bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Activin A–Mediated Polarization of Cancer-Associated Fibroblasts and Macrophages Confers Resistance to Checkpoint Immunotherapy in Skin Cancer
Authors: Pich-Bavastro Christine , Yerly Laura , Di Domizio Jeremy , Tissot-Renaud Stéphanie , Gilliet Michel , Kuonen François
Published: September 2023

AbstractPurpose:
Cemiplimab is approved for the treatment of locally advanced basal cell carcinomas (BCC), although with mitigated results. We sought to interrogate the cellular and molecular transcriptional reprogramming underlying BCC resistance to immunotherapy.
Experimental Design:
Here, we combined spatial and single-cell transcriptomics to deconvolute the spatial heterogeneity of the tumor microenvironment in regard with response to immunotherapy, in a cohort of both naïve and resistant BCCs.
Results:
We identified subsets of intermingled cancer-associated fibroblasts (CAF) and macrophages contributing the most to CD8 T-cell exclusion and immunosuppression. Within this spatially resolved peritumoral immunosuppressive niche, CAFs and adjacent macrophages were found to display Activin A–mediated transcriptional reprogramming towards extracellular matrix remodeling, suggesting active participation to CD8 T-cell exclusion. In independent datasets of human skin cancers, Activin A–conditioned CAFs and macrophages were associated with resistance to immune checkpoint inhibitors (ICI).
Conclusions:
Altogether, our data identify the cellular and molecular plasticity of tumor microenvironment (TME) and the pivotal role of Activin A in polarizing the TME towards immune suppression and ICI resistance.
Data from Efficacy and Quality-of-Life Following Involved Nodal Radiotherapy for Head and Neck Squamous Cell Carcinoma: The INRT-AIR Phase II Clinical Trial
Authors: Sher David J. , Moon Dominic H. , Vo Dat , Wang Jing , Chen Liyuan , Dohopolski Michael , Hughes Randall , Sumer Baran D. , Ahn Chul , Avkshtol Vladimir
Published: September 2023

AbstractPurpose:
Elective neck irradiation (ENI) has long been considered mandatory when treating head and neck squamous cell carcinoma (HNSCC) with definitive radiotherapy, but it is associated with significant dose to normal organs-at-risk (OAR). In this prospective phase II study, we investigated the efficacy and tolerability of eliminating ENI and strictly treating involved and suspicious lymph nodes (LN) with intensity-modulated radiotherapy.
Patients and Methods:
Patients with newly diagnosed HNSCC of the oropharynx, larynx, and hypopharynx were eligible for enrollment. Each LN was characterized as involved or suspicious based on radiologic criteria and an in-house artificial intelligence (AI)–based classification model. Gross disease received 70 Gray (Gy) in 35 fractions and suspicious LNs were treated with 66.5 Gy, without ENI. The primary endpoint was solitary elective volume recurrence, with secondary endpoints including patterns-of-failure and patient-reported outcomes.
Results:
Sixty-seven patients were enrolled, with 18 larynx/hypopharynx and 49 oropharynx cancer. With a median follow-up of 33.4 months, the 2-year risk of solitary elective nodal recurrence was 0%. Gastrostomy tubes were placed in 14 (21%), with median removal after 2.9 months for disease-free patients; no disease-free patient is chronically dependent. Grade I/II dermatitis was seen in 90%/10%. There was no significant decline in composite MD Anderson Dysphagia Index scores after treatment, with means of 89.1 and 92.6 at 12 and 24 months, respectively.
Conclusions:
These results suggest that eliminating ENI is oncologically sound for HNSCC, with highly favorable quality-of-life outcomes. Additional prospective studies are needed to support this promising paradigm before implementation in any nontrial setting.
Data from Results of an Open-label, Phase Ia/b Study of Pembrolizumab plus Olaratumab in Patients with Unresectable, Locally Advanced, or Metastatic Soft-Tissue Sarcoma
Authors: Schöffski Patrick , Bahleda Rastislav , Wagner Andrew J. , Burgess Melissa A. , Junker Niels , Chisamore Michael , Peterson Patrick , Szpurka Anna M. , Ceccarelli Matteo , Tap William D.
Published: September 2023

