bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Heparanase Accelerates Obesity-Associated Breast Cancer Progression
Authors: Hermano Esther , Goldberg Rachel , Rubinstein Ariel M. , Sonnenblick Amir , Maly Bella , Nahmias Daniela , Li Jin-Ping , Bakker Marinka A.H. , van der Vlag Johan , Vlodavsky Israel , Peretz Tamar , Elkin Michael
Published: March 2023

Abstract
Obese women have higher risk of bearing breast tumors that are highly aggressive and resistant to therapies. Tumor-promoting effects of obesity occur locally via adipose inflammation and related alterations to the extracellular matrix (ECM) as well as systemically via circulating metabolic mediators (e.g., free fatty acids, FFA) associated with excess adiposity and implicated in toll-like receptor-mediated activation of macrophages—key cellular players in obesity-related cancer progression. Although the contribution of macrophages to proneoplastic effects of obesity is well documented, the role of ECM components and their enzymatic degradation is less appreciated. We show that heparanase, the sole mammalian endoglucuronidase that cleaves heparan sulfate in ECM, is preferentially expressed in clinical/experimental obesity-associated breast tumors. Heparanase deficiency abolished obesity-accelerated tumor progression in vivo. Heparanase orchestrated a complex molecular program that occurred concurrently in adipose and tumor tissue and sustained the cancer-promoting action of obesity. Heparanase was required for adipose tissue macrophages to produce inflammatory mediators responsible for local induction of aromatase, a rate-limiting enzyme in estrogen biosynthesis. Estrogen upregulated heparanase in hormone-responsive breast tumors. In subsequent stages, elevated levels of heparanase induced acquisition of procancerous phenotype by tumor-associated macrophages, resulting in activation of tumor-promoting signaling and acceleration of breast tumor growth under obese conditions. As techniques to screen for heparanase expression in tumors become available, these findings provide rational and a mechanistic basis for designing antiheparanase approaches to uncouple obesity and breast cancer in a rapidly growing population of obese patients.
Significance:
This study reveals the role of heparanase in promoting obesity-associated breast cancer and provides a mechanistically informed approach to uncouple obesity and breast cancer in a rapidly growing population of obese patients.
Data from Metabolic Reprogramming by MYCN Confers Dependence on the Serine-Glycine-One-Carbon Biosynthetic Pathway
Authors: Xia Yingfeng , Ye Bingwei , Ding Jane , Yu Yajie , Alptekin Ahmet , Thangaraju Muthusamy , Prasad Puttur D. , Ding Zhi-Chun , Park Eun Jeong , Choi Jeong-Hyeon , Gao Bei , Fiehn Oliver , Yan Chunhong , Dong Zheng , Zha Yunhong , Ding Han-Fei
Published: March 2023

Abstract
MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN-amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy.
Significance:
This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy.

See related commentary by Rodriguez Garcia and Arsenian-Henriksson, p. 3818
Data from Oncogenic MYC Induces the Impaired Ribosome Biogenesis Checkpoint and Stabilizes p53 Independent of Increased Ribosome Content
Authors: Morcelle Carmen , Menoyo Sandra , Morón-Duran Francisco D. , Tauler Albert , Kozma Sara C. , Thomas George , Gentilella Antonio
Published: March 2023

Abstract
The role of MYC in regulating p53 stability as a function of increased ribosome biogenesis is controversial. On the one hand, it was suggested that MYC drives the overexpression of ribosomal proteins (RP)L5 and RPL11, which bind and inhibit HDM2, stabilizing p53. On the other, it has been proposed that increased ribosome biogenesis leads the consumption of RPL5/RPL11 into nascent ribosomes, reducing p53 levels and enhancing tumorigenesis. Here, we show that the components that make up the recently described impaired ribosome biogenesis checkpoint (IRBC) complex, RPL5, RPL11, and 5S rRNA, are reduced following MYC silencing. This leads to a rapid reduction in p53 protein half-life in an HDM2-dependent manner. In contrast, MYC induction leads to increased ribosome biogenesis and p53 protein stabilization. Unexpectedly, there is no change in free RPL5/RPL11 levels, but there is a striking increase in IRBC complex bound to HDM2. Our data support a cell-intrinsic tumor-suppressor response to MYC expression, which is presently being exploited to treat cancer.
Significance:
Oncogenic MYC induces the impaired ribosome biogenesis checkpoint, which could be potentially targeted for cancer treatment.
Data from Radiation Drives the Evolution of Orthotopic Xenografts Initiated from Glioblastoma Stem–like Cells
Authors: McAbee Joseph H. , Rath Barbara H. , Valdez Kristin , Young Dejauwne L. , Wu Xiaolin , Shankavaram Uma T. , Camphausen Kevin , Tofilon Philip J.
Published: March 2023

