bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S1 from CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Authors: Wadhwa Anju , Wang Sinan , Patiño-Escobar Bonell , Bidkar Anil P. , Bobba Kondapa Naidu , Chan Emily , Meher Niranjan , Bidlingmaier Scott , Su Yang , Dhrona Suchi , Geng Huimin , Sarin Vishesh , VanBrocklin Henry F. , Wilson David M. , He Jiang , Zhang Li , Steri Veronica , Wong Sandy W. , Martin Thomas G. , Seo Youngho , Liu Bin , Wiita Arun P. , Flavell Robert R.
Published: March 2024

Figure S1: Cell binding assay (1 million compared to 30 million cells experiment shown in Figure-1(A)) indicates specific binding of [89Zr]Zr-DFO-YS5 to MM cells (n=3).
Supplementary Data 1 from Spatiotemporal Quantification of HER2-targeting Antibody–Drug Conjugate Bystander Activity and Enhancement of Solid Tumor Penetration
Authors: Wei Qing , Yang Teng , Zhu Jiayu , Zhang Ziwen , Yang Le , Zhang Yuchao , Hu Can , Chen Jiahui , Wang Jinchao , Tian Xuefei , Shimura Takaya , Fang Jianmin , Ying Jieer , Fan Mengyang , Guo Peng , Cheng Xiangdong
Published: March 2024

Supplementary methods and figures
Supplementary Figure S3 from Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer
Authors: Oaknin Ana , Ghamande Sharad A. , Kasamatsu Yuka , Gil-Martin Marta , Grau-Bejar Juan Francisco , Garcia-Duran Carmen , Sato Masashi , Siddiqui Abdul , Chaudhary Surendra Pal , Vugmeyster Yulia , Hasegawa Kosei
Published: March 2024

Figure S3. Patient-level concentration profile of bintrafusp alfa at Day 1 postdose.
Supplementary Figure S2 from Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer
Authors: Oaknin Ana , Ghamande Sharad A. , Kasamatsu Yuka , Gil-Martin Marta , Grau-Bejar Juan Francisco , Garcia-Duran Carmen , Sato Masashi , Siddiqui Abdul , Chaudhary Surendra Pal , Vugmeyster Yulia , Hasegawa Kosei
Published: March 2024

Figure S2. Change from baseline in sum of diameters of all target lesions per RECIST v1.1 for Cohort 2. CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.
Supplementary Table 2 from Niraparib plus Dostarlimab in Pleural Mesothelioma or Non–Small Cell Lung Cancer Harboring HRR Mutations: Interim Results of the UNITO-001 Phase II Prospective Trial
Authors: Passiglia Francesco , Righi Luisella , Bironzo Paolo , Listì Angela , Farinea Giovanni , Capelletto Enrica , Novello Silvia , Merlini Alessandra , Scagliotti Giorgio V.
Published: March 2024

Supplementary Table 2. Clinical Responses to Niraparib plus Dostarlimab in the analyzed population.
Supplementary Figure S1 from Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer
Authors: Oaknin Ana , Ghamande Sharad A. , Kasamatsu Yuka , Gil-Martin Marta , Grau-Bejar Juan Francisco , Garcia-Duran Carmen , Sato Masashi , Siddiqui Abdul , Chaudhary Surendra Pal , Vugmeyster Yulia , Hasegawa Kosei
Published: March 2024

Figure S1. Change from baseline in sum of diameters of all target lesions per RECIST v1.1 for (A) Cohort 1A and (B) Cohort 1B. CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.
Supplementary Figure 3 from Niraparib plus Dostarlimab in Pleural Mesothelioma or Non–Small Cell Lung Cancer Harboring HRR Mutations: Interim Results of the UNITO-001 Phase II Prospective Trial
Authors: Passiglia Francesco , Righi Luisella , Bironzo Paolo , Listì Angela , Farinea Giovanni , Capelletto Enrica , Novello Silvia , Merlini Alessandra , Scagliotti Giorgio V.
Published: March 2024

Supplementary Figure 3. ID patients 3# IGV screen of BRCA2 p.A406Lfs*9 variant.
Data from Surface and Global Proteome Analyses Identify ENPP1 and Other Surface Proteins as Actionable Immunotherapeutic Targets in Ewing Sarcoma
Authors: Mooney Brian , Negri Gian Luca , Shyp Taras , Delaidelli Alberto , Zhang Hai-Feng , Spencer Miko Sandra E. , Weiner Amber K. , Radaoui Alexander B. , Shraim Rawan , Lizardo Michael M. , Hughes Christopher S. , Li Amy , El-Naggar Amal M. , Rouleau Melanie , Li Wei , Dimitrov Dimiter S. , Kurmasheva Raushan T. , Houghton Peter J. , Diskin Sharon J. , Maris John M. , Morin Gregg B. , Sorensen Poul H.
Published: March 2024

