ha Taehoon , Demerdash Osama E. , Wee Tse-Luen , Spector David L. , Lyons Scott K. , Tuveson David A. , Cifani Paolo , Vakoc Christopher R.
Published: December 2024

Mass spectrometric identification and quantification of MARK2 substrate peptides This document contains mass spectrometric data supporting phosphorylation of specific phosphorylation sites on CDC25C, YAP, TAZ, and NF2. For each considered site, the fragmentation spectrum supporting peptide identity and phosphorylation localization, and the extracted precursor ion chromatogram (XIC) of the corresponding ions in samples treated with MARK2 and untreated (used for label-free quantification) are provided. All spectral intensity values are without normalization. For each phosphorylation site considered, both the phosphorylated and unmodified peptides are reported. To control for unspecific MARK2 activity, a peptide containing S and/or T residues and not detected as phosphorylated is considered for each protein. For these peptides, XIC for the theoretical m/z of the unmodified and phosphorylated peptides is reported to confirm that missed identification by MS2 was not caused by precursor under-sampling. To control for differences in the abundance of MARK2 substrate proteins, a peptide containing no S and T residues was reported, when available.
Supplementary Figure S7 from Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS-Mutant Colorectal Cancers
Authors: Loi Patrick , Schade Amy E. , Rodriguez Carrie L. , Krishnan Anjana , Perurena Naiara , Nguyen Van T.M. , Xu Yilin , Watanabe Marina , Davis Rachel A. , Gardner Alycia , Pilla Natalie F. , Mattioli Kaia , Popow Olesja , Gunduz Nuray , Lannagan Tamsin R.M. , Fitzgerald Samantha , Sicinska Ewa T. , Lin Jia-Ren , Tan William , Brais Lauren K. , Haigis Kevin M. , Giannakis Marios , Ng Kimmie , Santagata Sandro , Helin Kristian , Sansom Owen J. , Cichowski Karen
Published: December 2024

Extended data related to Figure 7.
Supplementary Figure S2 from Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS-Mutant Colorectal Cancers
Authors: Loi Patrick , Schade Amy E. , Rodriguez Carrie L. , Krishnan Anjana , Perurena Naiara , Nguyen Van T.M. , Xu Yilin , Watanabe Marina , Davis Rachel A. , Gardner Alycia , Pilla Natalie F. , Mattioli Kaia , Popow Olesja , Gunduz Nuray , Lannagan Tamsin R.M. , Fitzgerald Samantha , Sicinska Ewa T. , Lin Jia-Ren , Tan William , Brais Lauren K. , Haigis Kevin M. , Giannakis Marios , Ng Kimmie , Santagata Sandro , Helin Kristian , Sansom Owen J. , Cichowski Karen
Published: December 2024

EZH2 and MEK inhibitors do not cause toxicity in vivo.
Supplementary Figure S1 from Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS-Mutant Colorectal Cancers
Authors: Loi Patrick , Schade Amy E. , Rodriguez Carrie L. , Krishnan Anjana , Perurena Naiara , Nguyen Van T.M. , Xu Yilin , Watanabe Marina , Davis Rachel A. , Gardner Alycia , Pilla Natalie F. , Mattioli Kaia , Popow Olesja , Gunduz Nuray , Lannagan Tamsin R.M. , Fitzgerald Samantha , Sicinska Ewa T. , Lin Jia-Ren , Tan William , Brais Lauren K. , Haigis Kevin M. , Giannakis Marios , Ng Kimmie , Santagata Sandro , Helin Kristian , Sansom Owen J. , Cichowski Karen
Published: December 2024

Extended data related to Figure 1.
Supplementary Tables S1 to S7 from TREM2-Expressing Multinucleated Giant Macrophages Are a Biomarker of Good Prognosis in Head and Neck Squamous Cell Carcinoma
Authors: Gessain Grégoire , Anzali Ahmed-Amine , Lerousseau Marvin , Mulder Kevin , Bied Mathilde , Auperin Anne , Stockholm Daniel , Signolle Nicolas , Sassi Farah , Marques Da Costa Maria Eugenia , Marchais Antonin , Sayadi Alexandre , Weidner Daniela , Uderhardt Stefan , Blampey Quentin , Nakkireddy Sumanth Reddy , Broutin Sophie , Dutertre Charles-Antoine , Busson Pierre , Walter Thomas , Marhic Alix , Moya-Plana Antoine , Guerlain Johanne , Breuskin Ingrid , Casiraghi Odile , Gorphe Philippe , Classe Marion , Scoazec Jean-Yves , Blériot Camille , Ginhoux Florent
Published: December 2024