Abstract
A consequence of the intratumor heterogeneity (ITH) of glioblastoma (GBM) is the susceptibility to treatment-driven evolution. To determine the potential of radiotherapy to influence GBM evolution, we used orthotopic xenografts initiated from CD133+ GBM stem–like cells (GSC). Toward this end, orthotopic xenografts grown in nude mice were exposed to a fractionated radiation protocol, which resulted in a significant increase in animal survival. Brain tumors from control and irradiated mice were then collected at morbidity and compared in terms of growth pattern, clonal diversity, and genomic architecture. In mice that received fractionated radiation, tumors were less invasive, with more clearly demarcated borders and tumor core hypercellularity as compared with controls, suggesting a fundamental change in tumor biology. Viral integration site analysis indicated a reduction in clonal diversity in the irradiated tumors, implying a decrease in ITH. Changes in clonal diversity were not detected after irradiation of GSCs in vitro, suggesting that the radiation-induced reduction in ITH was dependent on the brain microenvironment. Whole-exome sequencing revealed differences in mutation patterns between control and irradiated tumors, which included modifications in the presence and clonality of driver mutations associated with GBM. Moreover, changes in the distribution of mutations as a function of subpopulation size between control and irradiated tumors were consistent with subclone expansion and contraction, that is, subpopulation evolution. Taken together, these results indicate that radiation drives the evolution of the GSC-initiated orthotopic xenografts and suggest that radiation-driven evolution may have therapeutic implications for recurrent GBM.
Significance:
Radiation drives the evolution of glioblastoma orthotopic xenografts; when translated to the clinic, this may have therapeutic implications for recurrent tumors.
Data from Epidemiologic and Clinical Analysis of Cervical Cancer Using Data from the Population-Based Osaka Cancer Registry
Authors: Yagi Asami , Ueda Yutaka , Kakuda Mamoru , Tanaka Yusuke , Ikeda Sayaka , Matsuzaki Shinya , Kobayashi Eiji , Morishima Toshitaka , Miyashiro Isao , Fukui Keisuke , Ito Yuri , Nakayama Tomio , Kimura Tadashi
Published: March 2023

Abstract
Cervical cancer screening rate is extremely low and the governmental recommendation of HPV vaccine has been suspended for 5 years in Japan. Here, we utilized data from the Osaka Cancer Registry, collected between 1976 and 2012, to evaluate cervical cancer trends in Japan. Age-adjusted incidence, relative survival, and conditional survival rates were calculated using multiple imputation methods and period analyses in 25,826 cervical cancer cases. Association of survival rates and clinical factors, including patients' age, clinical stage, and treatment procedures, were also analyzed. A trend for significantly decreasing age-adjusted incidence of cervical cancer (per 100,000) began in 1976 but reversed after 2000, increasing significantly to date (annual percent change = 3.8, 95% confidence interval, 2.7–4.8; age-adjusted rate: 28.0 in 1976, 9.1 in 2000, 14.1 in 2012). The 10-year relative survival rate improved significantly after 2002, especially in cases of “localized” and “adjacent organs” disease; this was likely due to the introduction of concurrent chemotherapy and radiation. The conditional 5-year relative survival rate improved significantly yearly until the fourth survival year. In the surgery-based group, we observed no age-dependent differences in outcomes. Unexpectedly, however, prognosis for younger age groups was poorer in the radiation-based treatment group. These results indicate that although relative survival rates have recently increased, treatment for more advanced cases with distant metastasis requires further improvement. In addition, this study is the first to suggest that age might be an important predictor of radiotherapy resistance in cervical cancer.

Significance: A large-cohort analysis of cervical cancer cases reveals that age-adjusted incidence in Japan has increased since 2000 and that age may negatively correlate with resistance to radiotherapy.
Data from Banding Together: A Systematic Comparison of The Cancer Genome Atlas and the Mitelman Databases
Authors: Denomy Connor , Germain Samuel , Haave Bjorn , Vizeacoumar Frederick S. , Freywald Andrew , Weaver Beth A. , Vizeacoumar Franco J.
Published: March 2023

Abstract
Cytogenetic aberrations at the single-cell level represent an important characteristic of cancer cells relevant to tumor evolution and prognosis. However, with the advent of The Cancer Genome Atlas (TCGA), there has been a major shift in cancer research to the use of data from aggregate cell populations. Given that tumor cells harbor hundreds to thousands of biologically relevant genetic alterations that manifest as intratumor heterogeneity, these aggregate analyses may miss alterations readily observable at single-cell resolution. Using the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer, we developed an algorithm to parse International System for Cytogenetic Nomenclature notation for quantitative abnormalities. Comparison of the Mitelman database and TCGA demonstrated that the Mitelman database is a powerful resource, and that cytogenetic aberrations captured by traditional approaches used in Mitelman database are on par with population-based genomic analyses used in TCGA. This algorithm will help nonspecialists to overcome the challenges associated with the format and syntax of the Mitelman database.
Significance:
A novel in silico approach compares cytogenetic data between the Mitelman database and TCGA, highlighting the advantages and limitations of both datasets.
Data from Smoking and Urinary Cotinine Levels Are Predictors of Increased Risk for Gastric Intestinal Metaplasia
Authors: Kim Kyungeun , Chang Yoosoo , Ahn Jiin , Yang Hyo-Joon , Jung Ju Young , Kim Seokkyun , Sohn Chong Il , Ryu Seungho
Published: March 2023

