bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S3 from Targeting the immunoglobulin IGSF9 enhances anti-tumor T cell activity and sensitivity to anti-PD-1 immunotherapy
Authors: Liu Yifan , Wang Hongying , Zhao Xinyu , Zhang Jiashen , Zhao Zhiling , Lian Xia , Zhang Juan , Kong Feng , Hu Tao , Wang Ting , Li Xiaohua , Wang Lei , Wang Dapeng , Li Chunling , Luan Huiwen , Liu Xiaoli , Wang Chunyan , Jiang Yun , Li Xiaomin , Li Fangmin , Ji Shuhao , Wang Yaopeng , Li Zunling
Published: September 2024

Human IGSF9 was detected in myeloid cells of peripheral blood from healthy donors and tumor patients.
Figure S2 from Breast cancer-secreted factors promote lung metastasis by signaling systemically to induce a fibrotic pre-metastatic niche
Authors: Cohen Noam , Mundhe Dhanashree , Deasy Sarah K. , Adler Omer , Ershaid Nour , Shami Tamar , Levi-Galibov Oshrat , Wassermann Rina , Scherz-Shouval Ruth , Erez Neta
Published: September 2024

Supplementary data to Figure 4
Supplementary Figure Legends from Parkin deficiency suppresses antigen presentation to promote tumor immune evasion and immunotherapy resistance
Authors: Perales-Linares Renzo , Leli Nektaria Maria , Mohei Hesham , Beghi Silvia , Rivera Osvaldo D. , Kostopoulos Nektarios , Giglio Andrea , George Subin S. , Uribe-Herranz Mireia , Costabile Francesca , Pierini Stefano , Pustylnikov Sergei , Skoufos Giorgos , Barash Yoseph , Hatzigeorgiou Artemis G. , Koumenis Constantinos , Maity Amit , Lotze Michael T. , Facciabene Andrea
Published: September 2024

Supplementary Figure Legends
Supp. Figure 4 from Parkin deficiency suppresses antigen presentation to promote tumor immune evasion and immunotherapy resistance
Authors: Perales-Linares Renzo , Leli Nektaria Maria , Mohei Hesham , Beghi Silvia , Rivera Osvaldo D. , Kostopoulos Nektarios , Giglio Andrea , George Subin S. , Uribe-Herranz Mireia , Costabile Francesca , Pierini Stefano , Pustylnikov Sergei , Skoufos Giorgos , Barash Yoseph , Hatzigeorgiou Artemis G. , Koumenis Constantinos , Maity Amit , Lotze Michael T. , Facciabene Andrea
Published: September 2024

Figure S4
Tables S1-S3 from Integrative genomic analyses identify lncRNA regulatory networks across pediatric leukemias and solid tumors
Authors: Modi Apexa , Lopez Gonzalo , Conkrite Karina L. , Su Chun , Leung Tsz Ching , Ramanan Sathvik , Manduchi Elisabetta , Johnson Matthew E. , Cheung Daphne , Gadd Samantha , Zhang Jinghui , Smith Malcolm A. , Guidry Auvil Jaime M. , Meshinchi Soheil , Perlman Elizabeth J. , Hunger Stephen P. , Maris John M. , Wells Andrew D. , Grant Struan F.A. , Diskin Sharon J.
Published: September 2024

Table S1: TARGET clinical sample and RNA-sequencing characteristics, Table S2: Genomic loci for lncRNA and protein coding genes in this study, Table S3: Number and types of genes expressed per cancer
Figure S8 from Integrative genomic analyses identify lncRNA regulatory networks across pediatric leukemias and solid tumors
Authors: Modi Apexa , Lopez Gonzalo , Conkrite Karina L. , Su Chun , Leung Tsz Ching , Ramanan Sathvik , Manduchi Elisabetta , Johnson Matthew E. , Cheung Daphne , Gadd Samantha , Zhang Jinghui , Smith Malcolm A. , Guidry Auvil Jaime M. , Meshinchi Soheil , Perlman Elizabeth J. , Hunger Stephen P. , Maris John M. , Wells Andrew D. , Grant Struan F.A. , Diskin Sharon J.
Published: September 2024

Figure S8: RNA expression profiling following TBX2-AS1 and TBX2 knockdown in NLF
Figure S3 from Integrative genomic analyses identify lncRNA regulatory networks across pediatric leukemias and solid tumors
Authors: Modi Apexa , Lopez Gonzalo , Conkrite Karina L. , Su Chun , Leung Tsz Ching , Ramanan Sathvik , Manduchi Elisabetta , Johnson Matthew E. , Cheung Daphne , Gadd Samantha , Zhang Jinghui , Smith Malcolm A. , Guidry Auvil Jaime M. , Meshinchi Soheil , Perlman Elizabeth J. , Hunger Stephen P. , Maris John M. , Wells Andrew D. , Grant Struan F.A. , Diskin Sharon J.
Published: September 2024

Figure S3: Regions of somatic copy number aberration across cancers and genes dysregulated due to copy number
Data from AKT blocks SIK1-mediated repression of STAT3 to promote breast tumorigenesis
Authors: Sun Zhicheng , Jiang Qiwei , Gao Bing , Zhang Xiaomei , Bu Lang , Wang Lei , Lin Ying , Xie Wei , Li Jie , Guo Jianping
Published: September 2024