AbstractPurpose:
The study evaluated safety and efficacy of olaratumab + pembrolizumab in patients with unresectable locally advanced/metastatic soft-tissue sarcoma (STS) with disease progression on standard treatment.
Patients and Methods:
This was open-label, multicenter, nonrandomized, phase Ia/Ib dose-escalation study followed by cohort expansion (olaratumab + pembrolizumab intravenous infusion). Primary objectives were safety and tolerability.
Results:
The majority of patients enrolled (n = 41) were female [phase Ia: 9 of 13, phase Ib/dose-expansion cohort (DEC), 17 of 28], aged < 65 years. In phases Ia and Ib, 13 and 26 patients received prior systemic therapy, respectively. Patients received olaratumab 15 mg/kg (phase Ia; cohort 1) or 20 mg/kg (phase Ia; cohort 2 and phase Ib) and pembrolizumab 200 mg (phase Ia/Ib). The median (Q1–Q3) duration of therapy (olaratumab) was 6.0 (3.0–11.9; cohort 1), 14.4 (12.4–20.9; cohort 2), and 14.0 (6.0–21.8) weeks (DEC). No dose-limiting toxicities and few grade ≥ 3 treatment-emergent adverse events [TEAE; 15 mg/kg: 2 (increased lipase); 20 mg/kg: 1 (increased lipase), 1 (colitis), 2 (diarrhea), 3 (anemia)] were reported. Two TEAEs (increased lipase) were related to study discontinuations. Twenty-one patients reported mild (grade ≤ 2) TEAEs [phase Ia, disease control rate (DCR):14.3% (1/7, cohort 1); 66.7% (4/6, cohort 2); no responses were reported; phase Ib, DCR: 53.6% (15/28); objective response rate: 21.4% (6/28; RECIST and irRECIST criteria)]. No response was observed in patients with programmed death ligand-1–positive tumors.
Conclusions:
Antitumor activity was observed in some patients in DEC, and combination was well tolerated with manageable safety profile. Further studies are warranted to evaluate the efficacy and mechanistic impact of platelet-derived growth factor receptor inhibitors with immune checkpoint modulator coadministration.
Data from Early Clearance of Plasma Epidermal Growth Factor Receptor Mutations as a Predictor of Outcome on Osimertinib in Advanced Non–Small Cell Lung Cancer; Exploratory Analysis from AURA3 and FLAURA
Authors: Gray Jhanelle E. , Ahn Myung-Ju , Oxnard Geoffrey R. , Shepherd Frances A. , Imamura Fumio , Cheng Ying , Okamoto Isamu , Cho Byoung Chul , Lin Meng-Chih , Wu Yi-Long , Majem Margarita , Gautschi Oliver , Boyer Michael , Bulusu Krishna C. , Markovets Aleksandra , Barrett J. Carl , Hodge Rachel , McKeown Astrid , Hartmaier Ryan J. , Chmielecki Juliann , Papadimitrakopoulou Vassiliki A. , Ramalingam Suresh S.
Published: September 2023

AbstractPurpose:
Plasma circulating tumor DNA (ctDNA) analysis is used for genotyping advanced non–small cell lung cancer (NSCLC); monitoring dynamic ctDNA changes may be used to predict outcomes.
Patients and Methods:
This was a retrospective, exploratory analysis of two phase III trials [AURA3 (NCT02151981), FLAURA (NCT02296125)]. All patients had EGFR mutation-positive (EGFRm; ex19del or L858R) advanced NSCLC; AURA3 also included T790M-positive NSCLC. Osimertinib (FLAURA, AURA3), or comparator EGFR–tyrosine kinase inhibitor (EGFR-TKI; gefitinib/erlotinib; FLAURA), or platinum-based doublet chemotherapy (AURA3) was given. Plasma EGFRm was analyzed at baseline and Weeks 3/6 by droplet digital PCR. Outcomes were assessed by detectable/non-detectable baseline plasma EGFRm and plasma EGFRm clearance (non-detection) at Weeks 3/6.
Results:
In AURA3 (n = 291), non-detectable versus detectable baseline plasma EGFRm had longer median progression-free survival [mPFS; HR, 0.48; 95% confidence interval (CI), 0.33–0.68; P < 0.0001]. In patients with Week 3 clearance versus non-clearance (n = 184), respectively, mPFS (months; 95% CI) was 10.9 (8.3–12.6) versus 5.7 (4.1–9.7) with osimertinib and 6.2 (4.0–9.7) versus 4.2 (4.0–5.1) with platinum-pemetrexed. In FLAURA (n = 499), mPFS was longer with non-detectable versus detectable baseline plasma EGFRm (HR, 0.54; 95% CI, 0.41–0.70; P < 0.0001). For Week 3 clearance versus non-clearance (n = 334), respectively, mPFS was 19.8 (15.1 to not calculable) versus 11.3 (9.5–16.5) with osimertinib and 10.8 (9.7–11.1) versus 7.0 (5.6–8.3) with comparator EGFR-TKI. Similar outcomes were observed by Week 6 clearance/non-clearance.
Conclusions:
Plasma EGFRm analysis as early as 3 weeks on-treatment has the potential to predict outcomes in EGFRm advanced NSCLC.
Data from De Novo and Histologically Transformed Small-Cell Lung Cancer Is Sensitive to Lurbinectedin Treatment Through the Modulation of EMT and NOTCH Signaling Pathways
Authors: Chakraborty Subhamoy , Coleman Charles , Manoj Parvathy , Demircioglu Deniz , Shah Nisargbhai , de Stanchina Elisa , Rudin Charles M. , Hasson Dan , Sen Triparna
Published: September 2023