Abstract
Studies on a longitudinal relationship between smoking status and intestinal metaplasia (IM), a premalignant lesion of stomach cancer, are limited. Here we examined the association of smoking status and urinary cotinine levels, an objective measure of smoking, with the development of endoscopic IM. This cohort study included 199,235 Korean adults free of endoscopic IM who underwent upper endoscopy at baseline and subsequent visits and who were followed for up to 6.8 years (median, 3.7 years). Former and current smoking status and pack-years based on self-reports were associated with an increased risk of new-onset IM in men but not in women. However, urinary cotinine levels were positively associated with incident IM in a dose–response manner in both men and women. For men, the multivariable-adjusted HR [95% confidence interval (CI)] for incident IM comparing the urinary cotinine levels of 50 to 99 ng/mL, 100 to 499 ng/mL, and ≥500 ng/mL with <50 ng/mL were 1.20 (0.94–1.55), 1.26 (1.14–1.40), and 1.54 (1.44–1.64), respectively, whereas for women, corresponding HR (95% CI) were 0.75 (0.19–2.99), 1.86 (1.20–2.88), and 1.57 (1.07–2.30), respectively. These associations were observed when changes in smoking status and other confounders were updated during follow-up as time-varying covariates. In this large cohort of young and middle-aged men and women, urinary cotinine levels were independently associated with an increased incidence of endoscopic IM in a dose–response manner. Collectively, these data confirm smoking as an independent risk factor for the development of gastric IM, a precursor lesion of stomach cancer.
Significance:
A large-scale cohort study of nearly 200,000 adults associates smoking with increased risk for gastric intestinal metaplasia, a precursor lesion of stomach cancer.
Data from Secretion of Acid Sphingomyelinase and Ceramide by Endothelial Cells Contributes to Radiation-Induced Intestinal Toxicity
Authors: Leonetti Daniela , Estéphan Hala , Ripoche Natacha , Dubois Nolwenn , Aguesse Audrey , Gouard Sébastien , Brossard Lisa , Chiavassa Sophie , Corre Isabelle , Pecqueur Claire , Neunlist Michel , Hadchity Elie , Gaugler Marie-Hélène , Mahé Maxime M. , Paris François
Published: March 2023

Abstract
Ceramide-induced endothelial cell apoptosis boosts intestinal stem cell radiosensitivity. However, the molecular connection between these two cellular compartments has not been clearly elucidated. Here we report that ceramide and its related enzyme acid sphingomyelinase (ASM) are secreted by irradiated endothelial cells and act as bystander factors to enhance the radiotoxicity of intestinal epithelium. Ceramide and the two isoforms of ASM were acutely secreted in the blood serum of wild-type mice after 15 Gy radiation dose, inducing a gastrointestinal syndrome. Interestingly, serum ceramide was not enhanced in irradiated ASMKO mice, which are unable to develop intestinal failure injury. Because ASM/ceramide were secreted by primary endothelial cells, their contribution was studied in intestinal epithelium dysfunction using coculture of primary endothelial cells and intestinal T84 cells. Adding exogenous ASM or ceramide enhanced epithelial cell growth arrest and death. Conversely, blocking their secretion by endothelial cells using genetic, pharmacologic, or immunologic approaches abolished intestinal T84 cell radiosensitivity. Use of enteroid models revealed ASM and ceramide-mediated deleterious mode-of-action: when ceramide reduced the number of intestinal crypt-forming enteroids without affecting their structure, ASM induced a significant decrease of enteroid growth without affecting their number. Identification of specific and different roles for ceramide and ASM secreted by irradiated endothelial cells opens new perspectives in the understanding of intestinal epithelial dysfunction after radiation and defines a new class of potential therapeutic radiomitigators.
Significance:
This study identifies secreted ASM and ceramide as paracrine factors enhancing intestinal epithelial dysfunction, revealing a previously unknown class of mediators of radiosensitivity.
Data from Spatiotemporal Regulation of ΔNp63 by TGFβ-Regulated miRNAs Is Essential for Cancer Metastasis
Authors: Bui Ngoc H.B. , Napoli Marco , Davis Andrew John , Abbas Hussein A. , Rajapakshe Kimal , Coarfa Cristian , Flores Elsa R.
Published: March 2023