Abstract
The PI3K-AKT signaling pathway is frequently dysregulated in cancer, and it is hyperactivated in approximately 50% of breast cancers. While inhibitors directly targeting the PI3K-AKT axis have been developed, clinical efficacy has been limited to only a subset of patients. Identification of mechanisms underlying AKT-driven tumorigenesis could lead to alternative approaches to block pathway signaling and suppress breast tumor growth. Mass spectrometry-based analyses demonstrated that salt-inducible kinase 1 (SIK1) binds AKT and undergoes AKT-mediated phosphorylation, which compromises SIK1 tumor-suppressive functions. As a result, AKT relieved the binding and repression of STAT3 by SIK1 in a phosphorylation-dependent manner, resulting in breast cell tumorigenesis. Following AKT-mediated phosphorylation, SIK1 interacted with 14-3-3 and was translocated to the cytoplasm where the isomerase Pin1 facilitated SIK1 interaction with the E3 ligase ITCH to promote SIK1 ubiquitination and subsequent degradation. These findings indicate that SIK1 is a substrate of AKT that links AKT oncogenic function to STAT3 activation, highlighting targeting of the JAK2-STAT3 axis as a strategy to treat AKT-driven breast cancer.
Data from Dysregulation of mitochondrial translation caused by CBFB deficiency cooperates with mutant PIK3CA and is a vulnerability in breast cancer
Authors: Malik Navdeep , Kim Young-Im , Yan Hualong , Tseng Yu-Chou , du Bois Wendy , Ayaz Gamze , Tran Andy D. , Vera Ramírez Laura , Yang Howard H. , Michalowski Aleksandra M. , Kruhlak Michael , Lee Maxwell , Hunter Kent W. , Huang Jing
Published: September 2024

Abstract
Understanding functional interactions between cancer mutations is an attractive strategy for discovering unappreciated cancer pathways and developing new combination therapies to improve personalized treatment. However, distinguishing driver gene pairs from passenger pairs remains challenging. Here, we designed an integrated omics approach to identify driver gene pairs by leveraging genetic interaction analyses of top mutated breast cancer genes and the proteomics interactome data of their encoded proteins. This approach identified that PIK3CA oncogenic gain‐of-function (GOF) and CBFB loss‐of‐function (LOF) mutations cooperate to promote breast tumor progression in both mice and humans. The transcription factor CBFB localized to mitochondria and moonlighted in translating the mitochondrial genome. Mechanistically, CBFB enhanced the binding of mitochondrial mRNAs to TUFM, a mitochondrial translation elongation factor. Independent of mutant PI3K, mitochondrial translation defects caused by CBFB LOF led to multiple metabolic reprogramming events, including defective oxidative phosphorylation (OXPHOS), the Warburg effect, and autophagy/mitophagy addiction. Furthermore, autophagy and PI3K inhibitors synergistically killed breast cancer cells and impaired the growth of breast tumors, including patient‐derived xenografts (PDXs) carrying CBFB LOF and PIK3CA GOF mutations. Thus, our study offers mechanistic insights into the functional interaction between mutant PI3K and mitochondrial translation dysregulation in breast cancer progression and provides a strong preclinical rationale for combining autophagy and PI3K inhibitors in precision medicine for breast cancer.
Data from Microenvironment-driven dynamic chromatin changes in glioblastoma recapitulate early neural development at single-cell resolution
Authors: Pine Allison R. , Cirigliano Stefano M. , Singhania Richa , Nicholson James , Da Silva Barbara , Leslie Christina S. , Fine Howard A.
Published: September 2024

Abstract
The tumor microenvironment is necessary for recapitulating the intratumoral heterogeneity and cell state plasticity found in human primary glioblastoma (GBM). Conventional models do not accurately recapitulate the spectrum of GBM cellular states, hindering elucidation of the underlying transcriptional regulation of these states. Using our Glioblastoma Cerebral Organoid (GLICO) model, we profiled the chromatin accessibility of 28,040 single cells in five patient-derived glioma stem cell lines. Integration of paired epigenomes and transcriptomes within the context of tumor-normal host cell interactions was used to probe the gene-regulatory networks underlying individual GBM cellular states in a way not readily possible in other in vitro models. These analyses identified the epigenetic underpinnings of GBM cellular states and characterized dynamic chromatin changes reminiscent of early neural development that underlie GBM cell state transitions. Despite large differences between tumors, a shared cellular compartment made up of neural progenitor-like cells and outer radial glia-like cells was observed. Together, these results shed light on the transcriptional regulation program in GBM and offer novel therapeutic targets across a broad range of genetically heterogenous GBMs.
Data from ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma
Authors: Jackson Evangeline R. , Duchatel Ryan J. , Staudt Dilana E. , Persson Mika L. , Mannan Abdul , Yadavilli Sridevi , Parackal Sarah , Game Shaye , Chong Wai Chin , Jayasekara W. Samantha Nilanthi. , Le Grand Marion , Kearney Padraic S. , Douglas Alicia M. , Findlay Izac J. , Germon Zacary P. , McEwen Holly P. , Beitaki Tyrone S. , Patabendige Adjanie , Skerrett-Byrne David A. , Nixon Brett , Smith Nathan D. , Day Bryan , Manoharan Neevika , Nagabushan Sumanth , Hansford Jordan R. , Govender Dinisha , McCowage Geoffrey B. , Firestein Ron , Howlett Meegan , Endersby Raelene , Gottardo Nicholas G. , Alvaro Frank , Waszak Sebastian M. , Larsen Martin R. , Colino-Sanguino Yolanda , Valdés-Mora Fatima , Rakotomalala Andria , Meignan Samuel , Pasquier Eddy , Andre Nicolas , Hulleman Esther , Eisenstat David D. , Vitanza Nicholas A. , Nazarian Javad , Koschmann Carl , Mueller Sabine , Cain Jason E. , Dun Matthew D.
Published: September 2024

Abstract
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.
Data from The m6A reader YTHDF2 promotes bladder cancer progression by suppressing RIG-I-mediated immune response
Authors: Zhang Lei , Li Yuqing , Zhou Lingli , Zhou Houhong , Ye Liefu , Ou Tong , Hong Huaishan , Zheng Shiwen , Zhou Ziyu , Wu Kang , Yan Zeqin , Thiery Jean Paul. , Cui Jun , Wu Song
Published: September 2024