AbstractPurpose:
Small-cell lung cancer (SCLC) is a high-grade neuroendocrine tumor with dismal prognosis and limited treatment options. Lurbinectedin, conditionally approved as a second-line treatment for metastatic SCLC, drives clinical responses in about 35% of patients, and the overall survival (OS) of those who benefit from it remains very low (∼9.3 months). This finding highlights the need to develop improved mechanistic insight and predictive biomarkers of response.
Experimental Design:
We used human and patient-derived xenograft (PDX)-derived SCLC cell lines to evaluate the effect of lurbinectedin in vitro. We also demonstrate the antitumor effect of lurbinectedin in multiple de novo and transformed SCLC PDX models. Changes in gene and protein expression pre- and post-lurbinectedin treatment was assessed by RNA sequencing and Western blot analysis.
Results:
Lurbinectedin markedly reduced cell viability in the majority of SCLC models with the best response on POU2F3-driven SCLC cells. We further demonstrate that lurbinectedin, either as a single agent or in combination with osimertinib, causes an appreciable antitumor response in multiple models of EGFR-mutant lung adenocarcinoma with histologic transformation to SCLC. Transcriptomic analysis identified induction of apoptosis, repression of epithelial–mesenchymal transition, modulation of PI3K/AKT, NOTCH signaling associated with lurbinectedin response in de novo, and transformed SCLC models.
Conclusions:
Our study provides a mechanistic insight into lurbinectedin response in SCLC and the first demonstration that lurbinectedin is a potential therapeutic target after SCLC transformation.
Data from A Prognostic Model Based on Residual Cancer Burden and Tumor-Infiltrating Lymphocytes on Residual Disease after Neoadjuvant Therapy in HER2+ Breast Cancer
Authors: Miglietta Federica , Ragazzi Moira , Fernandes Bethania , Griguolo Gaia , Massa Davide , Girardi Fabio , Bottosso Michele , Bisagni Alessandra , Zarrilli Giovanni , Porra Francesca , Iannaccone Daniela , Dore Leocadia , Gaudio Mariangela , Santandrea Giacomo , Fassan Matteo , Lo Mele Marcello , De Sanctis Rita , Zambelli Alberto , Bisagni Giancarlo , Guarneri Valentina , Dieci Maria Vittoria
Published: September 2023

AbstractPurpose:
We aim to evaluate the prognostic significance of tumor-infiltrating lymphocyte on residual disease (RD-TIL) in HER2+ patients with breast cancer who failed to achieve pathologic complete response (pCR) after anti-HER2+ chemotherapy (CT)-based neoadjuvant treatment (NAT). We assessed the feasibility of combining the prognostic information provided by residual cancer burden (RCB) and RD-TILs into a composite score (RCB+TIL).
Experimental Design:
HER2+ patients with breast cancer treated with CT+anti-HER2-based NAT at three institutions were retrospectively included. RCB and TIL levels were evaluated on hematoxylin and eosin–stained slides from surgical samples according to available recommendations. Overall survival (OS) was used as an outcome measure.
Results:
A total of 295 patients were included, of whom 195 had RD. RCB was significantly associated with OS. Higher RD-TILs were significantly associated with poorer OS as compared with lower RD-TILs (15% cutoff). In multivariate analysis, both RCB and RD-TIL maintained their independent prognostic value. A combined score, RCB+TIL, was calculated from the estimated coefficient of RD-TILs and the RCB index in a bivariate logistic model for OS. The RCB+TIL score was significantly associated with OS. The C-index for OS of the RCB+TIL score was numerically higher than that of RCB and significantly higher than that of RD-TILs.
Conclusions:
We have reported an independent prognostic impact of RD-TILs after anti-HER2+CT NAT, which might underlie an imbalance of the RD microenvironment towards immunosuppressive features. We provided a new composite prognostic score based on RCB+TIL, which was significantly associated with OS and proved to be more informative than the isolated evaluation of RCB and RD-TILs.
Data from A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer
Authors: Pook David , Geynisman Daniel M. , Carles Joan , de Braud Filippo , Joshua Anthony M. , Pérez-Gracia José Luis , Llácer Pérez Casilda , Shin Sang Joon , Fang Bruno , Barve Minal , Maruzzo Marco , Bracarda Sergio , Kim Miso , Kerloeguen Yannick , Gallo Jorge Daniel , Maund Sophia L. , Harris Adam , Huang Kuan-Chieh , Poon Victor , Sutaria Dhruvitkumar S. , Gurney Howard
Published: September 2023

AbstractPurpose:
To report the safety and efficacy of ipatasertib (AKT inhibitor) combined with rucaparib (PARP inhibitor) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with second-generation androgen receptor inhibitors.
Patients and Methods:
In this two-part phase Ib trial (NCT03840200), patients with advanced prostate, breast, or ovarian cancer received ipatasertib (300 or 400 mg daily) plus rucaparib (400 or 600 mg twice daily) to assess safety and identify a recommended phase II dose (RP2D). A part 1 dose-escalation phase was followed by a part 2 dose-expansion phase in which only patients with mCRPC received the RP2D. The primary efficacy endpoint was prostate-specific antigen (PSA) response (≥50% reduction) in patients with mCRPC. Patients were not selected on the basis of tumor mutational status.
Results:
Fifty-one patients were enrolled (part 1 = 21; part 2 = 30). Ipatasertib 400 mg daily plus rucaparib 400 mg twice daily was the selected RP2D, received by 37 patients with mCRPC. Grade 3/4 adverse events occurred in 46% (17/37) of patients, with one grade 4 adverse event (anemia, deemed related to rucaparib) and no deaths. Adverse events leading to treatment modification occurred in 70% (26/37). The PSA response rate was 26% (9/35), and the objective response rate per Response Criteria in Solid Tumors (RECIST) 1.1 was 10% (2/21). Median radiographic progression-free survival per Prostate Cancer Working Group 3 criteria was 5.8 months [95% confidence interval (CI), 4.0–8.1], and median overall survival was 13.3 months (95% CI, 10.9–not evaluable).
Conclusions:
Ipatasertib plus rucaparib was manageable with dose modification but did not demonstrate synergistic or additive antitumor activity in previously treated patients with mCRPC.
Supplementary Movies Description 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 2023