AbstractPurpose:
Ewing sarcoma is the second most common bone sarcoma in children, with 1 case per 1.5 million in the United States. Although the survival rate of patients diagnosed with localized disease is approximately 70%, this decreases to approximately 30% for patients with metastatic disease and only approximately 10% for treatment-refractory disease, which have not changed for decades. Therefore, new therapeutic strategies are urgently needed for metastatic and refractory Ewing sarcoma.
Experimental Design:
This study analyzed 19 unique Ewing sarcoma patient- or cell line–derived xenografts (from 14 primary and 5 metastatic specimens) using proteomics to identify surface proteins for potential immunotherapeutic targeting. Plasma membranes were enriched using density gradient ultracentrifugation and compared with a reference standard of 12 immortalized non–Ewing sarcoma cell lines prepared in a similar manner. In parallel, global proteome analysis was carried out on each model to complement the surfaceome data. All models were analyzed by Tandem Mass Tags–based mass spectrometry to quantify identified proteins.
Results:
The surfaceome and global proteome analyses identified 1,131 and 1,030 annotated surface proteins, respectively. Among surface proteins identified, both approaches identified known Ewing sarcoma–associated proteins, including IL1RAP, CD99, STEAP1, and ADGRG2, and many new cell surface targets, including ENPP1 and CDH11. Robust staining of ENPP1 was demonstrated in Ewing sarcoma tumors compared with other childhood sarcomas and normal tissues.
Conclusions:
Our comprehensive proteomic characterization of the Ewing sarcoma surfaceome provides a rich resource of surface-expressed proteins in Ewing sarcoma. This dataset provides the preclinical justification for exploration of targets such as ENPP1 for potential immunotherapeutic application in Ewing sarcoma.

See related commentary by Bailey, p. 934
Data from Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression
Authors: Mitchell Dana K. , Burgess Breanne , White Emily E. , Smith Abbi E. , Sierra Potchanant Elizabeth A. , Mang Henry , Hickey Brooke E. , Lu Qingbo , Qian Shaomin , Bessler Waylan , Li Xiaohong , Jiang Li , Brewster Kylee , Temm Constance , Horvai Andrew , Albright Eric A. , Fishel Melissa L. , Pratilas Christine A. , Angus Steven P. , Clapp D. Wade , Rhodes Steven D.
Published: March 2024

AbstractPurpose:
Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance, these neoplasms exhibit diverse evolutionary trajectories, with a subset progressing to malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathologic features and CDKN2A copy-number loss. Although genomic studies have uncovered key driver events promoting tumor progression, the transcriptional changes preceding malignant transformation remain poorly defined.
Experimental Design:
Here we resolve gene-expression profiles in PNST across the neurofibroma-to-MPNST continuum in NF1 patients and mouse models, revealing early molecular features associated with neurofibroma evolution and transformation.
Results:
Our findings demonstrate that ANF exhibit enhanced signatures of antigen presentation and immune response, which are suppressed as malignant transformation ensues. MPNST further displayed deregulated survival and mitotic fidelity pathways, and targeting key mediators of these pathways, CENPF and BIRC5, disrupted the growth and viability of human MPNST cell lines and primary murine Nf1-Cdkn2a-mutant Schwann cell precursors. Finally, neurofibromas contiguous with MPNST manifested distinct alterations in core oncogenic and immune surveillance programs, suggesting that early molecular events driving disease progression may precede histopathologic evidence of malignancy.
Conclusions:
If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathologic diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.
Data from Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer
Authors: Oaknin Ana , Ghamande Sharad A. , Kasamatsu Yuka , Gil-Martin Marta , Grau-Bejar Juan Francisco , Garcia-Duran Carmen , Sato Masashi , Siddiqui Abdul , Chaudhary Surendra Pal , Vugmeyster Yulia , Hasegawa Kosei
Published: March 2024

AbstractPurpose:
Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGFβ receptor II (a TGFβ “trap”) fused to a human IgG1 mAb blocking programmed death-ligand 1 (PD-L1), was evaluated as treatment in patients with locally advanced or persistent, recurrent, or metastatic (P/R/M) cervical cancer.
Patients and Methods:
In this multicenter, open-label, phase Ib trial (NCT04551950), patients with P/R/M cervical cancer received bintrafusp alfa 2,400 mg once every 3 weeks plus cisplatin or carboplatin plus paclitaxel with (Cohort 1A; n = 8) or without (Cohort 1B; n = 9) bevacizumab; patients with locally advanced cervical cancer received bintrafusp alfa 2,400 mg every 3 weeks plus cisplatin plus radiation, followed by bintrafusp alfa monotherapy maintenance (Cohort 2; n = 8). The primary endpoint was safety; secondary endpoints included efficacy (including objective response rate) and pharmacokinetics.
Results:
At the data cutoff of April 27, 2022, patients in Cohorts 1A, 1B, and 2 had received bintrafusp alfa for a median duration of 37.9, 31.1, and 16.7 weeks, respectively. Two dose-limiting toxicities (grade 4 amylase elevation and grade 3 menorrhagia) unrelated to bintrafusp alfa were observed in Cohort 1B and none in other cohorts. Most treatment-emergent adverse events of special interest were grades 1–2 in severity, most commonly anemia (62.5%–77.8%) and bleeding events (62.5%–77.8%). Objective response rate was 75.0% [95% confidence interval (CI), 34.9–96.8], 44.4% (95% CI, 13.7–78.8), and 62.5% (95% CI, 24.5–91.5) in Cohorts 1A, 1B, and 2, respectively.
Conclusions:
Bintrafusp alfa had manageable safety and demonstrated clinical activity, further supporting the investigation of TGFβ/PD-L1 inhibition in human papillomavirus–associated cancers, including cervical cancer.
Data from The Effect of Diet on Breast Cancer Recurrence: The DIANA-5 Randomized Trial
Authors: Berrino Franco , Villarini Anna , Gargano Giuliana , Krogh Vittorio , Grioni Sara , Bellegotti Manuela , Venturelli Elisabetta , Raimondi Milena , Traina Adele , Zarcone Maurizio , Amodio Rosalba , Mano Maria Piera , Johansson Harriet , Panico Salvatore , Santucci de Magistris Maria , Barbero Maggiorino , Gavazza Cristina , Mercandino Angelica , Consolaro Elena , Galasso Rocco , Del Riccio Luciana , Bassi Maria Chiara , Simeoni Milena , Premoli Paolo , Pasanisi Patrizia , Bonanni Bernardo , Bruno Eleonora
Published: March 2024