Abstract
N6-Methyladenosine (m6A) is the most prevalent internal modification among mammalian mRNAs. Recent studies show that m6A methyltransferases, METTL3 and METTL14, play important roles in bladder carcinoma (BLCA). However, the impact of YTHDF2, a crucial m6A reader, has yet to be investigated. Here, we found that YTHDF2 is frequently up-regulated at both the RNA and protein level in bladder cancers. Functionally, YTHDF2 promotes the proliferation and tumor growth of BLCA cells in vitro and in vivo, respectively. Integrative RNA-sequencing and m6A-sequencing analyses show that RIG-I is a downstream target of YTHDF2. Mechanistically, YTHDF2 binds to the coding sequence of DDX58 mRNA and mediates its degradation in an m6A-dependent manner. Knock-down of RIG-I inhibits apoptosis and promotes the proliferation of BLCA cells. Depleting DDX58 also restores the phenotype abrogated by YTHDF2 deficiency. Moreover, bladder cancer Ythdf2-deficient cells implanted orthotopically activate an innate immune response and promote the recruitment of CD8+ T lymphocytes into the tumor bed and the urothelium. Consequently, targeting YTHDF2 may be beneficial in Bacillus Calmette-Guérin (BCG) immunotherapy. Our study reveals that YTHDF2 acts as an oncogene and RIG-I as a tumor suppressor in BLCA. These findings highlight the functional importance of the m6A modification in BLCA and implicate YTHDF2 as a potential therapeutic target of BLCA treatment.
Data from A self-propagating c-Met-SOX2 axis drives cancer-derived IgG signaling that promotes lung cancer cell stemness
Authors: Huang Xinmei , Zhang Shenghua , Tang Jingshu , Tian Tian , Pan Yilin , Wu Lina , Zhang Jingxuan , Liu Yang , Huang Jing , Dai Hui , Xu Weiyan , Zhang Youhui , Chen Jinfeng , Cao Mengshu , Zhang Liang , Qiu Xiaoyan
Published: September 2024

Abstract
Elevated IgG expression in cancer cells has been implicated in exacerbated malignancy and poor clinical prognosis. Accumulating evidence indicates that a nonconventional sialylation modification is critical for the function of cancer-derived IgG, indicating the need for a better understanding of the regulatory mechanisms that control the expression and function of sialylated cancer IgG (SIA-cIgG). Here, we conducted genome-wide CRISPR activation screening and identified OCT4 and SOX2 as the key factors that promote SIA-cIgG expression. Functional investigation revealed that SIA-cIgG reciprocally stimulated SOX2 by activating the c-Met/Akt/Erk signaling axis, constituting a self-propagating loop of SIA-cIgG/c-Met/SOX2/SIA-cIgG signaling. This signaling loop was highly active in stem-like cells from many epithelial cancers and was crucial for cancer stemness in vitro and in vivo. Notably, the monoclonal antibody RP215, which specifically recognizes the Asn162 sialylation-related epitope on SIA-cIgG, effectively blocked the SIA-cIgG-driven signaling loop. Furthermore, RP215 significantly inhibited lung cancer cell stemness and tumor growth in a patient-derived xenograft model. In conclusion, these findings revealed a self-propagating c-Met/SOX2/SIA-cIgG signaling loop that promotes cancer stemness, identifying novel therapeutic strategies for cancer treatment.
Data from Dual impact of IGF2 on alveolar stem cell function during tobacco-induced injury repair and development of pulmonary emphysema and cancer
Authors: Boo Hye-Jin , Min Hye-Young , Park Choon-Sik , Park: Jong-Sook , Jeong Ji Yun , Lee Shin Yup , Kim Woo-Young , Lee Jae-Won , Oh Sei-Ryang , Park Rang-Woon , Lee Ho-Young
Published: September 2024

Abstract
Pulmonary emphysema is a destructive inflammatory disease primarily caused by cigarette smoking (CS). Recovery from CS-induced injury requires proper stem cell (SC) activities with a tightly controlled balance of proliferation and differentiation. Here we show that acute alveolar injury induced by two representative tobacco carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (N/B), increased IGF2 expression in alveolar type 2 cells (AT2s) to promote their SC function and facilitate alveolar regeneration. Autocrine IGF2 signaling upregulated Wnt genes, particularly Wnt3, to stimulate AT2 proliferation and alveolar barrier regeneration after N/B-induced acute injury. In contrast, repetitive N/B exposure provoked sustained IGF2-Wnt signaling through DNMT3A-mediated epigenetic control of IGF2 expression, causing a proliferation/differentiation imbalance in AT2s and development of emphysema and cancer. Hypermethylation of the IGF2 promoter and overexpression of DNMT3A, IGF2, and the Wnt target gene AXIN2 were seen in the lungs of patients with CS-associated emphysema and cancer. Pharmacological or genetic approaches targeting IGF2-Wnt signaling or DNMT prevented the development of N/B-induced pulmonary diseases. These findings support dual roles of AT2 cells, which can either stimulate alveolar repair or promote emphysema and cancer depending on IGF2 expression levels.
Data from Terminally Exhausted CD8+ T Cells Resistant to PD-1 Blockade Promote Generation and Maintenance of Aggressive Cancer Stem Cells
Authors: Chakravarti Mohona , Dhar Sukanya , Bera Saurav , Sinha Abhipsa , Roy Kamalika , Sarkar Anirban , Dasgupta Shayani , Bhuniya Avishek , Saha Akata , Das Juhina , Banerjee Saptak , Vernekar Manisha , Pal Chiranjib , Alam Neyaz , Datta Dipak , Baral Rathindranath , Bose Anamika
Published: September 2024