Supplemental Movie 1
PC-3 cell treated with water, stained for Golgi (GRASP65, green) and MGAT3 (red). Surfaces were reconstructed by Imaris.
Supplemental Movie 2
PC-3 cell treated with HCQ, stained for Golgi (GRASP65, green) and MGAT3 (red). Surfaces were reconstructed by Imaris.
Supplemental Movie 3
PC-3 cell treated with water, stained for Integrin αv (red), Gal-3 (green), EEA1 (magenta). Areas of 3-color colocalization are highlighted with white. Surfaces were reconstructed by Imaris.
Supplemental Movie 4
PC-3 cell treated with HCQ, stained for Integrin αv (red), Gal-3 (green), EEA1 (magenta). Areas of 3-color colocalization are highlighted with white. Surfaces were reconstructed by Imaris.
Supplementary Figure 8 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 2023

Figure S8. AST (A) and ALT (B) serum activity from the indicated mice. ALT and AST activity were examined using the ALT Assay Kit (Abcam, ab241035) and the AST Assay Kit (Abcam, ab105135), respectively, per the manufacturer's protocol. Kruskal-Wallis test, all p>0.05, mean ± SD; n represents number of mice tested.
Supplementary Figure 3 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 2023

Figure S3. (A) Representative images of triple IHC staining of Integrin αvβ6 (green), Gal-3 (brown), and Na+/K+-ATPase (red) in normal prostate and tumor tissues from PCa patients with different grades. Deconvoluted images of Integrin αvβ6 are shown on the right; bars, 100 µm. (B) Quantification of Integrin αvβ6 H-score at PM from samples in A. Dunn Test (1964) Kruskal-Wallis multiple comparisons, p-adjusted using Benjamini-Hochberg; ****p<0.0001 and **p<0.01, median ± SD. (C) Quantification of Integrin αvβ6 and Gal-3 colocalization at PM in normal prostate and PCa, grades 2-5. Mann Whitney test; ***p<0.001, mean ± SD.
Supplementary Figure 10 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 2023

Figure S10. (A) Evaluation of MGAT5-mediated Integrin αv glycosylation in the orthotopic tumor samples. Tissue samples were co-stained with Integrin αv (green) and Cy3 labeled PHA-L lectin (red). Representative Z-stack images were collected by SIM and reconstructed using Imaris for clarity. (B) Mander's colocalization between red and green in the samples from A. Kruskal-Wallis test; n indicates the number of foci counted. For all statistics: median ± SD, ****p<0.0001, ***p<0.001, **p<0.005, *p<0.05. (C) Evaluation of MGAT3-mediated Integrin αv glycosylation in the orthotopic tumor samples. Tissue samples were co-stained with Integrin αv (green) and Cy3 labeled PHA-E lectin (red). Representative Z-stack images were collected by SIM and reconstructed using Imaris for clarity; bars, 3 µm. (D) Mander's colocalization between red and green in the samples from C. Kruskal-Wallis test; n indicates the number of foci counted; mean ± SD, ****p<0.0001, **p<0.01, and *p<0.05.
Movie S3 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 2023

PC-3 cell treated with water, stained for Integrin αv (red), Gal-3 (green), EEA1 (magenta). Areas of 3-color colocalization are highlighted with white. Surfaces were reconstructed by Imaris.
Movie S1 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 2023

PC-3 cell treated with water, stained for Golgi (GRASP65, green) and MGAT3 (red). Surfaces were reconstructed by Imaris.
Figure S7 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 2023

Figure S7. In the CUTC60-PDX model, BRAF and ERK1/2 inhibition have no significant effect on invasion.
Supplementary Figure S8 from Single-Cell Evolutionary Analysis Reveals Drivers of Plasticity and Mediators of Chemoresistance in Small Cell Lung Cancer
Authors: Wollenzien Hannah , Afeworki Tecleab Yohannes , Szczepaniak-Sloane Robert , Restaino Anthony , Kareta Michael S.
Published: September 2023

Validation of the LBC labeling and xenograft growth.
Supplementary Figure 8 from Targeting c-Jun Is a Potential Therapy for Luminal Breast Cancer Bone Metastasis
Authors: Han Yuxuan , Katayama Shota , Futakuchi Mitsuru , Nakamichi Kazuya , Wakabayashi Yutaro , Sakamoto Mai , Nakayama Jun , Semba Kentaro
Published: September 2023