Clinical Tables and Statistical Analyses
Supplementary Table S9 from TREM2-Expressing Multinucleated Giant Macrophages Are a Biomarker of Good Prognosis in Head and Neck Squamous Cell Carcinoma
Authors: Gessain Grégoire , Anzali Ahmed-Amine , Lerousseau Marvin , Mulder Kevin , Bied Mathilde , Auperin Anne , Stockholm Daniel , Signolle Nicolas , Sassi Farah , Marques Da Costa Maria Eugenia , Marchais Antonin , Sayadi Alexandre , Weidner Daniela , Uderhardt Stefan , Blampey Quentin , Nakkireddy Sumanth Reddy , Broutin Sophie , Dutertre Charles-Antoine , Busson Pierre , Walter Thomas , Marhic Alix , Moya-Plana Antoine , Guerlain Johanne , Breuskin Ingrid , Casiraghi Odile , Gorphe Philippe , Classe Marion , Scoazec Jean-Yves , Blériot Camille , Ginhoux Florent
Published: December 2024

This table provides the DEG between MGC spots and non-MGC spots
Figure S5 from TREM2-Expressing Multinucleated Giant Macrophages Are a Biomarker of Good Prognosis in Head and Neck Squamous Cell Carcinoma
Authors: Gessain Grégoire , Anzali Ahmed-Amine , Lerousseau Marvin , Mulder Kevin , Bied Mathilde , Auperin Anne , Stockholm Daniel , Signolle Nicolas , Sassi Farah , Marques Da Costa Maria Eugenia , Marchais Antonin , Sayadi Alexandre , Weidner Daniela , Uderhardt Stefan , Blampey Quentin , Nakkireddy Sumanth Reddy , Broutin Sophie , Dutertre Charles-Antoine , Busson Pierre , Walter Thomas , Marhic Alix , Moya-Plana Antoine , Guerlain Johanne , Breuskin Ingrid , Casiraghi Odile , Gorphe Philippe , Classe Marion , Scoazec Jean-Yves , Blériot Camille , Ginhoux Florent
Published: December 2024

Supervised MGC signature
Supplementary methods from TCR-Engineered T Cells Directed against Ropporin-1 Constitute a Safe and Effective Treatment for Triple-Negative Breast Cancer
Authors: Kortleve Dian , Hammerl Dora , van Brakel Mandy , Wijers Rebecca , Roelofs Daphne , Kroese Kim , Timmermans Mieke M. , Liao Chen-Yi , Huang Shaozhuo , Trapman-Jansen Anita , Foekens Renée , Michaux Justine , de Beijer Monique T.A. , Buschow Sonja I. , Demmers Jeroen A.A. , Kok Marleen , Danen Erik H.J. , Bassani-Sternberg Michal , Martens John W.M. , Abbott Rachel J.M. , Debets Reno
Published: December 2024

This file contains supplementary methods and references.
Supplementary Table 3 from TCR-Engineered T Cells Directed against Ropporin-1 Constitute a Safe and Effective Treatment for Triple-Negative Breast Cancer
Authors: Kortleve Dian , Hammerl Dora , van Brakel Mandy , Wijers Rebecca , Roelofs Daphne , Kroese Kim , Timmermans Mieke M. , Liao Chen-Yi , Huang Shaozhuo , Trapman-Jansen Anita , Foekens Renée , Michaux Justine , de Beijer Monique T.A. , Buschow Sonja I. , Demmers Jeroen A.A. , Kok Marleen , Danen Erik H.J. , Bassani-Sternberg Michal , Martens John W.M. , Abbott Rachel J.M. , Debets Reno
Published: December 2024

Overview of healthy cell lines.
Supplementary Figure 8 from TCR-Engineered T Cells Directed against Ropporin-1 Constitute a Safe and Effective Treatment for Triple-Negative Breast Cancer
Authors: Kortleve Dian , Hammerl Dora , van Brakel Mandy , Wijers Rebecca , Roelofs Daphne , Kroese Kim , Timmermans Mieke M. , Liao Chen-Yi , Huang Shaozhuo , Trapman-Jansen Anita , Foekens Renée , Michaux Justine , de Beijer Monique T.A. , Buschow Sonja I. , Demmers Jeroen A.A. , Kok Marleen , Danen Erik H.J. , Bassani-Sternberg Michal , Martens John W.M. , Abbott Rachel J.M. , Debets Reno
Published: December 2024

Stepwise approach from retrieval and identification of TCRs to the functional testing of their sensitivity, specificity and reactivity.
Figure S6 from Identification and Characterization of Chemotherapy-Resistant High-Risk Neuroblastoma Persister Cells
Authors: Grossmann Liron D. , Chen Chia-Hui , Uzun Yasin , Thadi Anusha , Wolpaw Adam J. , Louault Kevin , Goldstein Yael , Surrey Lea F. , Martinez Daniel , Calafatti Matteo , Gerelus Mark , Gao Peng , Lee Lobin , Patel Khushbu , Kaufman Rebecca S. , Shani Guy , Farrel Alvin , Moshitch-Moshkovitz Sharon , Grimaldi Paris , Shapiro Matthew , Kendsersky Nathan M. , Lindsay Jarrett M. , Casey Colleen E. , Krytska Kateryna , Scolaro Laura , Tsang Matthew , Groff David , Matkar Smita , Kalna Josh R. , Mycek Emily , McDevitt Jayne , Runbeck Erin , Patel Tasleema , Bernt Kathrin M. , Asgharzadeh Shahab , DeClerck Yves A. , Mossé Yael P. , Tan Kai , Maris John M.
Published: December 2024

