bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Very Long-Acting PARP Inhibitor Suppresses Cancer Cell Growth in DNA Repair-Deficient Tumor Models
Authors: Fontaine Shaun D. , Ashley Gary W. , Houghton Peter J. , Kurmasheva Raushan T. , Diolaiti Morgan , Ashworth Alan , Peer Cody J. , Nguyen Ryan , Figg William D. , Beckford-Vera Denis R. , Santi Daniel V.
Published: March 2023

Abstract
PARP inhibitors are approved for treatment of cancers with BRCA1 or BRCA2 defects. In this study, we prepared and characterized a very long-acting PARP inhibitor. Synthesis of a macromolecular prodrug of talazoparib (TLZ) was achieved by covalent conjugation to a PEG40kDa carrier via a β-eliminative releasable linker. A single injection of the PEG∼TLZ conjugate was as effective as ∼30 daily oral doses of TLZ in growth suppression of homologous recombination-defective tumors in mouse xenografts. These included the KT-10 Wilms' tumor with a PALB2 mutation, the BRCA1-deficient MX-1 triple-negative breast cancer, and the BRCA2-deficient DLD-1 colon cancer; the prodrug did not inhibit an isogenic DLD-1 tumor with wild-type BRCA2. Although the half-life of PEG∼TLZ and released TLZ in the mouse was only ∼1 day, the exposure of released TLZ from a single safe, effective dose of the prodrug exceeded that of oral TLZ given daily over one month. μPET/CT imaging showed high uptake and prolonged retention of an 89Zr-labeled surrogate of PEG∼TLZ in the MX-1 BRCA1-deficient tumor. These data suggest that the long-lasting antitumor effect of the prodrug is due to a combination of its long t1/2, the high exposure of TLZ released from the prodrug, increased tumor sensitivity upon continued exposure, and tumor accumulation. Using pharmacokinetic parameters of TLZ in humans, we designed a long-acting PEG∼TLZ for humans that may be superior in efficacy to daily oral TLZ and would be useful for treatment of PARP inhibitor-sensitive cancers in which oral medications are not tolerated.
Significance:
These findings demonstrate that a single injection of a long-acting prodrug of the PARP inhibitor talazoparib in murine xenografts provides tumor suppression equivalent to a month of daily dosing of talazoparib.
Data from Genomic and Epigenomic Landscaping Defines New Therapeutic Targets for Adenosquamous Carcinoma of the Pancreas
Authors: Lenkiewicz Elizabeth , Malasi Smriti , Hogenson Tara L. , Flores Luis F. , Barham Whitney , Phillips William J. , Roesler Alexander S. , Chambers Kendall R. , Rajbhandari Nirakar , Hayashi Akimasa , Antal Corina E. , Downes Michael , Grandgenett Paul M. , Hollingsworth Michael A. , Cridebring Derek , Xiong Yuning , Lee Jeong-Heon , Ye Zhenqing , Yan Huihuang , Hernandez Matthew C. , Leiting Jennifer L. , Evans Ronald M. , Ordog Tamas , Truty Mark J. , Borad Mitesh J. , Reya Tannishtha , Von Hoff Daniel D. , Fernandez-Zapico Martin E. , Barrett Michael T.
Published: March 2023

Abstract
Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion–positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer.
Significance:
These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this dismal cancer.
Data from Tumor Mutational Burden Is Polygenic and Genetically Associated with Complex Traits and Diseases
Authors: Sun Xiwei , Xue Angli , Qi Ting , Chen Dan , Shi Dandan , Wu Yang , Zheng Zhili , Zeng Jian , Yang Jian
Published: March 2023

Abstract
Tumor mutational burden (TMB) is an emerging biomarker of response to immunotherapy in solid tumors. However, the extent to which variation in TMB between patients is attributable to germline genetic variation remains elusive. Here, using 7,004 unrelated patients of European descent across 33 cancer types from The Cancer Genome Atlas, we show that pan-cancer TMB is polygenic with approximately 13% of its variation explained by approximately 1.1 million common variants altogether. We identify germline variants that affect TMB in stomach adenocarcinoma through altering the expression levels of BAG5 and KLC1. Further analyses provide evidence that TMB is genetically associated with complex traits and diseases, such as smoking, rheumatoid arthritis, height, and cancers, and some of the associations are likely causal. Overall, these results provide new insights into the genetic basis of somatic mutations in tumors and may inform future efforts to use genetic variants to stratify patients for immunotherapy.
Significance:
This study provides evidence for a polygenic architecture of tumor mutational burden and opens an avenue for the use of whole-genome germline genetic variations to stratify patients with cancer for immunotherapy.
Data from The Landscape of the Heritable Cancer Genome
Authors: Fanfani Viola , Citi Luca , Harris Adrian L. , Pezzella Francesco , Stracquadanio Giovanni
Published: March 2023

Abstract
Genome-wide association studies (GWAS) have found hundreds of single-nucleotide polymorphisms (SNP) associated with increased risk of cancer. However, the amount of heritable risk explained by SNPs is limited, leaving most of the cancer heritability unexplained. Tumor sequencing projects have shown that causal mutations are enriched in genic regions. We hypothesized that SNPs located in protein coding genes and nearby regulatory regions could explain a significant proportion of the heritable risk of cancer. To perform gene-level heritability analysis, we developed a new method, called Bayesian Gene Heritability Analysis (BAGHERA), to estimate the heritability explained by all genotyped SNPs and by those located in genic regions using GWAS summary statistics. BAGHERA was specifically designed for low heritability traits such as cancer and provides robust heritability estimates under different genetic architectures. BAGHERA-based analysis of 38 cancers reported in the UK Biobank showed that SNPs explain at least 10% of the heritable risk for 14 of them, including late onset malignancies. We then identified 1,146 genes, called cancer heritability genes (CHG), explaining a significant proportion of cancer heritability. CHGs were involved in hallmark processes controlling the transformation from normal to cancerous cells. Importantly, 60 of them also harbored somatic driver mutations, and 27 are tumor suppressors. Our results suggest that germline and somatic mutation information could be exploited to identify subgroups of individuals at higher risk of cancer in the broader population and could prove useful to establish strategies for early detection and cancer surveillance.
Significance:
This study describes a new statistical method to identify genes associated with cancer heritability in the broader population, creating a map of the heritable cancer genome with gene-level resolution.