Clinical clustering of breast cancer subtypes using c-Jun-regulated gene signatures.
Supplementary Figure 7 from Targeting c-Jun Is a Potential Therapy for Luminal Breast Cancer Bone Metastasis
Authors: Han Yuxuan , Katayama Shota , Futakuchi Mitsuru , Nakamichi Kazuya , Wakabayashi Yutaro , Sakamoto Mai , Nakayama Jun , Semba Kentaro
Published: September 2023

Evaluation of JNK-IN-8 inhibition of MCF7-BM cells.
Supplementary Figure 2 from Targeting c-Jun Is a Potential Therapy for Luminal Breast Cancer Bone Metastasis
Authors: Han Yuxuan , Katayama Shota , Futakuchi Mitsuru , Nakamichi Kazuya , Wakabayashi Yutaro , Sakamoto Mai , Nakayama Jun , Semba Kentaro
Published: September 2023

TAM67 suppressed osteolytic bone metastasis of MCF7-BM02 cells.
Supplementary Figure 1 from Targeting c-Jun Is a Potential Therapy for Luminal Breast Cancer Bone Metastasis
Authors: Han Yuxuan , Katayama Shota , Futakuchi Mitsuru , Nakamichi Kazuya , Wakabayashi Yutaro , Sakamoto Mai , Nakayama Jun , Semba Kentaro
Published: September 2023

Characterization of c-Jun overexpression in MCF7-BM cells.
Fig. S6 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 2023

Fig S6 shows ingenuity pathway analysis for canonical pathways and upstream regulators
Fig. S3 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 2023

Fig S3 shows flow cytometry data for CD45, gating strategy and transcript levels of CD68 and TLR4
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 2023

S3. Generation of OSMR knock-out cells.
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 2023

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. Because 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, choline-deficient low-fat diet or choline-deficient high-fat diet. Blocking necroptosis reduced markers of inflammation [proinflammatory cytokines (TNFα, IL6, and IL1β), F4/80+ve macrophages, CCR2+ve infiltrating monocytes], inflammation-associated oncogenic pathways (JNK, PD-L1/PD-1, β-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 , Afeworki Tecleab Yohannes , Szczepaniak-Sloane Robert , Restaino Anthony , Kareta Michael S.
Published: September 2023

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 (CTA) PAGE5 and GAGE2A as mediators of chemoresistance in human SCLC. CTAs have been successfully 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.
Data 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 2023

Abstract
Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced metastatic disease and exhibit a poor response to therapy, resulting in poor outcomes. The tumor microenvironment cytokine Oncostatin-M (OSM) initiates PDAC plasticity, inducing the reprogramming to a stem-like/mesenchymal state, which enhances metastasis and therapy resistance. Using a panel of PDAC cells driven through epithelial–mesenchymal transition (EMT) by OSM or the transcription factors ZEB1 or SNAI1, we find that OSM uniquely induces tumor initiation and gemcitabine resistance independently of its ability to induce a CD44HI/mesenchymal phenotype. In contrast, while ZEB1 and SNAI1 induce a CD44HI/mesenchymal phenotype and migration comparable with OSM, they are unable to promote tumor initiation or robust gemcitabine resistance. Transcriptomic analysis identified that OSM-mediated stemness requires MAPK activation and sustained, feed-forward transcription of OSMR. MEK and ERK inhibitors prevented OSM-driven transcription of select target genes and stem-like/mesenchymal reprogramming, resulting in reduced tumor growth and resensitization to gemcitabine. We propose that the unique properties of OSMR, which hyperactivates MAPK signaling when compared with other IL6 family receptors, make it an attractive therapeutic target, and that disrupting the OSM-OSMR-MAPK feed-forward loop may be a novel way to therapeutically target the stem-like behaviors common to aggressive PDAC.
Implications:
Small-molecule MAPK inhibitors may effectively target the OSM/OSMR-axis that leads to EMT and tumor initiating properties that promote aggressive PDAC.
Data from Targeting c-Jun Is a Potential Therapy for Luminal Breast Cancer Bone Metastasis
Authors: Han Yuxuan , Katayama Shota , Futakuchi Mitsuru , Nakamichi Kazuya , Wakabayashi Yutaro , Sakamoto Mai , Nakayama Jun , Semba Kentaro
Published: September 2023