Abstract
ΔNp63 is a transcription factor of the p53 family and has crucial functions in normal development and disease. The expression pattern of ΔNp63 in human cancer suggests dynamic regulation of this isoform during cancer progression and metastasis. Many primary and metastatic tumors express high levels of ΔNp63, while ΔNp63 loss is crucial for tumor dissemination, indicating an oscillatory expression of ΔNp63 during cancer progression. Here, we use genetically engineered orthotopic mouse models of breast cancer to show that while depletion of ΔNp63 inhibits primary mammary adenocarcinoma development, oscillatory expression of ΔNp63 in established tumors is crucial for metastatic dissemination in breast cancer. A TGFβ-regulated miRNA network acted as upstream regulators of this oscillatory expression of ΔNp63 during cancer progression. This work sheds light on the pleiotropic roles of ΔNp63 in cancer and unveils critical functions of TGFβ in the metastatic process.
Significance:
This study unveils TGFβ signaling and a network of four miRNAs as upstream regulators of ΔNp63, providing key information for the development of therapeutic strategies to treat cancers that commonly overexpress ΔNp63.
Data from CHK1 Inhibition Is Synthetically Lethal with Loss of B-Family DNA Polymerase Function in Human Lung and Colorectal Cancer Cells
Authors: Rogers Rebecca F. , Walton Michael I. , Cherry Daniel L. , Collins Ian , Clarke Paul A. , Garrett Michelle D. , Workman Paul
Published: March 2023

Abstract
Checkpoint kinase 1 (CHK1) is a key mediator of the DNA damage response that regulates cell-cycle progression, DNA damage repair, and DNA replication. Small-molecule CHK1 inhibitors sensitize cancer cells to genotoxic agents and have shown single-agent preclinical activity in cancers with high levels of replication stress. However, the underlying genetic determinants of CHK1 inhibitor sensitivity remain unclear. We used the developmental clinical drug SRA737 in an unbiased large-scale siRNA screen to identify novel mediators of CHK1 inhibitor sensitivity and uncover potential combination therapies and biomarkers for patient selection. We identified subunits of the B-family of DNA polymerases (POLA1, POLE, and POLE2) whose silencing sensitized the human A549 non–small cell lung cancer (NSCLC) and SW620 colorectal cancer cell lines to SRA737. B-family polymerases were validated using multiple siRNAs in a panel of NSCLC and colorectal cancer cell lines. Replication stress, DNA damage, and apoptosis were increased in human cancer cells following depletion of the B-family DNA polymerases combined with SRA737 treatment. Moreover, pharmacologic blockade of B-family DNA polymerases using aphidicolin or CD437 combined with CHK1 inhibitors led to synergistic inhibition of cancer cell proliferation. Furthermore, low levels of POLA1, POLE, and POLE2 protein expression in NSCLC and colorectal cancer cells correlated with single-agent CHK1 inhibitor sensitivity and may constitute biomarkers of this phenotype. These findings provide a potential basis for combining CHK1 and B-family polymerase inhibitors in cancer therapy.
Significance:
These findings demonstrate how the therapeutic benefit of CHK1 inhibitors may potentially be enhanced and could have implications for patient selection and future development of new combination therapies.
Data from Therapy-Induced Senescence Drives Bone Loss
Authors: Yao Zhangting , Murali Bhavna , Ren Qihao , Luo Xianmin , Faget Douglas V. , Cole Tom , Ricci Biancamaria , Thotala Dinesh , Monahan Joseph , van Deursen Jan M. , Baker Darren , Faccio Roberta , Schwarz Julie K. , Stewart Sheila A.
Published: March 2023

Abstract
Chemotherapy is important for cancer treatment, however, toxicities limit its use. While great strides have been made to ameliorate the acute toxicities induced by chemotherapy, long-term comorbidities including bone loss remain a significant problem. Chemotherapy-driven estrogen loss is postulated to drive bone loss, but significant data suggests the existence of an estrogen-independent mechanism of bone loss. Using clinically relevant mouse models, we showed that senescence and its senescence-associated secretory phenotype (SASP) contribute to chemotherapy-induced bone loss that can be rescued by depleting senescent cells. Chemotherapy-induced SASP could be limited by targeting the p38MAPK-MK2 pathway, which resulted in preservation of bone integrity in chemotherapy-treated mice. These results transform our understanding of chemotherapy-induced bone loss by identifying senescent cells as major drivers of bone loss and the p38MAPK–MK2 axis as a putative therapeutic target that can preserve bone and improve a cancer survivor's quality of life.
Significance:
Senescence drives chemotherapy-induced bone loss that is rescued by p38MAPK or MK2 inhibitors. These findings may lead to treatments for therapy-induced bone loss, significantly increasing quality of life for cancer survivors.
Data from Inhibition of Haspin Kinase Promotes Cell-Intrinsic and Extrinsic Antitumor Activity
Authors: Melms Johannes C. , Vallabhaneni Sreeram , Mills Caitlin E. , Yapp Clarence , Chen Jia-Yun , Morelli Eugenio , Waszyk Patricia , Kumar Sushil , Deming Derrick , Moret Nienke , Rodriguez Steven , Subramanian Kartik , Rogava Meri , Cartwright Adam N.R. , Luoma Adrienne , Mei Shaolin , Brinker Titus J. , Miller David M. , Spektor Alexander , Schadendorf Dirk , Riggi Nicolo , Wucherpfennig Kai W. , Sorger Peter K. , Izar Benjamin
Published: March 2023