Supplementary Figure S6 shows the increase in NF-kB activity following chemotherapy and its role in survival which is enhanced by specific TAMs and CAFs
Figure S2 from Identification and Characterization of Chemotherapy-Resistant High-Risk Neuroblastoma Persister Cells
Authors: Grossmann Liron D. , Chen Chia-Hui , Uzun Yasin , Thadi Anusha , Wolpaw Adam J. , Louault Kevin , Goldstein Yael , Surrey Lea F. , Martinez Daniel , Calafatti Matteo , Gerelus Mark , Gao Peng , Lee Lobin , Patel Khushbu , Kaufman Rebecca S. , Shani Guy , Farrel Alvin , Moshitch-Moshkovitz Sharon , Grimaldi Paris , Shapiro Matthew , Kendsersky Nathan M. , Lindsay Jarrett M. , Casey Colleen E. , Krytska Kateryna , Scolaro Laura , Tsang Matthew , Groff David , Matkar Smita , Kalna Josh R. , Mycek Emily , McDevitt Jayne , Runbeck Erin , Patel Tasleema , Bernt Kathrin M. , Asgharzadeh Shahab , DeClerck Yves A. , Mossé Yael P. , Tan Kai , Maris John M.
Published: December 2024

Supplementary Figure S2 shows the details of the pathway-based clustering algorithm including the autocorrelation pathway scores, cell cycle annotation, pathway enrichment analysis and region analysis.
Supplementary Table 1 from Advancing Global Health Equity in Oncology Clinical Trial Access
Authors: Adewole Tolulope , Albrecht Bjorn , Beg Shaalan , Brawley Otis , Chang I-Fen , Daly Bobby , de Claro Angelo , Dent Jennifer , Dickler Maura , Ene-Obong Abasi , Fashoyin-Aje Lola , Finnegan Justin , Galbraith Susan , Gospodarowicz Mary , Gralow Julie , Haddad Tufia , Kalidas Chitkala , Katz Artur , Kaucic Karen , Keane Harriet , Lanasa Mark , Legos Jeff , Li Bob T. , Mills Jennifer , Oelrich Stefan , Olopade Stefan , Palma John , Pazdur Richard , Pilarski Piotr , Qian Jing , Rudd Kevin , Shokrpour Sepideh , Tendler Craig , Wilson Matt , Smart Victoria W. , Wu Yi-Long , Yan James , Zhang Lianshan , Li Diya , Shen Johanna , Silverstein Amy , Abou-Alfa Ghassan , Anderson Shelly , Beyrer Patrick , Carnival Danielle , Clarke Stephen , Conneran Terri , DeAngelis Lisa M. , Diakos Connie , Diaz Luis , dos Anjos Carlos Henrique , Drebin Jeffrey A. , Eisenmen Debra , Flannery Russell , Fredrickson David , Isbell James M. , Jones David R. , Joseph Adedayo , Kennedy Caroline , Kingham T. Peter , Lee Adrian , Lee Nancy Y. , Leigh Lillian , Li Zhi-Zhong , Liu An-Wen , Liu Dazhi , Liu Si-Yang , Maggie Liu Si-Yang , Makker Vicky , Mallafre-Larrosa Meritxell , McBride Sean , Mestres Isabel , Mondaca Sebastian , Nigro Paulo , Norton Larry , Oyler John V. , Pavlakis Nick , Powell Simon , Robinson Bruce , Qin Yi , Razavi Pedram , Reis-Filho Jorge , Rocco Gaetano , Rudin Charles M. , Schell Orville , Scher Howard I. , Schrag Deborah , Simon Greg , Smith Dorrance , Speece Morgan , Tu Hai-Yan , Umar-Sadiq Aminu , Wang Bu-Hai , Wheeler Helen , Xu Chong-Rui , Yan Li-Xu , Yang Fan , Yoon Byeong , Young Catharine , Zhang Jia-Tao , Zhou Qing
Published: December 2024