Abstract
Luminal breast cancer has the highest bone metastasis frequency among all breast cancer subtypes; however, its metastatic mechanism has not been elucidated because of a lack of appropriate models. We have previously developed useful bone metastatic cell lines of luminal breast cancer using MCF7 cells. In this study, we characterized bone metastatic MCF7-BM cell lines and identified c-Jun as a novel bone metastasis marker of luminal breast cancer. The protein level of c-Jun was upregulated in MCF7-BM cells compared with that in parental cells, and its deficiency resulted in the suppression of tumor cell migration, transformation, and reduced osteolytic ability. In vivo, dominant-negative c-Jun exhibited smaller bone metastatic lesions and a lower metastatic frequency. Histologic analysis revealed that c-Jun expression was heterogeneous in bone metastatic lesions, whereas c-Jun overexpression mediated a vicious cycle between MCF7-BM cells and osteoclasts by enhancing calcium-induced migration and releasing the osteoclast activator BMP5. Pharmacological inhibition of c-Jun by the Jun amino-terminal kinase (JNK) inhibitor JNK-IN-8 effectively suppressed tumorigenesis and bone metastasis in MCF7-BM cells. Furthermore, c-Jun downstream signals were specifically correlated with the clinical prognosis of patients with the luminal subtype of breast cancer. Our results illustrate the potential benefits of a therapy that targets c-Jun to prevent bone metastasis in luminal breast cancer.
Implications:
c-Jun expression mediates bone metastasis in luminal breast cancer by forming a vicious cycle in the bone microenvironment, which reveals potential strategies for subtype-specific bone metastasis therapy.
Data 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 2023

Abstract
Transcription and DNA damage repair act in a coordinated manner. The scaffolding protein SIN3B serves as a transcriptional co-repressor of hundreds of cell cycle–related genes. However, the contribution of SIN3B during the DNA damage response remains unknown. Here, we show that SIN3B inactivation delays the resolution of DNA double-strand breaks and sensitizes cancer cells to DNA-damaging agents, including the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, SIN3B is rapidly recruited to DNA damage sites where it directs the accumulation of Mediator of DNA Damage Checkpoint 1 (MDC1). In addition, we show that SIN3B inactivation favors the engagement of the alternative nonhomologous end joining (NHEJ) repair pathway over the canonical NHEJ. Altogether, our findings impute an unexpected function for the transcriptional co-repressor SIN3B as a gatekeeper of genomic integrity and a determining factor in the DNA repair choice pathway, and point to the inhibition of the SIN3B chromatin-modifying complex as a novel therapeutic vulnerability in cancer cells.
Implications:
Identifying SIN3B as a modulator of DNA damage repair choice provides novel potential therapeutic avenues to sensitize cancer cells to cytotoxic therapies.
Supplementary Table S4 from Association and Prediction Utilizing Craniocaudal and Mediolateral Oblique View Digital Mammography and Long-Term Breast Cancer Risk
Authors: Chen Simin , Tamimi Rulla M. , Colditz Graham A. , Jiang Shu
Published: September 2023

Supplementary Table S4: Hazards ratio (95% Confidence Interval) for association between baseline risk factors and breast cancer risk among pre-menopausal women using CC-VPD only.
Supplementary Figure S7 from Association and Prediction Utilizing Craniocaudal and Mediolateral Oblique View Digital Mammography and Long-Term Breast Cancer Risk
Authors: Chen Simin , Tamimi Rulla M. , Colditz Graham A. , Jiang Shu
Published: September 2023

Supplementary Figure S7: The proportional hazards assumption is deemed reasonable by checking the Schoenfeld residuals plot for Full-VPD.
Supplementary Figure S5 from Association and Prediction Utilizing Craniocaudal and Mediolateral Oblique View Digital Mammography and Long-Term Breast Cancer Risk
Authors: Chen Simin , Tamimi Rulla M. , Colditz Graham A. , Jiang Shu
Published: September 2023

Supplementary Figure S5: The proportional hazards assumption is deemed reasonable by checking the Schoenfeld residuals plot for CC-VPD.
Supplementary Figure S2 from Association and Prediction Utilizing Craniocaudal and Mediolateral Oblique View Digital Mammography and Long-Term Breast Cancer Risk
Authors: Chen Simin , Tamimi Rulla M. , Colditz Graham A. , Jiang Shu
Published: September 2023

Supplementary Figure S2: Pearson correlation between our algorithm and Volpara shows strong positive linear relationship of 0.81.
Supplementary Table 1 from Rates of Intervention and Cancer Detection on Initial versus Subsequent Whole-body MRI Screening in Li-Fraumeni Syndrome
Authors: Kagami Laura A.T. , Du Yun K. , Fernandes Conrad J. , Le Anh N. , Good Madeline , Duvall Melani M. , Baldino Sarah E. , Powers Jacquelyn , Zelley Kristin , States Lisa J. , Mathew Manoj C. , Katona Bryson W. , MacFarland Suzanne P. , Maxwell Kara N.
Published: September 2023

Supplementary Table 1 shows non-malignant findings identified on WBMRI screening in our patient cohort with corresponding patient IDs to cancer diagnoses identified on WBMRI screening.
Data from Rates of Intervention and Cancer Detection on Initial versus Subsequent Whole-body MRI Screening in Li-Fraumeni Syndrome
Authors: Kagami Laura A.T. , Du Yun K. , Fernandes Conrad J. , Le Anh N. , Good Madeline , Duvall Melani M. , Baldino Sarah E. , Powers Jacquelyn , Zelley Kristin , States Lisa J. , Mathew Manoj C. , Katona Bryson W. , MacFarland Suzanne P. , Maxwell Kara N.
Published: September 2023