Abstract
Patients with melanoma resistant to RAF/MEK inhibitors (RMi) are frequently resistant to other therapies, such as immune checkpoint inhibitors (ICI), and individuals succumb to their disease. New drugs that control tumor growth and favorably modulate the immune environment are therefore needed. We report that the small-molecule CX-6258 has potent activity against both RMi-sensitive (RMS) and -resistant (RMR) melanoma cell lines. Haspin kinase (HASPIN) was identified as a target of CX-6258. HASPIN inhibition resulted in reduced proliferation, frequent formation of micronuclei, recruitment of cGAS, and activation of the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway. In murine models, CX-6258 induced a potent cGAS-dependent type-I IFN response in tumor cells, increased IFNγ-producing CD8+ T cells, and reduced Treg frequency in vivo. HASPIN was more strongly expressed in malignant compared with healthy tissue and its inhibition by CX-6258 had minimal toxicity in ex vivo–expanded human tumor-infiltrating lymphocytes (TIL), proliferating TILs, and in vitro differentiated neurons, suggesting a potential therapeutic index for anticancer therapy. Furthermore, the activity of CX-6258 was validated in several Ewing sarcoma and multiple myeloma cell lines. Thus, HASPIN inhibition may overcome drug resistance in melanoma, modulate the immune environment, and target a vulnerability in different cancer lineages.
Significance:
HASPIN inhibition by CX-6258 is a novel and potent strategy for RAF/MEK inhibitor–resistant melanoma and potentially other tumor types. HASPIN inhibition has direct antitumor activity and induces a favorable immune microenvironment.
Data from Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Is Associated with Indigenous American Ancestry in Latin American Women
Authors: Marker Katie M. , Zavala Valentina A. , Vidaurre Tatiana , Lott Paul C. , Vásquez Jeannie Navarro , Casavilca-Zambrano Sandro , Calderón Mónica , Abugattas Julio E. , Gómez Henry L. , Fuentes Hugo A. , Picoaga Ruddy Liendo , Cotrina Jose M. , Neciosup Silvia P. , Castañeda Carlos A. , Morante Zaida , Valencia Fernando , Torres Javier , Echeverry Magdalena , Bohórquez Mabel E. , Polanco-Echeverry Guadalupe , Estrada-Florez Ana P. , Serrano-Gómez Silvia J. , Carmona-Valencia Jenny A. , Alvarado-Cabrero Isabel , Sanabria-Salas María Carolina , Velez Alejandro , Donado Jorge , Song Sikai , Cherry Daniel , Tamayo Lizeth I. , Huntsman Scott , Hu Donglei , Ruiz-Cordero Roberto , Balassanian Ronald , Ziv Elad , Zabaleta Jovanny , Carvajal-Carmona Luis , Fejerman Laura
Published: March 2023

Abstract
Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07–1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer.
Significance:
The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.
Data from Diagnostic Accuracy of Quantitative Micro-Elastography for Margin Assessment in Breast-Conserving Surgery
Authors: Kennedy Kelsey M. , Zilkens Renate , Allen Wes M. , Foo Ken Y. , Fang Qi , Chin Lixin , Sanderson Rowan W. , Anstie James , Wijesinghe Philip , Curatolo Andrea , Tan Hsern Ern I. , Morin Narelle , Kunjuraman Bindu , Yeomans Chris , Chin Synn Lynn , DeJong Helen , Giles Katharine , Dessauvagie Benjamin F. , Latham Bruce , Saunders Christobel M. , Kennedy Brendan F.
Published: March 2023

Abstract
Inadequate margins in breast-conserving surgery (BCS) are associated with an increased likelihood of local recurrence of breast cancer. Currently, approximately 20% of BCS patients require repeat surgery due to inadequate margins at the initial operation. Implementation of an accurate, intraoperative margin assessment tool may reduce this re-excision rate. This study determined, for the first time, the diagnostic accuracy of quantitative micro-elastography (QME), an optical coherence tomography (OCT)–based elastography technique that produces images of tissue microscale elasticity, for detecting tumor within 1 mm of the margins of BCS specimens. Simultaneous OCT and QME were performed on the margins of intact, freshly excised specimens from 83 patients undergoing BCS and on dissected specimens from 7 patients undergoing mastectomy. The resulting three-dimensional images (45 × 45 × 1 mm) were coregistered with postoperative histology to determine tissue types present in each scan. Data from 12 BCS patients and the 7 mastectomy patients served to build a set of images for reader training. One hundred and fifty-four subimages (10 × 10 × 1 mm) from the remaining 71 BCS patients were included in a blinded reader study, which resulted in 69.0% sensitivity and 79.0% specificity using OCT images, versus 92.9% sensitivity and 96.4% specificity using elasticity images. The quantitative nature of QME also facilitated development of an automated reader, which resulted in 100.0% sensitivity and 97.7% specificity. These results demonstrate high accuracy of QME for detecting tumor within 1 mm of the margin and the potential for this technique to improve outcomes in BCS.
Significance:
An optical imaging technology probes breast tissue elasticity to provide accurate assessment of tumor margin involvement in breast-conserving surgery.
Data from The Fire Within: NF-κB Involvement in Non–Small Cell Lung Cancer
Authors: Dimitrakopoulos Foteinos-Ioannis D. , Kottorou Anastasia E. , Kalofonou Melpomeni , Kalofonos Haralabos P.
Published: March 2023