Abstract
Heterogeneity within the tumor-infiltrating lymphocytes (TIL) population limits immunotherapeutic efficacy against cancer. Between two subpopulations of exhausted CD8+ TILs (progenitor-exhausted; TPEX, terminally exhausted; TTEX), TTEX cells remain unresponsive to anti–programmed cell death protein 1(PD-1) therapy. Deciphering whether and how PD-1–resistant TTEX cells engage in tumor promotion could improve the response to immunotherapy. Here, we report that TTEX cells actively participate in tumor progression by modulating cancer stem cells (CSC). TTEX cells strongly correlated with elevated CSC frequency in poorly immune-infiltrated (CD8+ TIL low) advanced human breast and ovarian carcinomas. TTEX directly upregulated CSC frequency in vitro, which was not affected by anti–PD-1 treatment. The TTEX-influenced CSCs were highly clonogenic and exhibited a multidrug-resistant phenotype, overexpressing drug efflux pumps like ABCC1 and ABCB1. These CSCs were highly invasive, displaying increased invadopodia development and elevated cofilin, CXCR4, and matrix metalloproteinase 7 (MMP7) expression. The invasive properties along with epithelial–mesenchymal plasticity of TTEX-educated CSCs increased metastasis in vivo. TTEX increased cell surface levels and activation of VEGFR2 in CSCs, and silencing or inhibition of VEGFR2 reversed the CSC-stimulatory effects of TTEX. LAMP3 and NRP1 on the surface of TTEX stimulated VEGFR2 in CSCs to promote aggressiveness. Cumulatively, these findings suggest that screening patients with carcinoma for both CD8+ TILs and TTEX frequency prior to anti–PD-1 therapy could improve patient outcomes. In addition, targeting the LAMP3/NRP1–VEGFR2 axis could be a therapeutic strategy in advanced patients with carcinoma with limited CD8+ T-cell infiltration and high TTEX frequency.
Significance:
Cross-talk with TTEX CD8+ T cells mediated by the VEGFR2 axis induces aggressive properties in cancer stem cells to promote tumor progression.
Data from Prospective analysis reveals associations between carbohydrate intakes, genetic predictors of short-chain fatty acid synthesis, and colorectal cancer risk
Authors: Watling Cody Z. , Kelly Rebecca K. , Murphy Neil , Gunter Marc , Piernas Carmen , Bradbury Kathryn E. , Schmidt Julie A. , Key Timothy J. , Perez-Cornago Aurora
Published: September 2024

Abstract
Whole grain and fiber intakes may decrease the risk of colorectal cancer. The interplay between host genetic factors, colonization of specific bacteria, production of short-chain fatty acids (SCFA), and intake of whole grains and fiber could alter the protective role of carbohydrates against colorectal cancer. Here, we assessed intakes of types and sources of carbohydrates in 114,217 UK Biobank participants with detailed dietary data (2-5 24-hour dietary assessments), and a host polygenic score (PGS) was applied to categorize participants as high or low for intra-luminal microbial SCFA production, namely butyrate and propionate. Multivariable Cox proportional hazards models were used to determine the associations of carbohydrates and SCFA with colorectal cancer incidence. During a median follow-up of 9.4 years, 1,193 participants were diagnosed with colorectal cancer. Risk was inversely associated with intakes of non-free sugar and whole grain fiber. Evidence of heterogeneity was observed by the butyrate PGS; consuming higher amounts of whole grain starch was only associated with a lower risk of colorectal cancer in those with predicted high SCFA production. Similarly, in additional analyses utilizing the larger UK Biobank cohort (N=343,621) with less detailed dietary assessment, only individuals with a high genetically predicted butyrate production had a lower risk of colorectal cancer per 5 g/day intake of bread and cereal fiber. This study suggests that colorectal cancer risk varies by intake of carbohydrate types and sources, and the impact of whole grain intake may be modified by SCFA production.
Data from Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression
Authors: DeBlasi Janine M. , Falzone Aimee , Caldwell Samantha , Prieto-Farigua Nicolas , Prigge Justin R. , Schmidt Edward E. , Chio Iok In Christine , Karreth Florian A. , DeNicola Gina M.
Published: September 2024

Abstract
Mutations in the KEAP1-NRF2 pathway occur in up to a third of non-small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic NRF2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors p53 or LKB1. When combined with KrasG12D/+, constitutive NRF2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by NRF2 deletion. Finally, NRF2 overexpression in KEAP1 mutant human NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, these results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process.
Data from TGF-β antagonizes IFN-γ-mediated adaptive immune evasion via activation of the AKT-Smad3-SHP1 axis in lung adenocarcinoma
Authors: Ye Fan , Cai Zihao , Wang Boyu , Zeng Chenxi , Xi Yu , Hu Shaojie , Qu Rirong , Yuan Zhiwei , Yue Jiaqi , Tian Yitao , Wang Xue , Fu Xiangning , Li Lequn
Published: September 2024