AbstractPurpose:
The DIANA-5 randomized controlled trial assessed the effectiveness of a diet based on Mediterranean and macrobiotic traditions (macro-Mediterranean diet) in reducing breast cancer recurrence.
Patients and Methods:
The DIANA-5 study involved 1,542 patients with breast cancer at high risk of recurrence because of estrogen receptor–negative cancer, or metabolic syndrome, or high plasma levels of insulin or testosterone. Women were randomly assigned to an active dietary intervention (IG) or a control group (CG). Both groups received the 2007 American Institute for Cancer Research/World Cancer Research Fund recommendations for cancer prevention. The intervention consisted of meetings with kitchen classes, community meals, and dietary recommendations. Recommended foods included whole grain cereals, legumes, soy products, vegetables, fruit, nuts, olive oil, and fish. Foods to be avoided were refined products, potatoes, sugar and desserts, red and processed meat, dairy products, and alcoholic drinks. A compliance Dietary Index was defined by the difference between recommended and discouraged foods.
Results:
Over the 5 years of follow-up, 95 patients of the IG and 98 of the CG developed breast cancer recurrence [HR = 0.99; 95% confidence interval (CI): 0.69–1.40]. The analysis by compliance to the dietary recommendations (IG and CG together) showed that the women in the upper tertile of Dietary Index change had an HR of recurrence of 0.59 (95% CI: 0.36–0.92) compared with women in the lower tertile.
Conclusions:
The DIANA-5 dietary intervention trial failed to show a reduction in breast cancer recurrence, although self-reported diet at year 1 in IG and CG combined showed a protective association with the higher Dietary Index change.

See related commentary by McTiernan, p. 931
Data from Niraparib plus Dostarlimab in Pleural Mesothelioma or Non–Small Cell Lung Cancer Harboring HRR Mutations: Interim Results of the UNITO-001 Phase II Prospective Trial
Authors: Passiglia Francesco , Righi Luisella , Bironzo Paolo , Listì Angela , Farinea Giovanni , Capelletto Enrica , Novello Silvia , Merlini Alessandra , Scagliotti Giorgio V.
Published: March 2024

AbstractPurpose:
Treatment of homologous recombination repair–deficient (HRD)-tumors with PARP inhibitors has the potential to further increase tumor immunogenicity, suggesting a synergistic effect with immunotherapy. Here we present the preliminary results of niraparib in combination with dostarlimab for pleural mesothelioma (PM) or non–small cell lung cancer (NSCLC) harboring HRR mutations.
Patients and Methods:
UNITO-001 is a phase II, prospective, study aiming to investigate the combination of niraparib plus dostarlimab in pretreated patients with HRD and programmed death ligand-1 (PD-L1) ≥1% NSCLC and/or PM. The primary endpoint is progression-free survival (PFS).
Results:
Seventeen of 183 (10%) screened patients (12 PM and 5 NSCLC) were included. The objective response rate (ORR) was 6% [95% confidence interval (CI): 0.1–28.7] and the disease control rate (DCR) was 53% (95% CI: 27.8–77). Median PFS was 3.1 (95% CI: 2.7–N.A) and median overall survival (OS) was 4.2 (95% CI: 1.58–NA) months. The PFS was 14.1 months in one PM patient harboring a germline BAP1 mutation. The treatment duration was 9.8 months in one PM patient harboring a somatic BRCA2 mutation. The most common adverse events (AE) were grade 1–2 lymphopenia (59%), anemia (35%), hyponatremia (29%), and hypokalemia (29%). Grade ≥3 AEs were reported in 23% of the patients.
Conclusions:
This preliminary analysis highlighted the lack of antitumor activity for the combination of niraparib and dostarlimab in patients with PM and/or advanced NSCLC harboring BAP1 somatic mutations. A potential antitumor activity emerged for PM with germline BAP1 and/or BRCA2 somatic mutations along with a good tolerability profile.
Supplementary Figure 5 from Single-Cell Transcriptomics Reveals Pre-existing COVID-19 Vulnerability Factors in Lung Cancer Patients
Authors: Liu Wendao , Li Wenbo , Zhao Zhongming
Published: March 2024

Supplementary Figure 5. Fibroblast subpopulations and collagen gene expression.
Supplementary Figure Legends 1-6, Supplementary Videos 1 and 2 from Mitochondria Transfer by Platelet-Derived Microparticles Regulates Breast Cancer Bioenergetic States and Malignant Features
Authors: Veilleux Vanessa , Pichaud Nicolas , Boudreau Luc H. , Robichaud Gilles A.
Published: March 2024

Descriptions of supplementary data figures and videos
Supplementary Figure 2 from Mitochondria Transfer by Platelet-Derived Microparticles Regulates Breast Cancer Bioenergetic States and Malignant Features
Authors: Veilleux Vanessa , Pichaud Nicolas , Boudreau Luc H. , Robichaud Gilles A.
Published: March 2024

Figure S2 demonstrates that the fluorescent microparticles do not simply interact bing the recipients' cell surface, but are internalized in the intracellular compartment. This is demonstrated by digestion of the cell surface receptors/ligands using pronase proteases, a common assay to distinguish between surface binding and intracellular entry.
Table S1 from TNFRSF19 within the 13q12.12 Risk Locus Functions as a Lung Cancer Suppressor by Binding Wnt3a to Inhibit Wnt/β-Catenin Signaling
Authors: Zuo Xianglin , Wang Xuchun , Ma Tingzheng , Chen Shuhan , Cao Pingping , Cheng He , Yang Nan , Han Xiao , Gao Wei , Liu Xiaoyu , Sun Yujie
Published: March 2024