See related commentary by Bader, p. 2586
Data from DMDRMR-Mediated Regulation of m6A-Modified CDK4 by m6A Reader IGF2BP3 Drives ccRCC Progression
Authors: Gu Yinmin , Niu Shaoxi , Wang Yang , Duan Liqiang , Pan Yongbo , Tong Zhou , Zhang Xu , Yang Zhenyu , Peng Bo , Wang Xiaodong , Han Xiaoqi , Li Yuxin , Cheng Tianyou , Liu Yajuan , Shang Lina , Liu Tongfeng , Yang Xiwang , Sun Minxuan , Jiang Siyuan , Zhang Chang , Zhang Ning , Ye Qinong , Gao Shan
Published: March 2023

Abstract
Aberrant N6-methyladenosine (m6A) modification has emerged as a driver of tumor initiation and progression, yet how long noncoding RNAs (lncRNA) are involved in the regulation of m6A remains unknown. Here we utilize data from 12 cancer types from The Cancer Genome Atlas to comprehensively map lncRNAs that are potentially deregulated by DNA methylation. A novel DNA methylation–deregulated and RNA m6A reader–cooperating lncRNA (DMDRMR) facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, DMDRMR bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell-cycle kinase CDK4 and three extracellular matrix components (COL6A1, LAMA5, and FN1), by specifically enhancing IGF2BP3 activity on them in an m6A-dependent manner. Consequently, DMDRMR and IGF2BP3 enhanced the G1–S transition, thus promoting cell proliferation in ccRCC. In patients with ccRCC, high coexpression of DMDRMR and IGF2BP3 was associated with poor outcomes. Our findings reveal that DMDRMR cooperates with IGF2BP3 to regulate target genes in an m6A-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC.
Significance:
This study demonstrates that the lncRNA DMDRMR acts as a cofactor for IGF2BP3 to stabilize target genes in an m6A-dependent manner, thus exerting essential oncogenic roles in ccRCC.
Data from A GRN Autocrine-Dependent FAM135B/AKT/mTOR Feedforward Loop Promotes Esophageal Squamous Cell Carcinoma Progression
Authors: Dong Dezuo , Zhang Weimin , Xiao Wenchang , Wu Qingnan , Cao Yiren , Gao Xiaohan , Huang Lijie , Wang Yan , Chen Jie , Wang Weihu , Zhan Qimin
Published: March 2023

Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly diseases. In our previous comprehensive genomics study, we found that family with sequence similarity 135 member B (FAM135B) was a novel cancer-related gene, yet its biological functions and molecular mechanisms remain unclear. In this study, we demonstrate that the protein levels of FAM135B are significantly higher in ESCC tissues than in precancerous tissues, and high expression of FAM135B correlates with poorer clinical prognosis. Ectopic expression of FAM135B promoted ESCC cell proliferation in vitro and in vivo, likely through its direct interaction with growth factor GRN, thus forming a feedforward loop with AKT/mTOR signaling. Patients with ESCC with overexpression of both FAM135B and GRN had worse prognosis; multivariate Cox model analysis indicated that high expression of both FAM135B and GRN was an independent prognostic factor for patients with ESCC. FAM135B transgenic mice bore heavier tumor burden than wild-type mice and survived a relatively shorter lifespan after 4-nitroquinoline 1-oxide treatment. In addition, serum level of GRN in transgenic mice was higher than in wild-type mice, suggesting that serum GRN levels might provide diagnostic discrimination for patients with ESCC. These findings suggest that the interaction between FAM135B and GRN plays critical roles in the regulation of ESCC progression and both FAM135B and GRN might be potential therapeutic targets and prognostic factors in ESCC.
Significance:
These findings investigate the mechanisms of FAM135B in promoting ESCC progression and suggest new potential prognostic biomarkers and therapeutic targets in patients with ESCC.
Data from KRAS Controls Pancreatic Cancer Cell Lipid Metabolism and Invasive Potential through the Lipase HSL
Authors: Rozeveld Cody N. , Johnson Katherine M. , Zhang Lizhi , Razidlo Gina L.
Published: March 2023

Abstract
Oncogene-induced metabolic reprogramming is a hallmark of pancreatic cancer (PDAC), yet the metabolic drivers of metastasis are unclear. In PDAC, obesity and excess fatty acids accelerate tumor growth and increase metastasis. Here, we report that excess lipids, stored in organelles called lipid droplets (LD), are a key resource to fuel the energy-intensive process of metastasis. The oncogene KRAS controlled the storage and utilization of LD through regulation of hormone-sensitive lipase (HSL), which was downregulated in human PDAC. Disruption of the KRAS–HSL axis reduced lipid storage, reprogrammed tumor cell metabolism, and inhibited invasive migration in vitro and metastasis in vivo. Finally, microscopy-based metabolic analysis revealed that migratory cells selectively utilize oxidative metabolism during the process of migration to metabolize stored lipids and fuel invasive migration. Taken together, these results reveal a mechanism that can be targeted to attenuate PDAC metastasis.
Significance:
KRAS-dependent regulation of HSL biases cells towards lipid storage for subsequent utilization during invasion of pancreatic cancer cells, representing a potential target for therapeutic intervention.