Abstract
Thirty-four years since its discovery, NF-κB remains a transcription factor with great potential for cancer therapy. However, NF-κB–targeted therapies have yet to find a way to be clinically translatable. Here, we focus exclusively on the role of NF-κB in non-small cell lung cancer (NSCLC) and discuss its contributing effect on cancer hallmarks such as inflammation, proliferation, survival, apoptosis, angiogenesis, epithelial–mesenchymal transition, metastasis, stemness, metabolism, and therapy resistance. In addition, we present our current knowledge of the clinical significance of NF-κB and its involvement in the treatment of patients with NSCLC with chemotherapy, targeted therapies, and immunotherapy.
Data from Serine Biosynthesis Is a Metabolic Vulnerability in IDH2-Driven Breast Cancer Progression
Authors: Barnabas Georgina D. , Lee Joo Sang , Shami Tamar , Harel Michal , Beck Lir , Selitrennik Michael , Jerby-Arnon Livnat , Erez Neta , Ruppin Eytan , Geiger Tamar
Published: March 2023

Abstract
Cancer-specific metabolic phenotypes and their vulnerabilities represent a viable area of cancer research. In this study, we explored the association of breast cancer subtypes with different metabolic phenotypes and identified isocitrate dehydrogenase 2 (IDH2) as a key player in triple-negative breast cancer (TNBC) and HER2. Functional assays combined with mass spectrometry–based analyses revealed the oncogenic role of IDH2 in cell proliferation, anchorage-independent growth, glycolysis, mitochondrial respiration, and antioxidant defense. Genome-scale metabolic modeling identified phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1) as the synthetic dosage lethal (SDL) partners of IDH2. In agreement, CRISPR-Cas9 knockout of PHGDH and PSAT1 showed the essentiality of serine biosynthesis proteins in IDH2-high cells. The clinical significance of the SDL interaction was supported by patients with IDH2-high/PHGDH-low tumors, who exhibited longer survival than patients with IDH2-high/PHGDH-high tumors. Furthermore, PHGDH inhibitors were effective in treating IDH2-high cells in vitro and in vivo. Altogether, our study creates a new link between two known cancer regulators and emphasizes PHGDH as a promising target for TNBC with IDH2 overexpression.
Significance:
These findings highlight the metabolic dependence of IDH2 on the serine biosynthesis pathway, adding an important layer to the connection between TCA cycle and glycolysis, which can be translated into novel targeted therapies.
Data from Noninvasive MRI Native T1 Mapping Detects Response to MYCN-targeted Therapies in the Th-MYCN Model of Neuroblastoma
Authors: Zormpas-Petridis Konstantinos , Poon Evon , Clarke Matthew , Jerome Neil P. , Boult Jessica K.R. , Blackledge Matthew D. , Carceller Fernando , Koers Alexander , Barone Giuseppe , Pearson Andrew D.J. , Moreno Lucas , Anderson John , Sebire Neil , McHugh Kieran , Koh Dow-Mu , Chesler Louis , Yuan Yinyin , Robinson Simon P. , Jamin Yann
Published: March 2023

Abstract
Noninvasive early indicators of treatment response are crucial to the successful delivery of precision medicine in children with cancer. Neuroblastoma is a common solid tumor of young children that arises from anomalies in neural crest development. Therapeutic approaches aiming to destabilize MYCN protein, such as small-molecule inhibitors of Aurora A and mTOR, are currently being evaluated in early phase clinical trials in children with high-risk MYCN-driven disease, with limited ability to evaluate conventional pharmacodynamic biomarkers of response. T1 mapping is an MRI scan that measures the proton spin-lattice relaxation time T1. Using a multiparametric MRI-pathologic cross-correlative approach and computational pathology methodologies including a machine learning–based algorithm for the automatic detection and classification of neuroblasts, we show here that T1 mapping is sensitive to the rich histopathologic heterogeneity of neuroblastoma in the Th-MYCN transgenic model. Regions with high native T1 corresponded to regions dense in proliferative undifferentiated neuroblasts, whereas regions characterized by low T1 were rich in apoptotic or differentiating neuroblasts. Reductions in tumor-native T1 represented a sensitive biomarker of response to treatment-induced apoptosis with two MYCN-targeted small-molecule inhibitors, Aurora A kinase inhibitor alisertib (MLN8237) and mTOR inhibitor vistusertib (AZD2014). Overall, we demonstrate the potential of T1 mapping, a scan readily available on most clinical MRI scanners, to assess response to therapy and guide clinical trials for children with neuroblastoma. The study reinforces the potential role of MRI-based functional imaging in delivering precision medicine to children with neuroblastoma.
Significance:
This study shows that MRI-based functional imaging can detect apoptotic responses to MYCN-targeted small-molecule inhibitors in a genetically engineered murine model of MYCN-driven neuroblastoma.
Data from Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-like Cells
Authors: Carruthers Ross D. , Ahmed Shafiq U. , Ramachandran Shaliny , Strathdee Karen , Kurian Kathreena M. , Hedley Ann , Gomez-Roman Natividad , Kalna Gabriela , Neilson Mathew , Gilmour Lesley , Stevenson Katrina H. , Hammond Ester M. , Chalmers Anthony J.
Published: March 2023