Supplementary Table 1: Authors and affiliations
Supplementary Figures S1-S17 from NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations
Authors: Lin Jessica J. , Horan Joshua C. , Tangpeerachaikul Anupong , Swalduz Aurélie , Valdivia Augusto , Johnson Melissa L. , Besse Benjamin , Camidge D. Ross , Fujino Toshio , Yoda Satoshi , Nguyen-Phuong Linh , Mizuta Hayato , Bigot Ludovic , Nobre Catline , Lee Jii Bum , Yu Mi Ra , Mente Scot , Sun Yuting , Kohl Nancy E. , Porter James R. , Shair Matthew D. , Zhu Viola W. , Felip Enriqueta , Cho Byoung Chul , Friboulet Luc , Hata Aaron N. , Pelish Henry E. , Drilon Alexander
Published: December 2024

Supplementary Figure S1. Chemistry/X-ray. Supplementary Figure S2. Biochemical activity of ALK TKIs. Supplementary Figure S3. Kinome profiling of NVL-655. Supplementary Figure S4. Potency in cell viability assay. Supplementary Figure S5. Maximal effect (Emax) in cell viability assay. Supplementary Figure S6. Cellular activity of NVL-655. Supplementary Figure S7. Comparing NVL-655 and lorlatinib potency. Supplementary Figure S8. Pathway analysis in cell lines. Supplementary Figure S9. Further evidence for on-target activity of NVL-655. Supplementary Figure S10. TRK activity. Supplementary Figure S11. Selectivity for ALK versus TRK using additional assays. Supplementary Figure S12. In vivo studies for ALK fusion with a wild-type kinase domain. Supplementary Figure S13. In vivo studies for ALK fusion with G1202R or I1171N single mutations. Supplementary Figure S14. In vivo studies for ALK fusion with G1202R compound mutations. Supplementary Figure S15. Pharmacodynamic analysis in G1202R compound mutation models. Supplementary Figure S16. Body weight and H&E staining for the YU-1077 intracranial study. Supplementary Figure S17. Estimating TRKB inhibition in humans and mice.
Data from Increased RNA and Protein Degradation Is Required for Counteracting Transcriptional Burden and Proteotoxic Stress in Human Aneuploid Cells
Authors: Ippolito Marica Rosaria , Zerbib Johanna , Eliezer Yonatan , Reuveni Eli , Viganò Sonia , De Feudis Giuseppina , Shulman Eldad D. , Savir Kadmon Anouk , Slutsky Rachel , Chang Tiangen , Campagnolo Emma M. , Taglietti Silvia , Scorzoni Simone , Gianotti Sara , Martin Sara , Muenzner Julia , Mülleder Michael , Rozenblum Nir , Rubolino Carmela , Ben-Yishay Tal , Laue Kathrin , Cohen-Sharir Yael , Vigorito Ilaria , Nicassio Francesco , Ruppin Eytan , Ralser Markus , Vazquez Francisca , Santaguida Stefano , Ben-David Uri
Published: December 2024

Abstract
Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. In this study, we dissected multiple diploid versus aneuploid cell models. We found that aneuploid cells cope with transcriptional burden by increasing several RNA degradation pathways, and are consequently more sensitive to the perturbation of RNA degradation. At the protein level, aneuploid cells mitigate proteotoxic stress by reducing protein translation and increasing protein degradation, rendering them more sensitive to proteasome inhibition. These findings were recapitulated across hundreds of human cancer cell lines and primary tumors, and aneuploidy levels were significantly associated with the response of patients with multiple myeloma to proteasome inhibitors. Aneuploid cells are therefore preferentially dependent on several key nodes along the gene expression process, creating clinically actionable vulnerabilities in aneuploid cells.

Significance: Aneuploidy is a hallmark of cancer that is associated with poor prognosis and worse drug response. We reveal that cells with extra chromosomes compensate for their imbalanced DNA content by altering their RNA and protein metabolism, rendering them more sensitive to perturbation of RNA and protein degradation.

See related commentary by Bakhoum, p. 2315
Data from Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy
Authors: Chand Dhan , Savitsky David A. , Krishnan Shanmugarajan , Mednick Gabriel , Delepine Chloe , Garcia-Broncano Pilar , Soh Kah Teong , Wu Wei , Wilkens Margaret K. , Udartseva Olga , Vincent Sylvia , Joshi Bishnu , Keith Justin G. , Manrique Mariana , Marques Marilyn , Tanne Antoine , Levey Daniel L. , Han Haiyong , Ng Serina , Ridpath Jackson , Huber Olivia , Morin Benjamin , Galand Claire , Bourdelais Sean , Gombos Randi B. , Ward Rebecca , Qin Yu , Waight Jeremy D. , Costa Matthew R. , Sebastian-Yague Alvaro , Rudqvist Nils-Petter , Pupecka-Swider Malgorzata , Venkatraman Vignesh , Slee Andrew , Patel Jaymin M. , Grossman Joseph E. , Wilson Nicholas S. , Von Hoff Daniel D. , Stebbing Justin , Curiel Tyler J. , Buell Jennifer S. , O’Day Steven J. , Stein Robert B.
Published: December 2024