Primers used in the present study
Figure S5 from TNFRSF19 within the 13q12.12 Risk Locus Functions as a Lung Cancer Suppressor by Binding Wnt3a to Inhibit Wnt/β-Catenin Signaling
Authors: Zuo Xianglin , Wang Xuchun , Ma Tingzheng , Chen Shuhan , Cao Pingping , Cheng He , Yang Nan , Han Xiao , Gao Wei , Liu Xiaoyu , Sun Yujie
Published: March 2024

Analysis of the TNFRSF19 gene promoter methylation based on TCGA and GEO database.
Figure S1 from TNFRSF19 within the 13q12.12 Risk Locus Functions as a Lung Cancer Suppressor by Binding Wnt3a to Inhibit Wnt/β-Catenin Signaling
Authors: Zuo Xianglin , Wang Xuchun , Ma Tingzheng , Chen Shuhan , Cao Pingping , Cheng He , Yang Nan , Han Xiao , Gao Wei , Liu Xiaoyu , Sun Yujie
Published: March 2024

The TNFRSF19 within 13q12.12 risk chromatin region functions as a lung cancer suppressor by binding Wnt3a to inhibit Wnt/β-catenin signaling.
Supplemental Table S2 from Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice
Authors: Barravecchia Ivana , Lee Jennifer M. , Manassa Jason , Magnuson Brian , Ferris Sarah F. , Cavanaugh Sophia , Steele Nina G. , Espinoza Carlos E. , Galban Craig J. , Ramnath Nithya , Frankel Timothy L. , Pasca di Magliano Marina , Galban Stefanie
Published: March 2024

Supplemental Table S2. Antibody panel used for CyTOF analysis.
Supplementary Table 5 from Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase
Authors: Savardekar Himanshu , Allen Carter , Jeon Hyeongseon , Li Jianying , Quiroga Dionisia , Schwarz Emily , Wu Richard C. , Zelinskas Sara , Lapurga Gabriella , Abreo Alexander , Stiff Andrew , Shaffer Jami , Blaser Bradley W. , Old Matthew , Wesolowski Robert , Xin Gang , Kendra Kari L. , Chung Dongjun , Carson William E.
Published: March 2024

Melanoma MDSC baseline gene expression.
Supplementary Table 4 from Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase
Authors: Savardekar Himanshu , Allen Carter , Jeon Hyeongseon , Li Jianying , Quiroga Dionisia , Schwarz Emily , Wu Richard C. , Zelinskas Sara , Lapurga Gabriella , Abreo Alexander , Stiff Andrew , Shaffer Jami , Blaser Bradley W. , Old Matthew , Wesolowski Robert , Xin Gang , Kendra Kari L. , Chung Dongjun , Carson William E.
Published: March 2024

Breast baseline MDSC gene expression.
Supplementary Figure 7 from Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase
Authors: Savardekar Himanshu , Allen Carter , Jeon Hyeongseon , Li Jianying , Quiroga Dionisia , Schwarz Emily , Wu Richard C. , Zelinskas Sara , Lapurga Gabriella , Abreo Alexander , Stiff Andrew , Shaffer Jami , Blaser Bradley W. , Old Matthew , Wesolowski Robert , Xin Gang , Kendra Kari L. , Chung Dongjun , Carson William E.
Published: March 2024

Analysis of subsets (PMN-MDSC DE vs. double positive MDSC).
Supplementary Figure 6 from Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase
Authors: Savardekar Himanshu , Allen Carter , Jeon Hyeongseon , Li Jianying , Quiroga Dionisia , Schwarz Emily , Wu Richard C. , Zelinskas Sara , Lapurga Gabriella , Abreo Alexander , Stiff Andrew , Shaffer Jami , Blaser Bradley W. , Old Matthew , Wesolowski Robert , Xin Gang , Kendra Kari L. , Chung Dongjun , Carson William E.
Published: March 2024

Expression thresholds for CD14 gene expression.
Supplementary Table 4 from LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation
Authors: Shao Xiaowen , Dang Yamei , Zhang Tingting , Bai Nan , Huang Jianing , Guo Mengya , Sun Li , Li Minghe , Sun Xiao , Zhang Xinran , Han Feng , Zhang Ning , Zhuang Hao , Li Yongmei
Published: March 2024

Sequences of the DNA primers for RT-qPCR and in vitro transcription, and the sequences of LINC00869 probes.
Supplementary Table 3 from LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation
Authors: Shao Xiaowen , Dang Yamei , Zhang Tingting , Bai Nan , Huang Jianing , Guo Mengya , Sun Li , Li Minghe , Sun Xiao , Zhang Xinran , Han Feng , Zhang Ning , Zhuang Hao , Li Yongmei
Published: March 2024

Sequences of the genes coding shRNA for LINC00869 knockdown experiments.
Supplementary Table 2 from LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation
Authors: Shao Xiaowen , Dang Yamei , Zhang Tingting , Bai Nan , Huang Jianing , Guo Mengya , Sun Li , Li Minghe , Sun Xiao , Zhang Xinran , Han Feng , Zhang Ning , Zhuang Hao , Li Yongmei
Published: March 2024