Abstract
IFN-γ-mediated signaling in tumor cells can induce immunosuppressive responses and cause tumor resistance to immunotherapy. Blocking TGF-β promotes T lymphocyte infiltration and turns immunologically cold tumors into hot tumors, thereby improving the efficacy of immunotherapy. Several studies have shown that TGF-β inhibits IFN-γ signaling in immune cells. We thus sought to determine whether TGF-β affects IFN-γ signaling in tumor cells and plays a role in the development of acquired resistance to immunotherapy. TGF-β stimulation of tumor cells increased SHP1 phosphatase activity in an AKT-Smad3-dependent manner, decreased IFN-γ-mediated tyrosine phosphorylation of JAK1/2 and STAT1, and suppressed the expression of STAT1-dependent immune evasion-related molecules, e.g., PD-L1, IDO1, HVEM, and Gal-9. In a lung cancer mouse model, dual blockade of TGF-β and PD-L1 led to superior antitumor activity and prolonged survival compared to anti-PD-L1 therapy alone. However, prolonged combined treatment resulted in tumor resistance to immunotherapy and increased expression of PD-L1, IDO1, HVEM, and Gal-9. Interestingly, after initial anti-PD-L1 monotherapy, dual TGF-β and PD-L1 blockade promoted both immune evasion gene expression and tumor growth compared to that in tumors treated with continuous PD-L1 monotherapy. Alternatively, treatment with JAK1/2 inhibitor following initial anti-PD-L1 therapy effectively suppressed tumor growth and downregulated immune evasion gene expression in tumors, indicating the involvement of IFN-γ signaling in immunotherapy resistance development. These results demonstrate an unappreciated effect of TGF-β on the development of IFN-γ-mediated tumor resistance to immunotherapy.
Data from Periostin+ stromal cells guide lymphovascular invasion by cancer cells
Authors: Null Jamie L. , Kim Dae Joong , McCann James V. , Pramoonjago Patcharin , Fox Jay W. , Zeng Jianhao , Kumar Pankaj , Edatt Lincy , Pecot Chad V. , Dudley Andrew C.
Published: September 2024

Abstract
Cancer cell dissemination to sentinel lymph nodes associates with poor patient outcomes, particularly in breast cancer. The process by which cancer cells egress from the primary tumor upon interfacing with the lymphatic vasculature is complex and driven by dynamic interactions between cancer cells and stromal cells, including cancer associated fibroblasts (CAFs). The matricellular protein periostin can distinguish CAF subtypes in breast cancer and is associated with increased desmoplasia and disease recurrence in patients. However, since periostin is secreted, periostin-expressing CAFs are difficult to characterize in situ, limiting our understanding of their specific contribution to cancer progression. Here, we used in vivo genetic labeling and ablation to lineage trace periostin+ cells and characterize their functions during tumor growth and metastasis. Periostin-expressing CAFs were spatially found at periductal and perivascular margins, were enriched at lymphatic vessel peripheries, and were differentially activated by highly-metastatic cancer cells versus poorly-metastatic counterparts. Surprisingly, genetically depleting periostin+ CAFs slightly accelerated primary tumor growth but impaired intratumoral collagen organization and inhibited lymphatic, but not lung, metastases. Periostin ablation in CAFs impaired their ability to deposit aligned collagen matrices and inhibited cancer cell invasion through collagen and across lymphatic endothelial cell monolayers. Thus, highly-metastatic cancer cells mobilize periostin-expressing CAFs in the primary tumor site that promote collagen remodeling and collective cell invasion within lymphatic vessels and ultimately to sentinel lymph nodes.
Data from Targeting CD44 variant 5 with an antibody-drug conjugate is an effective therapeutic strategy for intrahepatic cholangiocarcinoma
Authors: Bei Yuncheng , He Jian , Dong Xuhui , Wang Yuxin , Wang Sijie , Guo Wan , Cai Chengjie , Xu Zhiye , Wei Jia , Liu Baorui , Zhang Nan , Shen Pingping
Published: September 2024

Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most frequent type of primary liver cancer. ICC is among the deadliest malignancies, highlighting that novel treatments are urgently needed. Studies have shown that CD44 variant isoforms, rather than the CD44 standard isoform, are selectively expressed in ICC cells, providing an opportunity for the development of an antibody–drug conjugate (ADC)-based targeted therapeutic strategy. In this study, we observed the specific expression of CD44 variant 5 (CD44v5) in ICC tumors. CD44v5 protein was expressed on the surface of most ICC tumors (103 of 155). A CD44v5-targeted ADC, H1D8-DC, was developed that comprises a humanized anti-CD44v5 monoclonal antibody (mAb) conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE) via a cleavable valine-citrulline-based linker. H1D8-DC exhibited efficient antigen binding and internalization in cells expressing CD44v5 on the cell surface. Due to the high expression of cathepsin B in ICC cells, the drug was preferentially released in cancer cells but not in normal cells, thus inducing potent cytotoxicity at picomolar concentrations. In vivo studies showed that H1D8-DC was effective against CD44v5-positive ICC cells and induced tumor regression in patient-derived xenograft models, while no significant adverse toxicities were observed. These data demonstrate that CD44v5 is a bona fide target in ICC and provide a rationale for the clinical investigation of a CD44v5-targeted ADC-based approach.
Data from Immune Checkpoint Inhibitors and the Exposome: Host-Extrinsic Factors Determine Response, Survival, and Toxicity
Authors: Pizzutilo Elio Gregory. , Romanò Rebecca , Roazzi Laura , Agostara Alberto Giuseppe. , Oresti Sara , Zeppellini Annalisa , Giannetta Laura , Cerea Giulio , Signorelli Diego , Siena Salvatore , Sartore-Bianchi Andrea
Published: September 2024

Abstract
Cancer immunotherapy, largely represented by immune checkpoint inhibitors (ICIs), has led to substantial changes in preclinical cancer research and clinical oncology practice over the past decade. However, the efficacy and toxicity profiles of ICIs remain highly variable among patients, with only a fraction achieving a significant benefit. New combination therapeutic strategies are being investigated, and the search for novel predictive biomarkers is ongoing, mainly focusing on tumor- and host-intrinsic components. Less attention has been directed to all the external, potentially modifiable factors that compose the exposome, including diet and lifestyle, infections, vaccinations, and concomitant medications, which could affect the immune system response and its activity against cancer cells. We hereby provide a review of the available clinical evidence elucidating the impact of host-extrinsic factors on ICI response and toxicity.
Data from Unique transcriptional profiles underlie osteosarcomagenesis driven by different p53 mutants
Authors: Chachad Dhruv , Patel Lalit R. , Recio Carlos Vera. , Pourebrahim Rasoul , Whitley Elizabeth M. , Wang Wenyi , Su Xiaoping , Xu An , Lee Dung-Fang , Lozano Guillermina
Published: September 2024