See related commentary by Man et al., p. 4886
Data from RNA-Binding RING E3-Ligase DZIP3/hRUL138 Stabilizes Cyclin D1 to Drive Cell-Cycle and Cancer Progression
Authors: Kolapalli Srinivasa P. , Sahu Rinku , Chauhan Nishant R. , Jena Kautilya K. , Mehto Subhash , Das Saroj K. , Jain Ashish , Rout Manaswini , Dash Rupesh , Swain Rajeeb K. , Lee David Y. , Rusten Tor Erik , Chauhan Santosh , Chauhan Swati
Published: March 2023

Abstract
DZIP3/hRUL138 is a poorly characterized RNA-binding RING E3-ubiquitin ligase with functions in embryonic development. Here we demonstrate that DZIP3 is a crucial driver of cancer cell growth, migration, and invasion. In mice and zebrafish cancer models, DZIP3 promoted tumor growth and metastasis. In line with these results, DZIP3 was frequently overexpressed in several cancer types. Depletion of DZIP3 from cells resulted in reduced expression of Cyclin D1 and a subsequent G1 arrest and defect in cell growth. Mechanistically, DZIP3 utilized its two different domains to interact and stabilize Cyclin D1 both at mRNA and protein levels. Using an RNA-binding lysine-rich region, DZIP3 interacted with the AU-rich region in 3′ untranslated region of Cyclin D1 mRNA and stabilized it. Using a RING E3-ligase domain, DZIP3 interacted and increased K63-linked ubiquitination of Cyclin D1 protein to stabilize it. Remarkably, DZIP3 interacted with, ubiquitinated, and stabilized Cyclin D1 predominantly in the G1 phase of the cell cycle, where it is needed for cell-cycle progression. In agreement with this, a strong positive correlation of mRNA expression between DZIP3 and Cyclin D1 in different cancer types was observed. Additionally, DZIP3 regulated several cell cycle proteins by modulating the Cyclin D1–E2F axes. Taken together, this study demonstrates for the first time that DZIP3 uses a unique two-pronged mechanism in its stabilization of Cyclin D1 to drive cell-cycle and cancer progression.
Significance:
These findings show that DZIP3 is a novel driver of cell-cycle and cancer progression via its control of Cyclin D1 mRNA and protein stability in a cell-cycle phase-dependent manner.
Data from Estrogen Receptor Alpha Mutations in Breast Cancer Cells Cause Gene Expression Changes through Constant Activity and Secondary Effects
Authors: Arnesen Spencer , Blanchard Zannel , Williams Michelle M. , Berrett Kristofer C. , Li Zheqi , Oesterreich Steffi , Richer Jennifer K. , Gertz Jason
Published: March 2023

Abstract
While breast cancer patients with tumors that express estrogen receptor α (ER) generally respond well to hormone therapies that block ER activity, a significant number of patients relapse. Approximately 30% of these recurrences harbor activating mutations in the ligand binding domain (LBD) of ER, which have been shown to confer ligand-independent function. However, much is still unclear regarding the effect of mutant ER beyond its estrogen independence. To investigate the molecular effects of mutant ER, we developed multiple isogenic ER-mutant cell lines for the most common LBD mutations, Y537S and D538G. These mutations induced differential expression of thousands of genes, the majority of which were mutant allele specific and were not observed upon estrogen treatment of wild-type (WT) cells. These mutant-specific genes showed consistent differential expression across ER-mutant lines developed in other laboratories. WT cells with long-term estrogen exposure only exhibited some of these transcriptional changes, suggesting that mutant ER causes novel regulatory effects that are not simply due to constant activity. While ER mutations exhibited minor effects on ER genomic binding, with the exception of ligand independence, ER mutations conferred substantial differences in chromatin accessibility. Mutant ER was bound to approximately a quarter of mutant-enriched accessible regions that were enriched for other DNA binding factors, including FOXA1, CTCF, and OCT1. Overall, our findings indicate that mutant ER causes several consistent effects on gene expression, both indirectly and through constant activity.
Significance:
This study demonstrates the multiple roles of mutant ER in breast cancer progression, including constant ER activity and secondary regulatory effects on gene expression and chromatin accessibility.
Data from Transient Activation of the Hedgehog-Gli Pathway Rescues Radiotherapy-Induced Dry Mouth via Recovering Salivary Gland Resident Macrophages
Authors: Zhao Qingguo , Zhang Linying , Hai Bo , Wang Jun , Baetge Courtney L. , Deveau Michael A. , Kapler Geoffrey M. , Feng Jian Q. , Liu Fei
Published: March 2023