Clinicopathological information of HCC specimens for RNA-ISH.
Supplementary Table 1 from LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation
Authors: Shao Xiaowen , Dang Yamei , Zhang Tingting , Bai Nan , Huang Jianing , Guo Mengya , Sun Li , Li Minghe , Sun Xiao , Zhang Xinran , Han Feng , Zhang Ning , Zhuang Hao , Li Yongmei
Published: March 2024

Clinicopathological information of the HCC tissue samples for RT-qPCR.
Supplementary Figure 7 from LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation
Authors: Shao Xiaowen , Dang Yamei , Zhang Tingting , Bai Nan , Huang Jianing , Guo Mengya , Sun Li , Li Minghe , Sun Xiao , Zhang Xinran , Han Feng , Zhang Ning , Zhuang Hao , Li Yongmei
Published: March 2024

LINC00869 promotes cell migration, invasion and proliferation in HCC cells.
Supplementary Figure 5 from LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation
Authors: Shao Xiaowen , Dang Yamei , Zhang Tingting , Bai Nan , Huang Jianing , Guo Mengya , Sun Li , Li Minghe , Sun Xiao , Zhang Xinran , Han Feng , Zhang Ning , Zhuang Hao , Li Yongmei
Published: March 2024

LINC00869 increases tyrosine phosphorylation levels of WASp.
Data from FGFR1 Signaling Facilitates Obesity-Driven Pulmonary Outgrowth in Metastatic Breast Cancer
Authors: Kulkoyluoglu Cotul Eylem , Safdar Muhammad Hassan , Paez Sebastian Juan , Kulkarni Aneesha , Ayers Mitchell G. , Lin Hang , Xianyu Zilin , Teegarden Dorothy , Hursting Stephen D. , Wendt Michael K.
Published: March 2024

Abstract
Survival of dormant, disseminated breast cancer cells contributes to tumor relapse and metastasis. Women with a body mass index greater than 35 have an increased risk of developing metastatic recurrence. Herein, we investigated the effect of diet-induced obesity (DIO) on primary tumor growth and metastatic progression using both metastatic and systemically dormant mouse models of breast cancer. This approach led to increased PT growth and pulmonary metastasis. We developed a novel protocol to induce obesity in Balb/c mice by combining dietary and hormonal interventions with a thermoneutral housing strategy. In contrast to standard housing conditions, ovariectomized Balb/c mice fed a high-fat diet under thermoneutral conditions became obese over a period of 10 weeks, resulting in a 250% gain in fat mass. Obese mice injected with the D2.OR model developed macroscopic pulmonary nodules compared with the dormant phenotype of these cells in mice fed a control diet. Analysis of the serum from obese Balb/c mice revealed increased levels of FGF2 as compared with lean mice. We demonstrate that serum from obese animals, exogenous FGF stimulation, or constitutive stimulation through autocrine and paracrine FGF2 is sufficient to break dormancy and drive pulmonary outgrowth. Blockade of FGFR signaling or specific depletion of FGFR1 prevented obesity-associated outgrowth of the D2.OR model.
Implications:
Overall, this study developed a novel DIO model that allowed for demonstration of FGF2:FGFR1 signaling as a key molecular mechanism connecting obesity to breakage of systemic tumor dormancy and metastatic progression.
Data from Single-Cell Transcriptomics Reveals Pre-existing COVID-19 Vulnerability Factors in Lung Cancer Patients
Authors: Liu Wendao , Li Wenbo , Zhao Zhongming
Published: March 2024

Abstract
Coronavirus disease 2019 (COVID-19) and cancer are major health threats, and individuals may develop both simultaneously. Recent studies have indicated that patients with cancer are particularly vulnerable to COVID-19, but the molecular mechanisms underlying the associations remain poorly understood. To address this knowledge gap, we collected single-cell RNA-sequencing data from COVID-19, lung adenocarcinoma, small cell lung carcinoma patients, and normal lungs to perform an integrated analysis. We characterized altered cell populations, gene expression, and dysregulated intercellular communication in diseases. Our analysis identified pathologic conditions shared by COVID-19 and lung cancer, including upregulated TMPRSS2 expression in epithelial cells, stronger inflammatory responses mediated by macrophages, increased T-cell response suppression, and elevated fibrosis risk by pathologic fibroblasts. These pre-existing conditions in patients with lung cancer may lead to more severe inflammation, fibrosis, and weakened adaptive immune response upon COVID-19 infection. Our findings revealed potential molecular mechanisms driving an increased COVID-19 risk in patients with lung cancer and suggested preventive and therapeutic targets for COVID-19 in this population.
Implications:
Our work reveals the potential molecular mechanisms contributing to the vulnerability to COVID-19 in patients with lung cancer.
Data from TNFRSF19 within the 13q12.12 Risk Locus Functions as a Lung Cancer Suppressor by Binding Wnt3a to Inhibit Wnt/β-Catenin Signaling
Authors: Zuo Xianglin , Wang Xuchun , Ma Tingzheng , Chen Shuhan , Cao Pingping , Cheng He , Yang Nan , Han Xiao , Gao Wei , Liu Xiaoyu , Sun Yujie
Published: March 2024