Abstract
Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These mutations show gain-of-function activities, such as promoting increased metastatic incidence compared to p53 loss, often mediated by the interaction of mutant p53 with a set of transcription factors. These interactions are largely context specific. In order to understand the mechanisms by which p53 DNA binding domain mutations drive osteosarcoma progression, we created mouse models, in which either the p53 structural mutant p53R172H or the contact mutant p53R245W are expressed specifically in osteoblasts, yielding osteosarcoma tumor development. Survival significantly decreased and metastatic incidence increased in mice expressing p53 mutants compared to p53-null mice, suggesting gain of function. RNA-sequencing of primary osteosarcomas revealed vastly different gene expression profiles between tumors expressing the missense mutants and p53-null tumors. Further, p53R172H and p53R245W each regulated unique transcriptomes and pathways through interactions with a distinct repertoire of transcription factors. Validation assays showed that p53R245W, but not p53R172H, interacts with KLF15 to drive migration and invasion in osteosarcoma cell lines and promotes metastasis in allogeneic transplantation models. Additionally, analyses of p53R248W ChIP peaks showed enrichment of KLF15 motifs in human osteoblasts. Taken together, these data identify unique mechanisms of action of the structural and contact mutants of p53.
Data from Oncogenic Transformation Drives DNA Methylation Loss and Transcriptional Activation of Transposable Element Loci
Authors: Kanholm Tomas , Rentia Uzma , Hadley Melissa , Karlow Jennifer A. , Cox Olivia L. , Diab Noor , Bendall Matthew L. , Dawson Tyson , McDonald James I. , Xie Wenbing , Crandall Keith A. , Burns Kathleen H. , Baylin Stephen B. , Easwaran Hariharan , Chiappinelli Katherine B.
Published: September 2024

Abstract
Transposable elements (TEs) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression increases in a wide range of cancers and is correlated with global hypomethylation of cancer genomes. We assessed expression and DNA methylation of TEs in fibroblast cells that were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, which models the different steps of the tumorigenesis process. RNA-sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation. TE expression significantly increased as cells progressed through transformation, with the largest increase in expression after the final stage of transformation, consistent with data from human tumors. The upregulated TEs were dominated by endogenous retroviruses (LTRs). Most differentially methylated regions (DMRs) in all stages were hypomethylated, with the greatest hypomethylation in the final stage of transformation. A majority of the DMRs overlapped TEs from the RepeatMasker database, indicating that TEs are preferentially demethylated. Many hypomethylated TEs displayed a concordant increase in expression. Demethylation began during immortalization and continued into transformation, while upregulation of TE transcription occurred in transformation. Numerous LTR elements upregulated in the model were also identified in TCGA datasets of breast, colon, and prostate cancer. Overall, these findings indicate that transposable elements, specifically endogenous retroviruses, are demethylated and transcribed during transformation.
Data from Functional and clinical characterization of variants of uncertain significance identifies a hotspot for inactivating missense variants in RAD51C
Authors: Hu Chunling , Belur Nagaraj Anil , Shimelis Hermela , Montalban Gemma , Lee Kun Y. , Huang Huaizhi , Lumby Carolyn A. , Na Jie , Susswein Lisa R. , Roberts Maegan E. , Marshall Megan L. , Hiraki Susan , LaDuca Holly , Chao Elizabeth , Yussuf Amal , Pesaran Tina , Neuhausen Susan L. , Haiman Christopher A. , Kraft Peter , Lindström Sara , Palmer Julie R. , Teras Lauren R. , Vachon Celine M. , Yao Song , Ong Irene , Nathanson Katherine L. , Weitzel Jeffrey N. , Boddicker Nicholas , Gnanaolivu Rohan , Polley Eric C. , Mer Georges , Cui Gaofeng , Karam Rachid , Richardson Marcy E. , Domchek Susan M. , Yadav Siddhartha , Hruska Kathleen S. , Dolinsky Jill , Weroha S. John , Hart Steven N. , Simard Jacques , Masson Jean-Yves , Pang Yuan-Ping , Couch Fergus J.
Published: September 2024

Abstract
Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C-/- cells identified 30 non-functional (deleterious) variants, including 18 in a hotspot within the ATP binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C depleted cancer cells. Case-control association studies of deleterious variants in women with breast and ovarian cancer and non-cancer controls showed associations with moderate breast cancer risk (odds ratio (OR)=3.92; 95%CI:2.18-7.59) and high ovarian cancer risk (OR=14.8; 95%CI:7.71-30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers.
Data from Parkin deficiency suppresses antigen presentation to promote tumor immune evasion and immunotherapy resistance
Authors: Perales-Linares Renzo , Leli Nektaria Maria , Mohei Hesham , Beghi Silvia , Rivera Osvaldo D. , Kostopoulos Nektarios , Giglio Andrea , George Subin S. , Uribe-Herranz Mireia , Costabile Francesca , Pierini Stefano , Pustylnikov Sergei , Skoufos Giorgos , Barash Yoseph , Hatzigeorgiou Artemis G. , Koumenis Constantinos , Maity Amit , Lotze Michael T. , Facciabene Andrea
Published: September 2024