Abstract
Irreversible hypofunction of salivary glands is a common side effect of radiotherapy for head and neck cancer and is difficult to remedy. Recent studies indicate that transient activation of Hedgehog signaling rescues irradiation-impaired salivary function in animal models, but the underlying mechanisms are largely unclear. Here, we show in mice that activation of canonical Gli-dependent Hedgehog signaling by Gli1 gene transfer is sufficient to recover salivary function impaired by irradiation. Salivary gland cells responsive to Hedgehog/Gli signaling comprised small subsets of macrophages, epithelial cells, and endothelial cells, and their progeny remained relatively rare long after irradiation and transient Hedgehog activation. Quantities and activities of salivary gland resident macrophages were substantially and rapidly impaired by irradiation and restored by Hedgehog activation. Conversely, depletion of salivary gland macrophages by clodronate liposomes compromised the restoration of irradiation-impaired salivary function by transient Hedgehog activation. Single-cell RNA sequencing and qRT-PCR of sorted cells indicated that Hedgehog activation greatly enhances paracrine interactions between salivary gland resident macrophages, epithelial progenitors, and endothelial cells through Csf1, Hgf, and C1q signaling pathways. Consistently, expression of these paracrine factors and their receptors in salivary glands decreased following irradiation but were restored by transient Hedgehog activation. These findings reveal that resident macrophages and their prorepair paracrine factors are essential for the rescue of irradiation-impaired salivary function by transient Hedgehog activation and are promising therapeutic targets of radiotherapy-induced irreversible dry mouth.
Significance:
These findings illuminate a novel direction for developing effective treatment of irreversible dry mouth, which is common after radiotherapy for head and neck cancer and for which no effective treatments are available.
Data from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6
Authors: Patil Shilpa , Steuber Benjamin , Kopp Waltraut , Kari Vijayalakshmi , Urbach Laura , Wang Xin , Küffer Stefan , Bohnenberger Hanibal , Spyropoulou Dimitra , Zhang Zhe , Versemann Lennart , Bösherz Mark Sebastian , Brunner Marius , Gaedcke Jochen , Ströbel Philipp , Zhang Jin-San , Neesse Albrecht , Ellenrieder Volker , Singh Shiv K. , Johnsen Steven A. , Hessmann Elisabeth
Published: March 2023

Abstract
Recent studies have thoroughly described genome-wide expression patterns defining molecular subtypes of pancreatic ductal adenocarcinoma (PDAC), with different prognostic and predictive implications. Although the reversible nature of key regulatory transcription circuits defining the two extreme PDAC subtype lineages “classical” and “basal-like” suggests that subtype states are not permanently encoded but underlie a certain degree of plasticity, pharmacologically actionable drivers of PDAC subtype identity remain elusive. Here, we characterized the mechanistic and functional implications of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in controlling PDAC plasticity, dedifferentiation, and molecular subtype identity. Utilization of transgenic PDAC models and human PDAC samples linked EZH2 activity to PDAC dedifferentiation and tumor progression. Combined RNA- and chromatin immunoprecipitation sequencing studies identified EZH2 as a pivotal suppressor of differentiation programs in PDAC and revealed EZH2-dependent transcriptional repression of the classical subtype defining transcription factor Gata6 as a mechanistic basis for EZH2-dependent PDAC progression. Importantly, genetic or pharmacologic depletion of EZH2 sufficiently increased GATA6 expression, thus inducing a gene signature shift in favor of a less aggressive and more therapy-susceptible, classical PDAC subtype state. Consistently, abrogation of GATA6 expression in EZH2-deficient PDAC cells counteracted the acquisition of classical gene signatures and rescued their invasive capacities, suggesting that GATA6 derepression is critical to overcome PDAC progression in the context of EZH2 inhibition. Together, our findings link the EZH2-GATA6 axis to PDAC subtype identity and uncover EZH2 inhibition as an appealing strategy to induce subtype-switching in favor of a less aggressive PDAC phenotype.
Significance:
This study highlights the role of EZH2 in PDAC progression and molecular subtype identity and suggests EZH2 inhibition as a strategy to recalibrate GATA6 expression in favor of a less aggressive disease.
Data from MUC1-C Activates the BAF (mSWI/SNF) Complex in Prostate Cancer Stem Cells
Authors: Hagiwara Masayuki , Yasumizu Yota , Yamashita Nami , Rajabi Hasan , Fushimi Atsushi , Long Mark D. , Li Wei , Bhattacharya Atrayee , Ahmad Rehan , Oya Mototsugu , Liu Song , Kufe Donald
Published: March 2023

Abstract
The Brg/Brahma-associated factor (BAF, mSWI/SNF) chromatin remodeling complex is of importance in development and has been linked to prostate oncogenesis. The oncogenic MUC1-C protein promotes lineage plasticity in the progression of neuroendocrine prostate cancer (NEPC), however, there is no known association between MUC1-C and BAF. We report here that MUC1-C binds directly to the E2F1 transcription factor and that the MUC1-C→E2F1 pathway induces expression of embryonic stem cell–specific BAF (esBAF) components BRG1, ARID1A, BAF60a, BAF155, and BAF170 in castrate-resistant prostate cancer (CRPC) and NEPC cells. In concert with this previously unrecognized pathway, MUC1 was associated with increased expression of E2F1 and esBAF components in NEPC tumors as compared with CRPC, supporting involvement of MUC1-C in activating the E2F1→esBAF pathway with progression to NEPC. MUC1-C formed a nuclear complex with BAF and activated cancer stem cell (CSC) gene signatures and the core pluripotency factor gene network. The MUC1-C→E2F1→BAF pathway was necessary for induction of both the NOTCH1 effector of CSC function and the NANOG pluripotency factor, and collectively, this network drove CSC self-renewal. These findings indicate that MUC1-C promotes NEPC progression by integrating activation of E2F1 and esBAF with induction of NOTCH1, NANOG, and stemness.
Significance:
These findings show that MUC1-C, which promotes prostate cancer progression, activates a novel pathway that drives the BAF remodeling complex, induces NOTCH1 and NANOG, and promotes self-renewal of prostate cancer stem cells.
Data from Hypoxic Glioma Stem Cell–Derived Exosomes Containing Linc01060 Promote Progression of Glioma by Regulating the MZF1/c-Myc/HIF1α Axis
Authors: Li Junjun , Liao Tingting , Liu Hongya , Yuan Hongliang , Ouyang Taohui , Wang Jiajing , Chai Songshan , Li Jinsong , Chen Jingchao , Li Xiang , Zhao Hongyang , Xiong Nanxiang
Published: March 2023