Abstract
Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome with up to 90% lifetime cancer risk. Cancer screening, including annual whole-body MRI (WB-MRI), is recommended due to known survival advantage, with cancer detection rate of 7% on initial screening. Intervention and cancer detection rates on subsequent screenings are unknown. Clinical data for pediatric and adult patients with LFS (n = 182) were reviewed, including instances of WB-MRI screening and interventions based on screening results. For each WB-MRI screening, interventions including biopsy and secondary imaging, as well as rate of cancer diagnosis, were analyzed comparing initial versus subsequent WB-MRI. Of the total cohort (n = 182), we identified 68 adult patients and 50 pediatric patients who had undergone at least two WB-MRI screenings, with a mean of 3.8 ± 1.9 (adults) and 4.0 ± 2.1 (pediatric) screenings. Findings on initial screening led to an imaging or invasive intervention in 38% of adults and 20% of children. On follow up, overall intervention rates were lower for adults (19%, P = 0.0026) and stable for children (19%, P = NS). Thirteen cancers were detected overall (7% of adult and 14% of pediatric scans), on both initial (pediatric: 4%, adult: 3%) and subsequent (pediatric: 10%, adult: 6%) screenings. Rates of intervention after WB-MRI screening decreased significantly in adults between first and subsequent exams and remained stable in pediatric patients. Cancer detection rates were similar on screening (3%–4% initial, 6%–10% subsequent) for both children and adults. These findings provide important data for counseling patients with LFS about screening outcomes.
Prevention Relevance:
The cancer detection rate, burden of recommended interventions, and rate of false-positive findings found on subsequent WB-MRI screenings in patients with LFS are not well understood. Our findings suggest that annual WB-MRI screening has clinical utility and likely does not result in an unnecessary invasive intervention burden for patients.
Supplementary Table 1 from CCRL2 Expression by Specialized Lung Capillary Endothelial Cells Controls NK-cell Homing in Lung Cancer
Authors: Sozio Francesca , Schioppa Tiziana , Laffranchi Mattia , Salvi Valentina , Tamassia Nicola , Bianchetto-Aguilera Francisco M. , Tiberio Laura , Bonecchi Raffaella , Bosisio Daniela , Parmentier Marc , Bottazzi Barbara , Leone Roberto , Russo Eleonora , Bernardini Giovanni , Garofalo Stefano , Limatola Cristina , Gismondi Angela , Sciumè Giuseppe , Mantovani Alberto , Del Prete Annalisa , Sozzani Silvano
Published: September 2023

Supplementary Table 1
Supplementary Figure S1-S26 from Enhancing CAR T-cell Therapy Using Fab-Based Constitutively Heterodimeric Cytokine Receptors
Authors: Righi Matteo , Gannon Isaac , Robson Matthew , Srivastava Saket , Kokalaki Evangelia , Grothier Thomas , Nannini Francesco , Allen Christopher , Bai Yuchen V. , Sillibourne James , Cordoba Shaun , Thomas Simon , Pule Martin
Published: September 2023

Supplementary Figure S1-S26
Data from Host Interactions with Engineered T-cell Micropharmacies
Authors: Bourne Christopher M. , Wallisch Patrick , Dacek Megan M. , Gardner Thomas J. , Pierre Stephanie , Vogt Kristen , Corless Broderick C. , Bah Mamadou A. , Romero-Pichardo Jesus E. , Charles Angel , Kurtz Keifer G. , Tan Derek S. , Scheinberg David A.
Published: September 2023

Abstract
Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with a killing mechanism orthogonal to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Herein, we expanded the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with T-cell receptor (TCR)–engineered T cells. We demonstrate that SEAKER cells localized specifically to tumors, and activated bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells were efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.
Table S4 from HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion
Authors: Toyoda Kosuke , Yasunaga Jun-ichirou , Shichijo Takafumi , Arima Yuichiro , Tsujita Kenichi , Tanaka Azusa , Salah Tarig , Zhang Wenyi , Hussein Osama , Sonoda Miyu , Watanabe Miho , Kurita Daisuke , Nakashima Kazutaka , Yamada Kyohei , Miyoshi Hiroaki , Ohshima Koichi , Matsuoka Masao
Published: September 2023

Experimental reagents and resources with identifiers used in this study.
Table S2 from HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion
Authors: Toyoda Kosuke , Yasunaga Jun-ichirou , Shichijo Takafumi , Arima Yuichiro , Tsujita Kenichi , Tanaka Azusa , Salah Tarig , Zhang Wenyi , Hussein Osama , Sonoda Miyu , Watanabe Miho , Kurita Daisuke , Nakashima Kazutaka , Yamada Kyohei , Miyoshi Hiroaki , Ohshima Koichi , Matsuoka Masao
Published: September 2023

Mouse cluster 2 genes whose H3K27me3 in TSS's was decreased.
Figure S3 from HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion
Authors: Toyoda Kosuke , Yasunaga Jun-ichirou , Shichijo Takafumi , Arima Yuichiro , Tsujita Kenichi , Tanaka Azusa , Salah Tarig , Zhang Wenyi , Hussein Osama , Sonoda Miyu , Watanabe Miho , Kurita Daisuke , Nakashima Kazutaka , Yamada Kyohei , Miyoshi Hiroaki , Ohshima Koichi , Matsuoka Masao
Published: September 2023