Abstract
Cancer risk loci provide special clues for uncovering pathogenesis of cancers. The TNFRSF19 gene located within the 13q12.12 lung cancer risk locus encodes TNF receptor superfamily member 19 (TNFRSF19) protein and has been proved to be a key target gene of a lung tissue–specific tumor suppressive enhancer, but its functional role in lung cancer pathogenesis remains to be elucidated. Here we showed that the TNFRSF19 gene could protect human bronchial epithelial Beas-2B cells from pulmonary carcinogen nicotine-derived nitrosamine ketone (NNK)-induced malignant transformation. Knockout of the TNFRSF19 significantly increased NNK-induced colony formation rate on soft agar. Moreover, TNFRSF19 expression was significantly reduced in lung cancer tissues and cell lines. Restoration of TNFRSF19 expression in A549 lung cancer cell line dramatically suppressed the tumor formation in xenograft mouse model. Interestingly, the TNFRSF19 protein that is an orphan membrane receptor could compete with LRP6 to bind Wnt3a, thereby inhibiting the Wnt/β-catenin signaling pathway that is required for NNK-induced malignant transformation as indicated by protein pulldown, site mutation, and fluorescence energy resonance transfer experiments. Knockout of the TNFRSF19 enhanced LRP6–Wnt3a interaction, promoting β-catenin nucleus translocation and the downstream target gene expression, and thus sensitized the cells to NNK carcinogen. In conclusion, our study demonstrated that the TNFRSF19 inhibited lung cancer carcinogenesis by competing with LRP6 to combine with Wnt3a to inhibit the Wnt/β-catenin signaling pathway.
Implications:
These findings revealed a novel anti-lung cancer mechanism, highlighting the special significance of TNFRSF19 gene within the 13q12.12 risk locus in lung cancer pathogenesis.
Data from Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice
Authors: Barravecchia Ivana , Lee Jennifer M. , Manassa Jason , Magnuson Brian , Ferris Sarah F. , Cavanaugh Sophia , Steele Nina G. , Espinoza Carlos E. , Galban Craig J. , Ramnath Nithya , Frankel Timothy L. , Pasca di Magliano Marina , Galban Stefanie
Published: March 2024

Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. Patients with IPF have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognoses for those with chronic lung diseases and disease-associated cancer. Understanding the molecular pathogenesis of IPF-associated lung cancer is imperative for identifying diagnostic biomarkers and targeted therapies that will facilitate prevention of IPF and progression to lung cancer. To understand how IPF-associated fibroblast activation, matrix remodeling, epithelial-to-mesenchymal transition (EMT), and immune modulation influences lung cancer predisposition, we developed a mouse model to recapitulate the molecular pathogenesis of pulmonary fibrosis–associated lung cancer using the bleomycin and Lewis lung carcinoma models. We demonstrate that development of pulmonary fibrosis–associated lung cancer is likely linked to increased abundance of tumor-associated macrophages and a unique gene signature that supports an immune-suppressive microenvironment through secreted factors. Not surprisingly, preexisting fibrosis provides a pre-metastatic niche and results in augmented tumor growth, and tumors associated with bleomycin-induced fibrosis are characterized by a dramatic loss of cytokeratin expression, indicative of EMT.
Implications:
This characterization of tumors associated with lung diseases provides new therapeutic targets that may aid in the development of treatment paradigms for lung cancer patients with preexisting pulmonary diseases.
Data from LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation
Authors: Shao Xiaowen , Dang Yamei , Zhang Tingting , Bai Nan , Huang Jianing , Guo Mengya , Sun Li , Li Minghe , Sun Xiao , Zhang Xinran , Han Feng , Zhang Ning , Zhuang Hao , Li Yongmei
Published: March 2024

Abstract
Coordination of filament assembly and membrane remodeling is required for the directional migration of cancer cells. The Wiskott–Aldrich syndrome protein (WASP) recruits the actin-related protein (ARP) 2/3 complex to assemble branched actin networks. The goal of our study was to assess the potential regulatory role exerted by the novel long noncoding RNA (lncRNA) LINC00869 on hepatocellular carcinoma (HCC) cells. We used HCC cells to overexpress or knockdown LINC00869, analyzed patient data from publicly available databases and Cancer Hospital Affiliated with Zhengzhou University, and used a xenograft mouse model of HCC to study the molecular mechanism associated with LINC00869 expression. We found that high levels of LINC00869 expression were associated with poor prognosis in patients with HCC. Next, we detected an interaction between LINC00869 and both WASP and ARP2 in HCC cells, and observed a modulatory effect of LINC00869 on the phosphorylation of WASP at Y291 and the activity of cell division control protein 42 (CDC42). These modulatory roles were required for WASP/CDC42 activity on F-actin polymerization to enhance membrane protrusion formation and maintain persistent cell polarization. This, in turn, promoted the migration and invasion abilities of HCC cells. Finally, we confirmed the role of LINC00869in vivo, using the tumor xenograft mouse model; and identified a positive correlation between LINC00869 expression levels and the phosphorylation levels of WASP in HCC samples. Overall, our findings suggest a unique mechanism by which LINC00869 orchestrates membrane protrusion during migration and invasion of HCC cells.
Implications:
LncRNA LINC00869 regulates the activity of CDC42–WASP pathway and positively affects protrusion formation in HCC cells, which expands the current understanding of lncRNA functions as well as gives a better understanding of carcinogenesis.
Abstract A009: Addressing obesity’s impact on the PTEN mutant endometrium
Authors: Skalski Hilary J. , Harkins Shannon K. , Arendt Amelia R. , MacLachlan Madison , Becker Katelyn , Wegener Marc , Adams Marie , Hostetter Galen , Chandler Ronald L.
Published: March 2024