Abstract
Glioma stem cells (GSC) are a subpopulation of tumor cells with special abilities to proliferate and differentiate in gliomas. They are one of the main causes of tumor recurrence, especially under hypoxic conditions. Although long noncoding RNAs (lncRNA) are known to be involved in numerous biological processes and are implied in the occurrence of certain diseases, their role in tumor development and progression remains poorly understood. Here we explored the mechanisms by which lncRNA derived from hypoxic GSCs (H-GSC) cause glioma progression. Isolation and identification of the Linc01060 gene, the exosomes containing them, and the proteins from tumor cells regulating the gene allowed for studying the effects of Linc01060 on proliferation and glycometabolism. H-GSC exerted their effects by transferring exosomes to glioma cells, resulting in a significant increase in Linc01060 levels. Mechanistically, Linc01060 directly interacted with the transcription factor myeloid zinc finger 1 (MZF1) and enhanced its stability. Linc01060 facilitated nuclear translocation of MZF1 and promoted MZF1-mediated c-Myc transcriptional activities. In addition, c-Myc enhanced the accumulation of the hypoxia-inducible factor-1 alpha (HIF1α) at the posttranscriptional level. HIF1α bound the hormone response elements of the Linc01060 promoter, upregulating the transcription of Linc01060 gene. Clinically, Linc01060 was upregulated in glioma and was significantly correlated with tumor grade and poor clinical prognosis. Overall, these data show that secretion of Linc01060-containing exosomes from H-GSCs activates prooncogenic signaling pathways in glioma cells to promote disease progression.
Significance:
These findings suggest that inhibition of Linc01060-containing exosomes or targeting the Linc01060/MZF1/c-Myc/HIF1α axis may be an effective therapeutic strategy in glioma.
Data from Patterns of Human Leukocyte Antigen Class I and Class II Associations and Cancer
Authors: Liu Zhiwei , Derkach Andriy , Yu Kelly J. , Yeager Meredith , Chang Yu-Sun , Chen Chien-Jen , Gyllensten Ulf , Lan Qing , Lee Mei-Hsuan , McKay James D. , Rothman Nathaniel , Yang Hwai-I , Hildesheim Allan , Pfeiffer Ruth M.
Published: March 2023

Abstract
Human leukocyte antigen (HLA) gene variation is associated with risk of cancers, particularly those with infectious etiology or hematopoietic origin, given its role in immune presentation. Previous studies focused primarily on HLA allele/haplotype-specific associations. To answer whether associations are driven by HLA class I (essential for T-cell cytotoxicity) or class II (important for T-cell helper responses) genes, we analyzed GWAS from 24 case–control studies and consortia comprising 27 cancers (totaling >71,000 individuals). Associations for most cancers with infectious etiology or of hematopoietic origin were driven by multiple HLA regions, suggesting that both cytotoxic and helper T-cell responses are important. Notable exceptions were observed for nasopharyngeal carcinoma, an EBV-associated cancer, and CLL/SLL forms of non-Hodgkin lymphomas; these cancers were associated with HLA class I region only and HLA class II region only, implying the importance of cytotoxic T-cell responses for the former and CD4+ T-cell helper responses for the latter. Our findings suggest that increased understanding of the pattern of HLA associations for individual cancers could lead to better insights into specific mechanisms involved in cancer pathogenesis.
Significance:
GWAS of >71,000 individuals across 27 cancer types suggest that patterns of HLA Class I and Class II associations may provide etiologic insights for cancer.
Data from The Transcriptomic Landscape of Mismatch Repair-Deficient Intestinal Stem Cells
Authors: Bommi Prashant V. , Bowen Charles M. , Reyes-Uribe Laura , Wu Wenhui , Katayama Hiroyuki , Rocha Pedro , Parra Edwin R. , Francisco-Cruz Alejandro , Ozcan Zuhal , Tosti Elena , Willis Jason A. , Wu Hong , Taggart Melissa W. , Burks Jared K. , Lynch Patrick M. , Edelmann Winfried , Scheet Paul A. , Wistuba Ignacio I. , Sinha Krishna M. , Hanash Samir M. , Vilar Eduardo
Published: March 2023