Regulation of TP73 by BATF3 and IRF4.
Table S4 from Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel
Authors: Paiva Bruno , Manrique Irene , Rytlewski Julie , Campbell Timothy , Kazanecki Christian C. , Martin Nathan , Anderson Larry D. , Berdeja Jesús G. , Lonial Sagar , Raje Noopur S. , Lin Yi , Moreau Philippe , San-Miguel Jesús F. , Munshi Nikhil C. , Kaiser Shari M.
Published: September 2023

HR and P values for landmark PFS within first year
Table S3 from Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel
Authors: Paiva Bruno , Manrique Irene , Rytlewski Julie , Campbell Timothy , Kazanecki Christian C. , Martin Nathan , Anderson Larry D. , Berdeja Jesús G. , Lonial Sagar , Raje Noopur S. , Lin Yi , Moreau Philippe , San-Miguel Jesús F. , Munshi Nikhil C. , Kaiser Shari M.
Published: September 2023

CR and MRD on treated population
Table S1 from Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel
Authors: Paiva Bruno , Manrique Irene , Rytlewski Julie , Campbell Timothy , Kazanecki Christian C. , Martin Nathan , Anderson Larry D. , Berdeja Jesús G. , Lonial Sagar , Raje Noopur S. , Lin Yi , Moreau Philippe , San-Miguel Jesús F. , Munshi Nikhil C. , Kaiser Shari M.
Published: September 2023

Patient distribution of paired results
Figure S1 from Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel
Authors: Paiva Bruno , Manrique Irene , Rytlewski Julie , Campbell Timothy , Kazanecki Christian C. , Martin Nathan , Anderson Larry D. , Berdeja Jesús G. , Lonial Sagar , Raje Noopur S. , Lin Yi , Moreau Philippe , San-Miguel Jesús F. , Munshi Nikhil C. , Kaiser Shari M.
Published: September 2023

Consort Diagram
The Inflamed Niche: A Double-Edged Sword in AML?
Authors: Lisi-Vega Livia E. , Méndez-Ferrer Simón
Published: September 2023

Although inflammation has long been recognized as a hallmark of many cancers, including acute myeloid leukemia (AML), how it affects individual cells of the tumor microenvironment and their interaction with normal and neoplastic cells is incompletely understood. A comprehensive single-cell transcriptomic analysis of human bone marrow from patients with AML and healthy individuals identified skewing of stem cell and stromal cell populations in AML toward proinflammatory states associated with reduced risk of relapse, paralleling previous findings in mouse models and suggesting that inflamed bone marrow mesenchymal stromal cells might be a double-edged sword in AML by hampering normal hematopoiesis (while AML cells appear comparatively more resilient) but also rendering AML cells more susceptible to chemotherapy or immune attack.

See related article by Chen et al., p. 394 (7) .
Data from A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML
Authors: Chen Lanpeng , Pronk Eline , van Dijk Claire , Bian Yujie , Feyen Jacqueline , van Tienhoven Tim , Yildirim Meltem , Pisterzi Paola , de Jong Madelon M.E. , Bastidas Alejandro , Hoogenboezem Remco M. , Wevers Chiel , Bindels Eric M. , Löwenberg Bob , Cupedo Tom , Sanders Mathijs A. , Raaijmakers Marc H.G.P.
Published: September 2023

Abstract
Cancer initiation is orchestrated by an interplay between tumor-initiating cells and their stromal/immune environment. Here, by adapted single-cell RNA sequencing, we decipher the predicted signaling between tissue-resident hematopoietic stem/progenitor cells (HSPC) and their neoplastic counterparts with their native niches in the human bone marrow. LEPR+ stromal cells are identified as central regulators of hematopoiesis through predicted interactions with all cells in the marrow. Inflammatory niche remodeling and the resulting deprivation of critical HSPC regulatory factors are predicted to repress high-output hematopoietic stem cell subsets in NPM1-mutated acute myeloid leukemia (AML), with relative resistance of clonal cells. Stromal gene signatures reflective of niche remodeling are associated with reduced relapse rates and favorable outcomes after chemotherapy across all genetic risk categories. Elucidation of the intercellular signaling defining human AML, thus, predicts that inflammatory remodeling of stem cell niches drives tissue repression and clonal selection but may pose a vulnerability for relapse-initiating cells in the context of chemotherapeutic treatment.
Significance:
Tumor-promoting inflammation is considered an enabling characteristic of tumorigenesis, but mechanisms remain incompletely understood. By deciphering the predicted signaling between tissue-resident stem cells and their neoplastic counterparts with their environment, we identify inflammatory remodeling of stromal niches as a determinant of normal tissue repression and clinical outcomes in human AML.

See related commentary by Lisi-Vega and Méndez-Ferrer, p. 349.

This article is featured in Selected Articles from This Issue, p. 337