Abstract
Glioblastoma (GBM) is a lethal primary brain tumor characterized by treatment resistance and inevitable tumor recurrence, both of which are driven by a subpopulation of GBM cancer stem–like cells (GSC) with tumorigenic and self-renewal properties. Despite having broad implications for understanding GSC phenotype, the determinants of upregulated DNA-damage response (DDR) and subsequent radiation resistance in GSC are unknown and represent a significant barrier to developing effective GBM treatments. In this study, we show that constitutive DDR activation and radiation resistance are driven by high levels of DNA replication stress (RS). CD133+ GSC exhibited reduced DNA replication velocity and a higher frequency of stalled replication forks than CD133− non-GSC in vitro; immunofluorescence studies confirmed these observations in a panel of orthotopic xenografts and human GBM specimens. Exposure of non-GSC to low-level exogenous RS generated radiation resistance in vitro, confirming RS as a novel determinant of radiation resistance in tumor cells. GSC exhibited DNA double-strand breaks, which colocalized with “replication factories” and RNA: DNA hybrids. GSC also demonstrated increased expression of long neural genes (>1 Mbp) containing common fragile sites, supporting the hypothesis that replication/transcription collisions are the likely cause of RS in GSC. Targeting RS by combined inhibition of ATR and PARP (CAiPi) provided GSC-specific cytotoxicity and complete abrogation of GSC radiation resistance in vitro. These data identify RS as a cancer stem cell–specific target with significant clinical potential.

Significance: These findings shed new light on cancer stem cell biology and reveal novel therapeutics with the potential to improve clinical outcomes by overcoming inherent radioresistance in GBM. Cancer Res; 78(17); 5060–71. ©2018 AACR.
Data from Microenvironmental Cues Determine Tumor Cell Susceptibility to Neutrophil Cytotoxicity
Authors: Gershkovitz Maya , Fainsod-Levi Tanya , Khawaled Saleh , Shaul Merav E. , Sionov Ronit V. , Cohen-Daniel Leonor , Aqeilan Rami I. , Shaul Yoav D. , Fridlender Zvi G. , Granot Zvi
Published: March 2023

Abstract
We have recently shown that neutrophil antitumor cytotoxicity is Ca2+ dependent and is mediated by TRPM2, an H2O2-dependent Ca2+ channel. However, neutrophil antitumor activity is dependent on context and is manifested in the premetastatic niche, but not at the primary site. We therefore hypothesized that expression of TRPM2 and the consequent susceptibility to neutrophil cytotoxicity may be associated with the epithelial/mesenchymal cellular state. We found that TRPM2 expression was upregulated during epithelial-to-mesenchymal transition (EMT), and mesenchymal cells were more susceptible to neutrophil cytotoxicity. Conversely, cells undergoing mesenchymal-to-epithelial transition (MET) expressed reduced levels of TRPM2, rendering them resistant to neutrophil cytotoxicity. Cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung. These data identify TRPM2 as the link between environmental cues at the primary tumor site, tumor cell susceptibility to neutrophil cytotoxicity, and disease progression. Furthermore, these data identify EMT as a process enhancing tumor-cell immune susceptibility and, by contrast, MET as a novel mode of immune evasion.

Significance: EMT is required for metastatic spread and concomitantly enhances tumor cell susceptibility to neutrophil cytotoxicity. Cancer Res; 78(17); 5050–9. ©2018 AACR.
Data from FIP200 Suppresses Immune Checkpoint Therapy Responses in Breast Cancers by Limiting AZI2/TBK1/IRF Signaling Independent of Its Canonical Autophagy Function
Authors: Okamoto Takako , Yeo Syn Kok , Hao Mingang , Copley Mary Rose , Haas Michael A. , Chen Song , Guan Jun-Lin
Published: March 2023