Abstract
Lynch syndrome is the most common cause of hereditary colorectal cancer and is secondary to germline alterations in one of four DNA mismatch repair (MMR) genes. Here we aimed to provide novel insights into the initiation of MMR-deficient (MMRd) colorectal carcinogenesis by characterizing the expression profile of MMRd intestinal stem cells (ISC). A tissue-specific MMRd mouse model (Villin-Cre;Msh2LoxP/LoxP) was crossed with a reporter mouse (Lgr5-EGFP-IRES-creERT2) to trace and isolate ISCs (Lgr5+) using flow cytometry. Three different ISC genotypes (Msh2-KO, Msh2-HET, and Msh2-WT) were isolated and processed for mRNA-seq and mass spectrometry, followed by bioinformatic analyses to identify expression signatures of complete MMRd and haplo-insufficiency. These findings were validated using qRT-PCR, IHC, and whole transcriptomic sequencing in mouse tissues, organoids, and a cohort of human samples, including normal colorectal mucosa, premalignant lesions, and early-stage colorectal cancers from patients with Lynch syndrome and patients with familial adenomatous polyposis (FAP) as controls. Msh2-KO ISCs clustered together with differentiated intestinal epithelial cells from all genotypes. Gene-set enrichment analysis indicated inhibition of replication, cell-cycle progression, and the Wnt pathway and activation of epithelial signaling and immune reaction. An expression signature derived from MMRd ISCs successfully distinguished MMRd neoplastic lesions of patients with Lynch syndrome from FAP controls. SPP1 was specifically upregulated in MMRd ISCs and colocalized with LGR5 in Lynch syndrome colorectal premalignant lesions and tumors. These results show that expression signatures of MMRd ISC recapitulate the initial steps of Lynch syndrome carcinogenesis and have the potential to unveil novel biomarkers of early cancer initiation.
Significance:
The transcriptomic and proteomic profile of MMR-deficient intestinal stem cells displays a unique set of genes with potential roles as biomarkers of cancer initiation and early progression.
Data from Targeting CDK12 for Cancer Therapy: Function, Mechanism, and Drug Discovery
Authors: Liu Hui , Liu Kangdong , Dong Zigang
Published: March 2023

Abstract
Cyclin-dependent kinase 12 (CDK12) is a member of the CDK family of proteins (CDK) and is critical for cancer development. Years of study into CDK12 have generated much information regarding the intricacy of its function and mechanism as well as inhibitors against it for oncological research. However, there remains a lack of understanding regarding the role of CDK12 in carcinogenesis and cancer prevention. An exhaustive comprehension of CDK12 will highly stimulate the development of new strategies for treating and preventing cancer. Here, we review the literature of CDK12, with a focus on its function, its role in signaling, and how to use it as a target for discovery of novel drugs for cancer prevention and therapy.
Data from Interactive Classification of Whole-Slide Imaging Data for Cancer Researchers
Authors: Lee Sanghoon , Amgad Mohamed , Mobadersany Pooya , McCormick Matt , Pollack Brian P. , Elfandy Habiba , Hussein Hagar , Gutman David A. , Cooper Lee A.D.
Published: March 2023

Abstract
Whole-slide histology images contain information that is valuable for clinical and basic science investigations of cancer but extracting quantitative measurements from these images is challenging for researchers who are not image analysis specialists. In this article, we describe HistomicsML2, a software tool for learn-by-example training of machine learning classifiers for histologic patterns in whole-slide images. This tool improves training efficiency and classifier performance by guiding users to the most informative training examples for labeling and can be used to develop classifiers for prospective application or as a rapid annotation tool that is adaptable to different cancer types. HistomicsML2 runs as a containerized server application that provides web-based user interfaces for classifier training, validation, exporting inference results, and collaborative review, and that can be deployed on GPU servers or cloud platforms. We demonstrate the utility of this tool by using it to classify tumor-infiltrating lymphocytes in breast carcinoma and cutaneous melanoma.
Significance:
An interactive machine learning tool for analyzing digital pathology images enables cancer researchers to apply this tool to measure histologic patterns for clinical and basic science studies.
Data from Hypoxia-Induced Suppression of Alternative Splicing of MBD2 Promotes Breast Cancer Metastasis via Activation of FZD1
Authors: Liu Zhaoji , Sun Linchong , Cai Yongping , Shen Shengqi , Zhang Tong , Wang Nana , Wu Gongwei , Ma Wenhao , Li Shi-Ting , Suo Caixia , Hao Yijie , Jia Wei-Dong , Semenza Gregg L. , Gao Ping , Zhang Huafeng
Published: March 2023

Abstract
Metastasis is responsible for the majority of breast cancer–related deaths, however, the mechanisms underlying metastasis in this disease remain largely elusive. Here we report that under hypoxic conditions, alternative splicing of MBD2 is suppressed, favoring the production of MBD2a, which facilitates breast cancer metastasis. Specifically, MBD2a promoted, whereas its lesser known short form MBD2c suppressed metastasis. Activation of HIF1 under hypoxia facilitated MBD2a production via repression of SRSF2-mediated alternative splicing. As a result, elevated MBD2a outcompeted MBD2c for binding to promoter CpG islands to activate expression of FZD1, thereby promoting epithelial-to-mesenchymal transition and metastasis. Strikingly, clinical data reveal significantly correlated expression of MBD2a and MBD2c with the invasiveness of malignancy, indicating opposing roles for MBD2 splicing variants in regulating human breast cancer metastasis. Collectively, our findings establish a novel link between MBD2 switching and tumor metastasis and provide a promising therapeutic strategy and predictive biomarkers for hypoxia-driven breast cancer metastasis.
Significance:
This study defines the opposing roles and clinical relevance of MBD2a and MBD2c, two MBD2 alternative splicing products, in hypoxia-driven breast cancer metastasis.
Data from Targeting p300/CBP Attenuates Hepatocellular Carcinoma Progression through Epigenetic Regulation of Metabolism
Authors: Cai Ling-Yan , Chen Shi-Jie , Xiao Sen-Hao , Sun Qin-Juan , Ding Chen-Hong , Zheng Bai-Nan , Zhu Xin-Yan , Liu Shu-Qing , Yang Feng , Yang Ya-Xi , Zhou Bing , Luo Cheng , Zhang Xin , Xie Wei-Fen
Published: March 2023