Abstract
Conventional immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) elicit durable survival but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti–CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA coengagement seems critical for activity, potentially explaining the modest clinical benefits of approved anti–CTLA-4 antibodies. We demonstrate that anti–CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T-cell responsiveness, reduce intratumoral regulatory T cells, and enhance antigen-presenting cell activation. Fc-enhanced anti–CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti–CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti–CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment–refractory cancers. Efficacy was independent of tumor neoantigen burden or FCGR3A genotype. However, FCGR2A and FCGR3A expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti–CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.
Significance:
This study reveals that Fc-enhanced anti–CTLA-4 harnesses novel mechanisms to overcome the limitations of conventional anti–CTLA-4, effectively treating poorly immunogenic and treatment-refractory cancers. Our findings support the development of a new class of immuno-oncology agents, capable of extending clinical benefit to patients with cancers resistant to current immunotherapies.
Data from Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS-Mutant Colorectal Cancers
Authors: Loi Patrick , Schade Amy E. , Rodriguez Carrie L. , Krishnan Anjana , Perurena Naiara , Nguyen Van T.M. , Xu Yilin , Watanabe Marina , Davis Rachel A. , Gardner Alycia , Pilla Natalie F. , Mattioli Kaia , Popow Olesja , Gunduz Nuray , Lannagan Tamsin R.M. , Fitzgerald Samantha , Sicinska Ewa T. , Lin Jia-Ren , Tan William , Brais Lauren K. , Haigis Kevin M. , Giannakis Marios , Ng Kimmie , Santagata Sandro , Helin Kristian , Sansom Owen J. , Cichowski Karen
Published: December 2024

Abstract
Current treatments for KRAS-mutant colorectal cancers are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of histone methyltransferase, EZH2, synergize with various rat sarcoma virus (RAS) pathway inhibitors and promote dramatic tumor regression in vivo. Together these agents cooperatively suppress Wingless and Int-1 (WNT)-driven transcription and drive colorectal cancers into a more differentiated cell state by inducing the Groucho/transducin-like enhancer corepressor, TLE4, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the proapoptotic protein BCL2 modifying factor (BMF), which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, by blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant colorectal cancers and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis.
Significance:
Combined EZH2 and RAS pathway inhibitors kill KRAS-mutant colorectal cancer cells and promote durable tumor regression in vivo. These agents function by cooperatively suppressing the WNT pathway, driving differentiation, and epigenetically reprogramming cells to permit the induction of apoptotic signals, which then kill these more differentiated tumor cells.
Data from TCR-Engineered T Cells Directed against Ropporin-1 Constitute a Safe and Effective Treatment for Triple-Negative Breast Cancer
Authors: Kortleve Dian , Hammerl Dora , van Brakel Mandy , Wijers Rebecca , Roelofs Daphne , Kroese Kim , Timmermans Mieke M. , Liao Chen-Yi , Huang Shaozhuo , Trapman-Jansen Anita , Foekens Renée , Michaux Justine , de Beijer Monique T.A. , Buschow Sonja I. , Demmers Jeroen A.A. , Kok Marleen , Danen Erik H.J. , Bassani-Sternberg Michal , Martens John W.M. , Abbott Rachel J.M. , Debets Reno
Published: December 2024

Abstract
Triple-negative breast cancer (TNBC) has an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues. Human leukocyte antigen-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCR) from naïve repertoires. Following gene introduction into T cells and stringent selection, we retrieved a highly specific TCR directed against the epitope FLYTYIAKV that did not recognize noncognate epitopes from alternative source proteins. Notably, this TCR-mediated killing of three-dimensional (3D) tumoroids in vitro and tumor cells in vivo and outperformed standard-of-care drugs. Finally, the T-cell product expressing this TCR and manufactured using a clinical protocol fulfilled standard safety and efficacy assays. Collectively, we have identified and preclinically validated ROPN1 as a target and anti-ROPN1 TCR T cells as a treatment for the vast majority of patients with TNBC.

Significance: Metastatic TNBC has a dismal prognosis. This study discovers Ropporin-1 as a target for T-cell therapy for most patients. The selected TCR is highly specific and sensitive in advanced models, and preclinical testing shows that the T-cell product expressing this TCR, manufactured according to good manufacturing practice, has favorable safety and potency.
Data from Identification and Characterization of Chemotherapy-Resistant High-Risk Neuroblastoma Persister Cells
Authors: Grossmann Liron D. , Chen Chia-Hui , Uzun Yasin , Thadi Anusha , Wolpaw Adam J. , Louault Kevin , Goldstein Yael , Surrey Lea F. , Martinez Daniel , Calafatti Matteo , Gerelus Mark , Gao Peng , Lee Lobin , Patel Khushbu , Kaufman Rebecca S. , Shani Guy , Farrel Alvin , Moshitch-Moshkovitz Sharon , Grimaldi Paris , Shapiro Matthew , Kendsersky Nathan M. , Lindsay Jarrett M. , Casey Colleen E. , Krytska Kateryna , Scolaro Laura , Tsang Matthew , Groff David , Matkar Smita , Kalna Josh R. , Mycek Emily , McDevitt Jayne , Runbeck Erin , Patel Tasleema , Bernt Kathrin M. , Asgharzadeh Shahab , DeClerck Yves A. , Mossé Yael P. , Tan Kai , Maris John M.
Published: December 2024