Abstract
Parkin is an E3 ubiquitin ligase that plays a key role in the development of Parkinson’s disease. Parkin defects also occur in numerous cancers, and a growing body of evidence indicates that Parkin functions as a tumor suppressor that impedes a number of cellular processes involved in tumorigenesis. Here, we generated murine and human models that closely mimic the advanced-stage tumors where Parkin deficiencies are found to provide deeper insights into the tumor suppressive functions of Parkin. Loss of Parkin expression led to aggressive tumor growth that was associated with poor tumor antigen presentation and limited antitumor CD8+ T cell infiltration and activation. The effect of Parkin deficiency on tumor growth was lost following depletion of CD8+ T cells. In line with previous findings, Parkin deficiency was linked with mitochondria-associated metabolic stress, PTEN degradation, and enhanced AKT activation. Increased AKT signaling led to dysregulation of antigen presentation, and treatment with the AKT inhibitor MK2206-HCl restored antigen presentation in Parkin-deficient tumors. Analysis of data from clear cell renal cell carcinoma patients indicated that Parkin expression was downregulated in tumors and that low expression correlated with reduced overall survival. Furthermore, low Parkin expression correlated with reduced patient response to immunotherapy. Overall, these results identify a role for Parkin deficiency in promoting tumor immune evasion that may explain the poor prognosis associated with loss of Parkin across multiple types of cancer.
Data from The IGF2BP3-COPS7B axis facilitates mRNA translation to drive colorectal cancer progression
Authors: Tang Jing , Wang Shuoshuo , Weng Mingjiao , Guo Qingyu , Ren Lili , He Yan , Cui Zihan , Cong Mingqi , Qin Minglu , Yu Jia , Su Rui , Li Xiaobo
Published: September 2024

Abstract
Many studies have provided valuable information about genomic and transcriptomic changes that occur in colorectal cancer (CRC). However, protein abundance cannot be reliably predicted by DNA alteration or mRNA expression, which can be partially attributed to post-transcriptional and/or translational regulation of gene expression. In this study, we identified increased translational efficiency (TE) as a hallmark of CRC by evaluating the transcriptomic and proteomic features of CRC patients, along with comparative transcriptomic and ribosome-protected mRNA analysis in colon epithelial cells and colon cancer cells. COPS7B was among the key genes that consistently showed both significant TE increase and protein elevation without transcriptional alteration in CRC. IGF2BP3 enhanced the TE of COPS7B mRNA to promote CRC growth and metastasis. COPS7B was found to be a component of the ribo-interactome that interacted with ribosomes to facilitate ribosome biogenesis and mRNA translation initiation. Collectively, this study revealed the proteomic features of CRC and highlighted elevated mRNA translation as a hallmark of CRC. The identification of the IGF2BP3-COPS7B axis underlying the increased protein synthesis rate in CRC provided a promising therapeutic target to treat this aggressive disease.
Data from VPAC2 Receptor Signaling Promotes Growth and Immunosuppression in Pancreatic Cancer
Authors: Passang Tenzin , Wang Shuhua , Zhang Hanwen , Zeng Fanyuan , Hsu Po-Chih , Wang Wenxi , Li Jian-Ming , Liu Yuan , Ravindranathan Sruthi , Lesinski Gregory B. , Waller Edmund K.
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) harbors a complex tumor microenvironment, and cross-talk among cells in the tumor microenvironment can contribute to drug resistance and relapse. Vasoactive intestinal peptide (VIP) is overexpressed in PDAC, and VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to immunotherapy. In this study, we showed that pancreatic cancer cells engage in autocrine VIP signaling through VIP receptor 2 (VPAC2). High coexpression of VIP with VPAC2 correlated with reduced relapse-free survival in patients with PDAC. VPAC2 activation in PDAC cells upregulated Piwi-like RNA-mediated gene silencing 2, which stimulated cancer cell clonogenic growth. In addition, VPAC2 signaling increased expression of TGFβ1 to inhibit T-cell function. Loss of VPAC2 on PDAC cells led to reduced tumor growth and increased sensitivity to anti-PD-1 immunotherapy in mouse models of PDAC. Overall, these findings expand our understanding of the role of VIP/VPAC2 signaling in PDAC and provide the rationale for developing potent VPAC2-specific antagonists for treating patients with PDAC.

Significance: Autocrine VIP signaling via VPAC2 promotes cancer cell growth and inhibits T-cell function in pancreatic ductal adenocarcinoma, highlighting its potential as a therapeutic target to improve pancreatic cancer treatment.
Supplementary Table 1 from Hepatocellular Carcinoma Surveillance Among Individuals with Cirrhosis: Trends by Payer, Etiology and Calendar Year, from a Statewide, Multi-Payer Dataset, 2010-2018
Authors: Hsu Christine D. , Henderson Louise M. , Jackson Bradford E. , Baggett Christopher D. , Jonsson Funk Michele , Olshan Andrew F. , Gupta Parul , Barritt A Sidney. , Sanoff Hanna K. , Wheeler Stephanie B. , Moon Andrew M. , Lund Jennifer L.
Published: September 2024

Supplementary Table 1 includes the validated algorithms and ICD-9-CM and ICD-10-CM codes for cirrhosis, decompensated cirrhosis, and cirrhosis etiologies.
Supplementary Table 7 from Sleep Behaviors, Genetic Predispositions, and Risk of Esophageal Cancer
Authors: Wang Xiaoyan , Tian Ruiyi , Zong Xiaoyu , Jeon Myung Sik , Luo Jingqin , Colditz Graham A. , Wang Jean S. , Tsilidis Konstantinos K. , Ju Yo-El S. , Govindan Ramaswamy , Puri Varun , Cao Yin
Published: September 2024

Supplementary Table 7 shows the association between composite sleep score and EAC risk by BMI group
Supplementary Table 4 from Sleep Behaviors, Genetic Predispositions, and Risk of Esophageal Cancer
Authors: Wang Xiaoyan , Tian Ruiyi , Zong Xiaoyu , Jeon Myung Sik , Luo Jingqin , Colditz Graham A. , Wang Jean S. , Tsilidis Konstantinos K. , Ju Yo-El S. , Govindan Ramaswamy , Puri Varun , Cao Yin
Published: September 2024