Obesity is a rising epidemic in the United States, with approximately 50% of adult women predicted to be obese by 2030. Obesity is a risk factor for endometrial hyperplasia (EH), which is characterized by the benign overgrowth of the endometrial epithelium and is considered a precursor lesion for endometrial cancer (EC). Somatic PTEN mutations are commonly observed in EH and EC, with PTEN loss being one of the earliest mutations observed in the progression to EC. Previous obesity work in our lab utilized high-fat diet (HFD)-induced obese WT mice and found that obesity affected different cell types within the endometrium, including non-tumor prone cells. Our preliminary findings suggest that 60% HFD prolongs the estrus stage of the estrus cycle in WT mice. The aims of this study are to determine the cell-specific effects of obesity on the endometrial epithelia carrying PTEN mutations. Female PTENfl/fl; Pax8Cre/+ mutant and Pax8Cre+/+ control mice on a C57BL/6J background were fed either a 60% HFD or it’s sucrose-matched control diet (CD) for a minimum of 22 weeks. Weekly mouse and food weights were collected. Mice were tested for glucose tolerance after being on diet for at least 4.5 months. Uterus and blood were collected at estrus stage. Uteri were processed for single-cell RNA seq. PTENfl/fl; Pax8Cre/+ mice on both the HFD and CD had a diminished weight gain compared to Pax8Cre+/+ mice on the same diet. HFD-treated mice exhibited hyperphagia, weighed significantly more than the CD mice, and demonstrated glucose intolerance. H&E staining of the adipose tissue and liver revealed adipocyte hypertrophy and fatty liver infiltration in HFD mice. IHC of PTENfl/fl; Pax8Cre/+ uteri confirmed epithelial-specific loss of PTEN and displayed endometrial hyperplasia. PTENfl/fl; Pax8Cre/+ uteri had an influx of Ly6G+ neutrophils invading the endometrial epithelium compared to the Pax8Cre+/+ mice. Strikingly in PTENfl/+; Pax8Cre/+ we observe clonal loss of PTEN immunoreactivity in a subset of endometrial glands with similar phenotypic features. We propose that obesity’s impact on non-tumor cell types within the endometrium will be shaped by early genetic mutations in tumor-prone epithelia.

Citation Format: Hilary J. Skalski, Shannon K. Harkins, Amelia R. Arendt, Madison MacLachlan, Katelyn Becker, Marc Wegener, Marie Adams, Galen Hostetter, Ronald L. Chandler. Addressing obesity’s impact on the PTEN mutant endometrium [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A009.
Abstract B006: Mutant PPP2R1A induces the expression and secretion of IGFBP2 to promote uterine serous carcinoma metastasis
Authors: Haanen Terrance James , Boock Sophie , Taylor Sarah , O'Connor Caitlin , DiFeo Analisa , Narla Goutham
Published: March 2024

Uterine serous carcinoma (USC) tumors demonstrate a unique aggressiveness suggesting that the primary tumor is intrinsically equipped to disseminate, metastasize and initiate tumor formation at secondary sites. Yet the drivers and pathways regulating dissemination and metastasis in USC remain incompletely understood. Previous work by our group and others identified a mutational hotspot within PPP2R1A, which encodes the Aa scaffolding subunit of protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase and known tumor suppressor. Two recurrent mutations, P179R and S256F, occur exclusively within high-grade subtypes of uterine cancer at a rate of 30-40%. We previously published that the P179R mutant drives USC tumorigenesis through the inactivation of PP2A, and genetic correction of this mutant resulted in decreased primary and metastatic tumor formation. The underlying mechanisms for these observations, however, remain unclear. To study the mechanistic basis for these observations, we generated isogenic patient-derived USC cell lines expressing the Aa – P179R and S256F mutants. Expression of these mutants enhanced the tumor-initiating capacity (TIC), a hybrid epithelial to mesenchymal (EM) plasticity profile, and the secretion of tumor-promoting factors in vitro and in vivo. Molecular analysis of these cell lines and tumors demonstrated that these mutants drove increased NF-kb phosphorylation resulting in the upregulation and secretion of the EM cytokine, IGFBP2. We found that the Aa mutant phenotype was dependent on the IGFBP2 cytokine function in vitro and in vivo. Future experiments will focus on identifying which PP2A B regulatory subunits are responsible for regulating the onset of the NF-kb transcriptional program. Cellular reprogramming through the IGFBP2-induced NF-kb signaling pathway mediated by recurrent Aa mutants may explain the intrinsically aggressive nature of USC, through enhanced dissemination and metastasis.

Citation Format: Terrance James Haanen, Sophie Boock, Sarah Taylor, Caitlin O'Connor, Analisa DiFeo, Goutham Narla. Mutant PPP2R1A induces the expression and secretion of IGFBP2 to promote uterine serous carcinoma metastasis [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B006.
Abstract B023: The role of ribosomal protein L22 in regulating the immune landscape in mismatch repair deficient endometrial cancers
Authors: Osborne Macy L. , Atkins Hannah , Gladden Andrew B. , Broaddus Russell R.
Published: March 2024