Abstract
Relapse rates in high-risk neuroblastoma remain exceedingly high. The malignant cells that are responsible for relapse have not been identified, and mechanisms of therapy resistance remain poorly understood. In this study, we used single-nucleus RNA sequencing and bulk whole-genome sequencing to identify and characterize the residual malignant persister cells that survive chemotherapy from a cohort of 20 matched diagnosis and definitive surgery tumor samples from patients treated with high-risk neuroblastoma induction chemotherapy. We show that persister cells share common mechanisms of chemotherapy escape, including suppression of MYC(N) activity and activation of NFκB signaling, and the latter is further enhanced by cell–cell communication between the malignant cells and the tumor microenvironment. Overall, our work dissects the transcriptional landscape of cellular persistence in high-risk neuroblastoma and paves the way to the development of new therapeutic strategies to prevent disease relapse.

Significance: Approximately 50% of patients with high-risk neuroblastoma die of relapsed refractory disease. We identified the malignant cells that likely contribute to relapse and discovered key signaling pathways that mediate cellular persistence. Inhibition of these pathways and their downstream effectors is postulated to eliminate persister cells and prevent relapse.

See related commentary by Wolf et al., p. 2308
Data from Advancing Global Health Equity in Oncology Clinical Trial Access
Authors: Adewole Tolulope , Albrecht Bjorn , Beg Shaalan , Brawley Otis , Chang I-Fen , Daly Bobby , de Claro Angelo , Dent Jennifer , Dickler Maura , Ene-Obong Abasi , Fashoyin-Aje Lola , Finnegan Justin , Galbraith Susan , Gospodarowicz Mary , Gralow Julie , Haddad Tufia , Kalidas Chitkala , Katz Artur , Kaucic Karen , Keane Harriet , Lanasa Mark , Legos Jeff , Li Bob T. , Mills Jennifer , Oelrich Stefan , Olopade Stefan , Palma John , Pazdur Richard , Pilarski Piotr , Qian Jing , Rudd Kevin , Shokrpour Sepideh , Tendler Craig , Wilson Matt , Smart Victoria W. , Wu Yi-Long , Yan James , Zhang Lianshan , Li Diya , Shen Johanna , Silverstein Amy , Abou-Alfa Ghassan , Anderson Shelly , Beyrer Patrick , Carnival Danielle , Clarke Stephen , Conneran Terri , DeAngelis Lisa M. , Diakos Connie , Diaz Luis , dos Anjos Carlos Henrique , Drebin Jeffrey A. , Eisenmen Debra , Flannery Russell , Fredrickson David , Isbell James M. , Jones David R. , Joseph Adedayo , Kennedy Caroline , Kingham T. Peter , Lee Adrian , Lee Nancy Y. , Leigh Lillian , Li Zhi-Zhong , Liu An-Wen , Liu Dazhi , Liu Si-Yang , Maggie Liu Si-Yang , Makker Vicky , Mallafre-Larrosa Meritxell , McBride Sean , Mestres Isabel , Mondaca Sebastian , Nigro Paulo , Norton Larry , Oyler John V. , Pavlakis Nick , Powell Simon , Robinson Bruce , Qin Yi , Razavi Pedram , Reis-Filho Jorge , Rocco Gaetano , Rudin Charles M. , Schell Orville , Scher Howard I. , Schrag Deborah , Simon Greg , Smith Dorrance , Speece Morgan , Tu Hai-Yan , Umar-Sadiq Aminu , Wang Bu-Hai , Wheeler Helen , Xu Chong-Rui , Yan Li-Xu , Yang Fan , Yoon Byeong , Young Catharine , Zhang Jia-Tao , Zhou Qing
Published: December 2024