Abstract
Targeting epigenetics in cancer has emerged as a promising anticancer strategy. p300/CBP is a central regulator of epigenetics and plays an important role in hepatocellular carcinoma (HCC) progression. Tumor-associated metabolic alterations contribute to the establishment and maintenance of the tumorigenic state. In this study, we used a novel p300 inhibitor, B029-2, to investigate the effect of targeting p300/CBP in HCC and tumor metabolism. p300/CBP–mediated acetylation of H3K18 and H3K27 increased in HCC tissues compared with surrounding noncancerous tissues. Conversely, treatment with B029-2 specifically decreased H3K18Ac and H3K27Ac and displayed significant antitumor effects in HCC cells in vitro and in vivo. Importantly, ATAC-seq and RNA-seq integrated analysis revealed that B029-2 disturbed metabolic reprogramming in HCC cells. Moreover, B029-2 decreased glycolytic function and nucleotide synthesis in Huh7 cells by reducing H3K18Ac and H3K27Ac levels at the promoter regions of amino acid metabolism and nucleotide synthesis enzyme genes, including PSPH, PSAT1, ALDH18A1, TALDO1, ATIC, and DTYMK. Overexpression of PSPH and DTYMK partially reversed the inhibitory effect of B029-2 on HCC cells. These findings suggested that p300/CBP epigenetically regulates the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC and highlights the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy.
Significance:
This study demonstrates p300/CBP as a critical epigenetic regulator of glycolysis-related metabolic enzymes in HCC and identifies the p300/CBP inhibitor B029-2 as a potential therapeutic strategy in this disease.
Data from Endocytosis-Mediated Replenishment of Amino Acids Favors Cancer Cell Proliferation and Survival in Chromophobe Renal Cell Carcinoma
Authors: Xiao Yi , Rabien Anja , Buschow René , Amtislavskiy Vyacheslav , Busch Jonas , Kilic Ergin , Villegas Sonia L. , Timmermann Bernd , Schütte Moritz , Mielke Thorsten , Yaspo Marie-Laure , Jung Klaus , Meierhofer David
Published: March 2023

Abstract
Chromophobe renal cell carcinoma (chRCC) accounts for approximately 5% of all renal cancers and around 30% of chRCC cases have mutations in TP53. chRCC is poorly supported by microvessels and has markably lower glucose uptake than clear cell RCC and papillary RCC. Currently, the metabolic status and mechanisms by which this tumor adapts to nutrient-poor microenvironments remain to be investigated. In this study, we performed proteome and metabolome profiling of chRCC tumors and adjacent kidney tissues and identified major metabolic alterations in chRCC tumors, including the classical Warburg effect, the downregulation of gluconeogenesis and amino acid metabolism, and the upregulation of protein degradation and endocytosis. chRCC cells depended on extracellular macromolecules as an amino acid source by activating endocytosis to sustain cell proliferation and survival. Inhibition of the phospholipase C gamma 2 (PLCG2)/inositol 1,4,5-trisphosphate (IP3)/Ca2+/protein kinase C (PKC) pathway significantly impaired the activation of endocytosis for amino acid uptakes into chRCC cells. In chRCC, whole-exome sequencing revealed that TP53 mutations were not related to expression of PLCG2 and activation of endocytosis. Our study provides novel perspectives on metabolic rewiring in chRCC and identifies the PLCG2/IP3/Ca2+/PKC axis as a potential therapeutic target in patients with chRCC.
Significance:
This study reveals macropinocytosis as an important process utilized by chRCC to gain extracellular nutrients in a p53-independent manner.
Data from Cooperative Targeting of Immunotherapy-Resistant Melanoma and Lung Cancer by an AXL-Targeting Antibody–Drug Conjugate and Immune Checkpoint Blockade
Authors: Boshuizen Julia , Pencheva Nora , Krijgsman Oscar , Altimari Daniela D'Empaire , Castro Patricia Garrido , de Bruijn Beaunelle , Ligtenberg Maarten A. , Gresnigt-Van den Heuvel Elke , Vredevoogd David W. , Song Ji-Ying , Visser Nils , Apriamashvili Georgi , Janmaat Maarten L. , Plantinga Theo S. , Franken Patrick , Houtkamp Mischa , Lingnau Andreas , Jure-Kunkel Maria , Peeper Daniel S.
Published: March 2023