Supplementary Table 4 shows the association between finer composite sleep score and EAC risk
Figure S1 from Field synopsis of environmental and genetic risk factors of sporadic early-onset colorectal cancer and advanced adenoma
Authors: Zhang Rongqi , Boakye Daniel , Yang Nan , Zhou Xuan , Zhou Yajing , Jiang Fangyuan , Yu Lili , Wang Lijuan , Sun Jing , Yuan Shuai , Chen Jie , Hamilton Ashleigh C. , Coleman Helen G. , Larsson Susanna C. , Little Julian , Dunlop Malcolm G. , Giovannucci Edward L. , Theodoratou Evropi , Li Xue
Published: September 2024

Supplementary Figure 1 shows the graphical abstract
Supplemental Figure 3 from Elevated EVL methylation level in the normal colon mucosa is a potential risk biomarker for developing recurrent adenomas
Authors: Yu Ming , Carter Kelly T. , Baker Kelsey K. , Redman Mary W. , Wang Ting , Vickers Kathy , Li Christopher I. , Cohen Stacey A. , Krane Mukta , Ose Jennifer , Gigic Biljana , Figueiredo Jane C. , Toriola Adetunji T. , Siegel Erin M. , Shibata David , Schneider Martin , Ulrich Cornelia M. , Dzubinski Lynda Ann. , Schoen Robert E. , Grady William M.
Published: September 2024

Supplemental Figure 3: EVL methylation levels of normal colon for patients with no history of adenoma or cancer after initial
colonoscopy (left group) and for levels patients with an adenoma or colorectal cancer detected after initial (middle group). Patients
with no follow-up colonoscopies (right group) were not included in the analyses for Comparison Set 2. %mEVL=percentage of DNA
that is methylated at the EVL locus assayed.
Supplementary Table 1 from Diabetes and prostate cancer outcomes in men with nonmetastatic castrate-resistant prostate cancer: Results from the SEARCH Cohort
Authors: Sergeyev Andrei , Gu Lin , De Hoedt Amanda M. , Amling Christopher L. , Aronson William J. , Cooperberg Matthew R. , Kane Christopher J. , Klaassen Zachary , Terris Martha K. , Guerrios-Rivera Lourdes , Freedland Stephen J. , Csizmadi Ilona
Published: September 2024

Supplementary Table 1. Demographic and disease characteristics of patients with and without biopsy grade groups
Supplementary Table S1 from Development of a breast cancer risk prediction model incorporating polygenic risk scores and non-genetic risk factors for Korean women
Authors: Choi Jihye , Ha Tae-woong , Choi Hye-Mi , Lee Han-Byoel , Shin Hee-Chul , Chung Woosung , Han Wonshik
Published: September 2024

Beta weights and number of breast cancer associated SNPs used to construct single PRS
Supplementary Figure S4 from Development of a breast cancer risk prediction model incorporating polygenic risk scores and non-genetic risk factors for Korean women
Authors: Choi Jihye , Ha Tae-woong , Choi Hye-Mi , Lee Han-Byoel , Shin Hee-Chul , Chung Woosung , Han Wonshik
Published: September 2024

The absolute risk was estimated using different combinations of PRS and NGRF risk levels. PRS was classified into three risk groups according to percentile distributions (0-20%: low, 20-80%: mid, 80-100%: high). NGRF score was classified into two groups divided at median (0-50%: low, 50-100%: high). The dotted lines represent the average risks. (A) Lifetime absolute risk (B) 5-year absolute risk
Supplementary Figure S1 from Development of a breast cancer risk prediction model incorporating polygenic risk scores and non-genetic risk factors for Korean women
Authors: Choi Jihye , Ha Tae-woong , Choi Hye-Mi , Lee Han-Byoel , Shin Hee-Chul , Chung Woosung , Han Wonshik
Published: September 2024

Distribution of PRS38_ASN+PRS190_EB among participants with (case) and without breast cancer (control).
Supplementary Table 1 from Associations of Dietary Patterns with Colorectal Adenomas in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Cohort
Authors: Nepal Sushma , Aslani Zahra , Shi Ni , Tabung Fred K.
Published: September 2024

Supplementary table 1 contains results for subgroup analysis by BMI and age group
Supplementary Table 5 from Relationship between ABO blood group alleles and pancreatic cancer is modulated by secretor (FUT2) genotype, but not Lewis antigen (FUT3) genotype
Authors: Kim Jihye , Yuan Chen , Amundadottir Laufey T. , Wolpin Brian M. , Klein Alison P. , Risch Harvey A. , Kraft Peter
Published: September 2024

Table S5 presents adjusted associations of ABO blood group alleles and pancreatic cancer risk, stratified by Lewis antigen and cohorts, and interactions between ABO blood group alleles and Lewis antigen.
Supplementary Methods 1 from Sources of disparities in surveillance mammography performance and risk-guided recommendations for supplemental breast imaging: A simulation study
Authors: Hubbard Rebecca A. , Pujol Toyya A. , Alhajjar Elie , Edoh Kossi , Martin Melissa L.
Published: September 2024

Supplementary Methods 1: Simulation study design description
Table S2 from Using DEPendency of association on the number of Top Hits (DEPTH) as a complementary tool to identify novel colorectal cancer susceptibility loci.
Authors: Lai John , Wong Chi Kuen , Schmidt Daniel F. , Kapuscinski Miroslaw K. , Alpen Karen , Maclnnis Robert J. , Buchanan Daniel D. , Win Aung K. , Figueiredo Jane C. , Chan Andrew T. , Harrison Tabitha A. , Hoffmeister Michael , White Emily , Le Marchand Loic , Pai Rish K. , Peters Ulrike , Hopper John L. , Jenkins Mark A. , Makalic Enes
Published: September 2024

Supplementary Table S2 shows the QC and harmonisation steps for both the GECCO and CCFR datasets