Summary:
Despite exponentially increased industry investment in oncology research and development with more than $80 billion spent annually, patient enrollment in clinical trials remains below 5% globally. Our multistakeholder international cancer coalition envisions ecosystem transformation with capacity building through a global “hub-and-spoke” network model to expand access to and accelerate clinical trials, thus ending cancer as a major cause of death in this lifetime.
Supplementary Figure 5 from Dynamic Evolution of Fibroblasts Revealed by Single-Cell RNA Sequencing of Human Pancreatic Cancer
Authors: Dimitrieva Slavica , Harrison Jon M. , Chang Jonathan , Piquet Michelle , Mino-Kenudson Mari , Gabriel Millicent , Sagar Vivek , Horn Heiko , Lage Kasper , Kim Julie , Li Gang , Weng Shaobu , Harris Cynthia , Kulkarni Anupriya S. , Ting David T. , Qadan Motaz , Fagenholz Peter J. , Ferrone Cristina R. , Grauel Angelo L. , Laszewski Tyler , Raza Alina , Riester Markus , Somerville Tim , Wagner Joel P. , Dranoff Glenn , Engelman Jeffrey A. , Kauffmann Audrey , Leary Rebecca , Warshaw Andrew L. , Lillemoe Keith D. , Fernández-del Castillo Carlos , Ruddy David A. , Liss Andrew S. , Cremasco Viviana
Published: December 2024

Supplementary Figure 5
Supplementary Figure 3 from Dynamic Evolution of Fibroblasts Revealed by Single-Cell RNA Sequencing of Human Pancreatic Cancer
Authors: Dimitrieva Slavica , Harrison Jon M. , Chang Jonathan , Piquet Michelle , Mino-Kenudson Mari , Gabriel Millicent , Sagar Vivek , Horn Heiko , Lage Kasper , Kim Julie , Li Gang , Weng Shaobu , Harris Cynthia , Kulkarni Anupriya S. , Ting David T. , Qadan Motaz , Fagenholz Peter J. , Ferrone Cristina R. , Grauel Angelo L. , Laszewski Tyler , Raza Alina , Riester Markus , Somerville Tim , Wagner Joel P. , Dranoff Glenn , Engelman Jeffrey A. , Kauffmann Audrey , Leary Rebecca , Warshaw Andrew L. , Lillemoe Keith D. , Fernández-del Castillo Carlos , Ruddy David A. , Liss Andrew S. , Cremasco Viviana
Published: December 2024

Supplementary Figure 3
Supplementary Figure 1 from Dynamic Evolution of Fibroblasts Revealed by Single-Cell RNA Sequencing of Human Pancreatic Cancer
Authors: Dimitrieva Slavica , Harrison Jon M. , Chang Jonathan , Piquet Michelle , Mino-Kenudson Mari , Gabriel Millicent , Sagar Vivek , Horn Heiko , Lage Kasper , Kim Julie , Li Gang , Weng Shaobu , Harris Cynthia , Kulkarni Anupriya S. , Ting David T. , Qadan Motaz , Fagenholz Peter J. , Ferrone Cristina R. , Grauel Angelo L. , Laszewski Tyler , Raza Alina , Riester Markus , Somerville Tim , Wagner Joel P. , Dranoff Glenn , Engelman Jeffrey A. , Kauffmann Audrey , Leary Rebecca , Warshaw Andrew L. , Lillemoe Keith D. , Fernández-del Castillo Carlos , Ruddy David A. , Liss Andrew S. , Cremasco Viviana
Published: December 2024

Supplementary Figure 1
Figure 7 from Dynamic Evolution of Fibroblasts Revealed by Single-Cell RNA Sequencing of Human Pancreatic Cancer
Authors: Dimitrieva Slavica , Harrison Jon M. , Chang Jonathan , Piquet Michelle , Mino-Kenudson Mari , Gabriel Millicent , Sagar Vivek , Horn Heiko , Lage Kasper , Kim Julie , Li Gang , Weng Shaobu , Harris Cynthia , Kulkarni Anupriya S. , Ting David T. , Qadan Motaz , Fagenholz Peter J. , Ferrone Cristina R. , Grauel Angelo L. , Laszewski Tyler , Raza Alina , Riester Markus , Somerville Tim , Wagner Joel P. , Dranoff Glenn , Engelman Jeffrey A. , Kauffmann Audrey , Leary Rebecca , Warshaw Andrew L. , Lillemoe Keith D. , Fernández-del Castillo Carlos , Ruddy David A. , Liss Andrew S. , Cremasco Viviana
Published: December 2024