Abstract
Although immune checkpoint blockade (ICB) has shown remarkable clinical benefit in a subset of patients with melanoma and lung cancer, most patients experience no durable benefit. The receptor tyrosine kinase AXL is commonly implicated in therapy resistance and may serve as a marker for therapy-refractory tumors, for example in melanoma, as we previously demonstrated. Here, we show that enapotamab vedotin (EnaV), an antibody–drug conjugate targeting AXL, effectively targets tumors that display insensitivity to immunotherapy or tumor-specific T cells in several melanoma and lung cancer models. In addition to its direct tumor cell killing activity, EnaV treatment induced an inflammatory response and immunogenic cell death in tumor cells and promoted the induction of a memory-like phenotype in cytotoxic T cells. Combining EnaV with tumor-specific T cells proved superior to either treatment alone in models of melanoma and lung cancer and induced ICB benefit in models otherwise insensitive to anti–PD-1 treatment. Our findings indicate that targeting AXL-expressing, immunotherapy-resistant tumors with EnaV causes an immune-stimulating tumor microenvironment and enhances sensitivity to ICB, warranting further investigation of this treatment combination.
Significance:
These findings show that targeting AXL-positive tumor fractions with an antibody–drug conjugate enhances antitumor immunity in several humanized tumor models of melanoma and lung cancer.
Data from Loss-of-Function Variants in the Tumor-Suppressor Gene PTPN14 Confer Increased Cancer Risk
Authors: Olafsdottir Thorhildur , Stacey Simon N. , Sveinbjornsson Gardar , Thorleifsson Gudmar , Norland Kristjan , Sigurgeirsson Bardur , Thorisdottir Kristin , Kristjansson Arni Kjalar , Tryggvadottir Laufey , Sarin Kavita Y. , Benediktsson Rafn , Jonasson Jon G. , Sigurdsson Asgeir , Jonasdottir Aslaug , Kristmundsdottir Snaedis , Jonsson Hakon , Gylfason Arnaldur , Oddsson Asmundur , Fridriksdottir Run , Gudjonsson Sigurjon A. , Zink Florian , Lund Sigrun H. , Rognvaldsson Solvi , Melsted Pall , Steinthorsdottir Valgerdur , Gudmundsson Julius , Mikaelsdottir Evgenia , Olason Pall I. , Stefansdottir Lilja , Eggertsson Hannes P. , Halldorsson Bjarni V. , Thorsteinsdottir Unnur , Agustsson Tomas T. , Olafsson Karl , Olafsson Jon H. , Sulem Patrick , Rafnar Thorunn , Gudbjartsson Daniel F. , Stefansson Kari
Published: March 2023

Abstract
The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in PTPN14 conferred substantial risks of BCC (OR, 8.0; P = 1.9 × 10−12), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the PTPN14 locus were associated with BCC, suggesting PTPN14 as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, P = 1.6 × 10−4) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis.
Significance:
This study identifies the tumor-suppressor gene PTPN14 as a high-impact BCC predisposition gene and indicates that inactivation of PTPN14 by germline sequence variants may also lead to increased risk of cervical cancer.
Data from Contacts with Macrophages Promote an Aggressive Nanomechanical Phenotype of Circulating Tumor Cells in Prostate Cancer
Authors: Osmulski Pawel A. , Cunsolo Alessandra , Chen Meizhen , Qian Yusheng , Lin Chun-Lin , Hung Chia-Nung , Mahalingam Devalingam , Kirma Nameer B. , Chen Chun-Liang , Taverna Josephine A. , Liss Michael A. , Thompson Ian M. , Huang Tim H.-M. , Gaczynska Maria E.
Published: March 2023

Abstract
Aggressive tumors of epithelial origin shed cells that intravasate and become circulating tumor cells (CTC). The CTCs that are able to survive the stresses encountered in the bloodstream can then seed metastases. We demonstrated previously that CTCs isolated from the blood of prostate cancer patients display specific nanomechanical phenotypes characteristic of cell endurance and invasiveness and patient sensitivity to androgen deprivation therapy. Here we report that patient-isolated CTCs are nanomechanically distinct from cells randomly shed from the tumor, with high adhesion as the most distinguishing biophysical marker. CTCs uniquely coisolated with macrophage-like cells bearing the markers of tumor-associated macrophages (TAM). The presence of these immune cells was indicative of a survival-promoting phenotype of “mechanical fitness” in CTCs based on high softness and high adhesion as determined by atomic force microscopy. Correlations between enumeration of macrophages and mechanical fitness of CTCs were strong in patients before the start of hormonal therapy. Single-cell proteomic analysis and nanomechanical phenotyping of tumor cell–macrophage cocultures revealed that macrophages promoted epithelial–mesenchymal plasticity in prostate cancer cells, manifesting in their mechanical fitness. The resulting softness and adhesiveness of the mechanically fit CTCs confer resistance to shear stress and enable protective cell clustering. These findings suggest that selected tumor cells are coached by TAMs and accompanied by them to acquire intermediate epithelial/mesenchymal status, thereby facilitating survival during the critical early stage leading to metastasis.
Significance:
The interaction between macrophages and circulating tumor cells increases the capacity of tumor cells to initiate metastasis and may constitute a new set of blood-based targets for pharmacologic intervention.
Data from A Transcriptionally Distinct Subpopulation of Healthy Acinar Cells Exhibit Features of Pancreatic Progenitors and PDAC
Authors: Gopalan Vishaka , Singh Arashdeep , Rashidi Mehrabadi Farid , Wang Li , Ruppin Eytan , Arda H. Efsun , Hannenhalli Sridhar
Published: March 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) tumors can originate either from acinar or ductal cells in the adult pancreas. We re-analyze multiple pancreas and PDAC single-cell RNA-seq datasets and find a subset of nonmalignant acinar cells, which we refer to as acinar edge (AE) cells, whose transcriptomes highly diverge from a typical acinar cell in each dataset. Genes upregulated among AE cells are enriched for transcriptomic signatures of pancreatic progenitors, acinar dedifferentiation, and several oncogenic programs. AE-upregulated genes are upregulated in human PDAC tumors, and consistently, their promoters are hypomethylated. High expression of these genes is associated with poor patient survival. The fraction of AE-like cells increases with age in healthy pancreatic tissue, which is not explained by clonal mutations, thus pointing to a nongenetic source of variation. The fraction of AE-like cells is also significantly higher in human pancreatitis samples. Finally, we find edge-like states in lung, liver, prostate, and colon tissues, suggesting that subpopulations of healthy cells across tissues can exist in pre-neoplastic states.
Significance:
These findings show “edge” epithelial cell states with oncogenic transcriptional activity in human organs without oncogenic mutations. In the pancreas, the fraction of acinar cells increases with age.