The purpose of this study is to identify novel mechanisms of immune evasion in mismatch repair deficient endometrial cancers. Despite having a hypermutated phenotype that is proposed to lead to the accumulation of many neoantigens for immune recognition, our group has found that mismatch repair deficient endometrial cancers characterized by MLH1 protein loss display large variations in the number of tumors infiltrating CD8+ T cells (TILs) across different tumors. To better understand how variations in TILs arise in mismatch repair deficient endometrial cancers, we utilized human endometrial cancer samples from the UNCseq cohort. Immunohistochemistry (IHC) was used to identify expression patterns in proteins of interest across mismatch repair deficient endometrial cancers. To determine how expression patterns of proteins of interest correlate with TILs in our patient samples, Definiens Tissue Studio was utilized to quantify immunofluorescent CD8+ TILs in our mismatch repair deficient endometrial cancer cohort. Although upregulation of programmed death ligand 1 (PD-L1) expression is often cited as an explanation for low TILs, analysis of human data by our group shows that PD-L1 expression does not correlate with TIL numbers in mismatch repair deficient endometrial cancers. Interestingly, The Cancer Genome Atlas (TCGA) data reported that ribosomal protein L22 (RPL22) is mutated in ~50% of mismatch repair deficient endometrial cancers. We analyzed RPL22 by IHC and found that it was lost in 52% of our human mismatch repair deficient endometrial cancer cohort. Loss of various ribosomal proteins can alter translation efficiency of proteins critical for promoting immunosurveillance and the immune response in cancer. In our cohort, mismatch repair deficient endometrial cancers that have lost expression of RPL22 have lower numbers of CD8+ TILs. Preliminary data also show that human endometrial cancer cell lines that do not express RPL22 also do not express beta-2-microglobulin (β2M), a component of the major histocompatibility complex I (MHC-I) molecules that is necessary for neoantigen presentation to CD8+ T cells. Thus, we hypothesize that RPL22 loss in mismatch repair deficient endometrial cancers results in decreased translation of β2M and CD8+ T cell evasion. Moving forward, we speculate that RPL22 could be utilized as a predictive biomarker for immunotherapy response in mismatch repair deficient endometrial cancers.

Citation Format: Macy L. Osborne, Hannah Atkins, Andrew B. Gladden, Russell R. Broaddus. The role of ribosomal protein L22 in regulating the immune landscape in mismatch repair deficient endometrial cancers [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B023.
Abstract B028: Epithelial-specific loss of PIK3R1 in a murine model result in endometrial hyperplasia
Authors: Harkins Shannon K. , Skalski Hilary J. , Arendt Amelia , Pavliscak Laura , Wilson Mike R. , Chandler Ronald L.
Published: March 2024

Somatic mutations in the phosphatidylinositol 3-kinase (PI3K) pathway occur in 84% of endometrial carcinomas (EC) and up to 68% of endometrial hyperplasia (EH). Regulation of PI3K/Akt/mTOR signaling is integral for normal endometrial function and is governed by tumor suppressor genes PTEN and PIK3R1 and proto-oncogene PIK3CA. While the actions of PTEN and PIK3CA are in direct opposition as a phosphatase and kinase, respectively, PIK3R1 regulates PI3K/Akt/mTOR signaling in two distinct ways. As the regulatory subunit of the PI3K enzyme, PIK3R1 controls the catalytic activity of PIK3CA and augments PTEN activity. Mutations or alterations in PIK3R1 are present in 33% of EC and 9% of EH, the majority of which lead to loss of PIK3R1 protein (p85a). Both loss of PTEN and PIK3R1 lead to increased proliferation through PI3K/Akt/mTOR signaling, but the structural, functional, and mechanistic implications of PIK3R1 loss in the endometrial epithelium (EE) in vivo are largely unexplored. To further interrogate the changes in the endometrium resulting from PIK3R1 loss, we have created a murine model of endometrial epithelial-specific PIK3R1 loss driven by Pax8-Cre. Mice were estrus cycle staged and sacrificed in the diestrus phase to reduce confounding variables when assessing phenotypes between genotypes. PIK3R1 loss was confirmed by immunohistochemistry (IHC). Histology and immunostaining of control and PIK3R1 knockout (KO) mice were assessed by IHC and immunofluorescence. We found that PIK3R1 loss in the EE leads to EH distinct from what is observed with PTEN loss. In contrast to the EH with atypia seen In PTEN KO mice, the EH resulting from PIKR1 loss more closely resembles EH without atypia. The endometrium of PIK3R1 KO mice is characterized by thickened luminal epithelia with jagged edges and irregularities, mild glandular crowding, and occasional nuclear atypia. PIK3R1 KO mice also showed an increase in proliferation (Ki-67) and downstream PI3K signaling (phospho-S6) in the EE. Gene expression changes occurring within the EE from PIK3R1 KO and Cre-negative control mice were also assessed by RNA-seq. In vivo genomic analyses were compared to in vitro knockdown of PIK3R1 and publicly available patient data. We found that PIK3R1 loss leads to an increase in signaling through the PI3K/Akt/mTOR and MAPK pathways. Our data show that the effect of PIK3R1 loss is sufficient to cause EH and may have shared and distinct actions from PTEN.

Citation Format: Shannon K. Harkins, Hilary J. Skalski, Amelia Arendt, Laura Pavliscak, Mike R. Wilson, Ronald L. Chandler. Epithelial-specific loss of PIK3R1 in a murine model result in endometrial hyperplasia [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B028.
Abstract IA014: Personalized adjuvant treatment in endometrial cancer
Authors: Bosse Tjalling
Published: March 2024

The majority of endometrial cancer patients are cured by surgical removal of the uterus. Adjuvant treatment is recommended for a subset of patients with tumor characteristics associated with increased risk of recurrence. Historically pathologists have played a central role in defining histopathological factors that together make-up a risk profile which directs the type of adjuvant treatment. This traditional approach suffers from interobserver variability and lacks a biological basis. With the advance of molecular pathology, we have been able to define molecularly distinct endometrial cancer subsets which also carry distinct prognostic information and may form a basis for targeted adjuvant treatment. The RAINBO program exploits this concept by running 4 molecular subclass specific clinical trials. During my talk I will go over the past, the present and the future of adjuvant treatment in endometrial cancer with an emphasis on the role of pathology.

Citation Format: Tjalling Bosse. Personalized adjuvant treatment in endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA014.