TGFβ is a key mediator of gene expression in both cancer cells and CAFs. A and B, Circos plots depicting inferred ligand-to-target signaling between target genes (red) in fibroblasts (A) and cancer cells (B) and their associated paracrine (blue) or autocrine (yellow) ligands identified using NicheNet. Selected target genes represent those enriched in CAFs and transitional fibroblasts from untreated PDAC, relative to normal fibroblasts (A) or cancer cells relative to normal ductal cells (B). Within each panel, arrow colors indicate the population of cells expressing the ligand and their width indicate the ligand–receptor interaction weights. C, Dotplot displaying the expression of ligands identified in A and B in each cell population. The size of the dot represents the percentage of cells expressing that ligand, and color indicates the average expression level of the ligand across all cells within a cell population. D, Heatmap depicting the inferred contribution of cell populations to TGFβ signaling using CellChat. E, Hierarchical network diagram visualizing the inferred intercellular communication patterns for TGFβ signaling. Source and target cell populations are represented by solid and open circles, respectively. Line thickness is proportional to the communication probability between cell populations.
Figure 2 from Dynamic Evolution of Fibroblasts Revealed by Single-Cell RNA Sequencing of Human Pancreatic Cancer
Authors: Dimitrieva Slavica , Harrison Jon M. , Chang Jonathan , Piquet Michelle , Mino-Kenudson Mari , Gabriel Millicent , Sagar Vivek , Horn Heiko , Lage Kasper , Kim Julie , Li Gang , Weng Shaobu , Harris Cynthia , Kulkarni Anupriya S. , Ting David T. , Qadan Motaz , Fagenholz Peter J. , Ferrone Cristina R. , Grauel Angelo L. , Laszewski Tyler , Raza Alina , Riester Markus , Somerville Tim , Wagner Joel P. , Dranoff Glenn , Engelman Jeffrey A. , Kauffmann Audrey , Leary Rebecca , Warshaw Andrew L. , Lillemoe Keith D. , Fernández-del Castillo Carlos , Ruddy David A. , Liss Andrew S. , Cremasco Viviana
Published: December 2024

Genetic and transcriptomic features define distinct ductal cell populations. A, UMAP projection based on the top five PCs of ductal cell transcriptomes. B, Bubble plot demonstrating relative expression of marker genes across clusters. The intensity of the color is proportional to the average expression of the marker within a cluster, and the bubble size is proportional to the number of cells expressing the marker. C, Quantification of each cluster within tissue types. D, UMAP projections of KRAS mutation status in single cells. Subclustering of the ductal cell population is shown on the right. E, Violin plots indicating the expression of marker genes for cancer (FXYD3), normal duct (SLCA4), and hybrid (CRISP3, MUC5B, and SCGB3A1) cells in the three ductal cell clusters. Expression values in natural-log scale. F, Representative images of RNA-ISH (top) and H&E (bottom)-stained section tissue. Composition of RNA-ISH probe cocktails is indicated below. Normal pancreas was used to demonstrate staining of centroacinar cells/small duct (HTB2875) and centroacinar cell/large ducts (HTB2953). PDAC samples were used to demonstrate the staining of acinar-to-ductal metaplasia (HTB2903) and cancer cells (HTB2883). Scale bars, 100 μm for large images and 25 μm for inset images. UMAP, Uniform Manifold Approximation and Projection for Dimension Reduction; H&E, hematoxylin and eosin.
Depletion of Adipose Stroma-Like Cancer-Associated Fibroblasts Potentiates Pancreatic Cancer Immunotherapy
Authors: Rupert Joseph , Daquinag Alexes , Yu Yongmei , Dai Yulin , Zhao Zhongming , Kolonin Mikhail G.
Published: December 2024

Immune checkpoint blockade therapy, transformative in some cancer types, has remained ineffective for patients with pancreatic cancer. The effects of subpopulations of cancer-associated fibroblasts (CAF) on cancer progression and therapy resistance are incompletely understood. In this study, the roles of CAFs expressing platelet-derived growth factor receptor β (Pdgfrb) and of CAFs expressing markers of adipose stromal cells (ASC) were analyzed in mice with pancreatic ductal adenocarcinoma. Ablation of Pdgfrb+ cells resulted in suppression of primary pancreatic tumor growth, reduction of extracellular matrix deposition, and increased cancer cell metastasis to the liver. A peptide D-CAN, which induces apoptosis in ASC-like CAFs, also reduced pancreatic tumor growth and extracellular matrix deposition while promoting metastases. Single-cell RNA sequencing demonstrated that depletion of either Pdgfrb+ or ASC-like CAFs decreased frequencies of tumor endothelial cells and viable cancer cells. However, whereas depletion of Pdgfrb+ CAFs led to stronger induction of cancer cell aggressiveness markers, depletion of ASC-like CAFs had an opposite effect on remaining CAFs. Depletion of ASC-like CAFs using D-CAN also led to higher infiltration of cytotoxic T-lymphocytes and B-lymphocytes. Administration of anti-PDL1 antibody (aPDL1), which inhibits the immune checkpoint, had a stronger suppressive effect on tumor growth when combined with D-CAN in both female and male mice. Liver metastases were also reduced by the D-CAN/aPDL1 combination more effectively than by aPDL1 alone in female mice. We conclude that improved approaches to target ASC-like CAFs may be effective in combination with immunotherapy.

Significance:

This study shows that populations of CAFs have distinct effects on pancreatic cancer progression and shows that depletion of CAFs expressing adipose markers potentiates tumor/metastasis suppression effects of immune checkpoint blockade.