Abstract
Immune checkpoint inhibitors (ICI) have the potential to induce durable therapeutic responses, yet response rates in breast cancer are modest and limited to particular subtypes. To expand the applicability of ICI, we examined the role of an essential autophagy gene, FIP200, which has been shown to be important for tumor progression in mammary tumors. Specific disruption of the autophagy function of FIP200 or complete ablation of FIP200 in genetic mouse models revealed that FIP200 autophagy function was required for progression of PyMT-driven mammary tumors. However, a noncanonical autophagy function of FIP200 was responsible for limiting T-cell recruitment and activation of the TBK1-IFN signaling axis. FIP200 also interacted with the TBK1 adaptor protein, AZI2, which was crucial for activation of TBK1 following FIP200 ablation. Accordingly, disrupting the noncanonical autophagy function of FIP200 in combination with ICI therapy led to superior, durable responses in immune-competent models of breast cancer. Collectively, these insights could guide future development of therapeutic agents against FIP200 for combinatorial ICI therapies in nonresponsive breast cancers.
Significance:
These findings show that deletion of FIP200 enhances immune checkpoint inhibitor efficacy in nonresponsive breast cancer.
Data from High PD-1/PD-L1 Checkpoint Interaction Infers Tumor Selection and Therapeutic Sensitivity to Anti-PD-1/PD-L1 Treatment
Authors: Sánchez-Magraner Lissete , Miles James , Baker Claire L. , Applebee Christopher J. , Lee Dae-Jin , Elsheikh Somaia , Lashin Shaimaa , Withers Katriona , Watts Andrew G. , Parry Richard , Edmead Christine , Lopez Jose Ignacio , Mehta Raj , Italiano Antoine , Ward Stephen G. , Parker Peter J. , Larijani Banafshé
Published: March 2023

Abstract
Many cancers are termed immunoevasive due to expression of immunomodulatory ligands. Programmed death ligand-1 (PD-L1) and cluster of differentiation 80/86 (CD80/86) interact with their receptors, programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), respectively, on tumor-infiltrating leukocytes eliciting immunosuppression. Immunotherapies aimed at blocking these interactions are revolutionizing cancer treatments, albeit in an inadequately described patient subset. To address the issue of patient stratification for immune checkpoint intervention, we quantitatively imaged PD-1/PD-L1 interactions in tumor samples from patients, employing an assay that readily detects these intercellular protein–protein interactions in the less than or equal to 10 nm range. These analyses across multiple patient cohorts demonstrated the intercancer, interpatient, and intratumoral heterogeneity of interacting immune checkpoints. The PD-1/PD-L1 interaction was not correlated with clinical PD-L1 expression scores in malignant melanoma. Crucially, among anti-PD-1–treated patients with metastatic non–small cell lung cancer, those with lower PD-1/PD-L1 interaction had significantly worsened survival. It is surmised that within tumors selecting for an elevated level of PD-1/PD-L1 interaction, there is a greater dependence on this pathway for immune evasion and hence, they exhibit more impressive patient response to intervention.
Significance:
Quantitation of immune checkpoint interaction by direct imaging demonstrates that immunotherapy-treated patients with metastatic NSCLC with a low extent of PD-1/PD-L1 interaction show significantly worse outcome.
Data from A Wnt-Induced Phenotypic Switch in Cancer-Associated Fibroblasts Inhibits EMT in Colorectal Cancer
Authors: Mosa Mohammed H. , Michels Birgitta E. , Menche Constantin , Nicolas Adele M. , Darvishi Tahmineh , Greten Florian R. , Farin Henner F.
Published: March 2023

Abstract
Tumor progression is recognized as a result of an evolving cross-talk between tumor cells and their surrounding nontransformed stroma. Although Wnt signaling has been intensively studied in colorectal cancer, it remains unclear whether activity in the tumor-associated stroma contributes to malignancy. To specifically interfere with stromal signals, we generated Wnt-independent tumor organoids that secrete the Wnt antagonist Sfrp1. Subcutaneous transplantation into immunocompetent as well as immunodeficient mice resulted in a strong reduction of tumor growth. Histologic and transcriptomic analyses revealed that Sfrp1 induced an epithelial–mesenchymal transition (EMT) phenotype in tumor cells without affecting tumor-intrinsic Wnt signaling, suggesting involvement of nonimmune stromal cells. Blockage of canonical signaling using Sfrp1, Dkk1, or fibroblast-specific genetic ablation of β-catenin strongly decreased the number of cancer-associated myofibroblasts (myCAF). Wnt activity in CAFs was linked with distinct subtypes, where low and high levels induced an inflammatory-like CAF (iCAF) subtype or contractile myCAFs, respectively. Coculture of tumor organoids with iCAFs resulted in significant upregulation of EMT markers, while myCAFs reverted this phenotype. In summary, we show that tumor growth and malignancy are differentially regulated via distinct fibroblast subtypes under the influence of juxtacrine Wnt signals.
Significance:
This study provides evidence for Wnt-induced functional diversity of colorectal cancer–associated fibroblasts, representing a non-cell autonomous mechanism for colon cancer progression.
Data from Radiomic Detection of EGFR Mutations in NSCLC
Authors: Rossi Giovanni , Barabino Emanuele , Fedeli Alessandro , Ficarra Gianluca , Coco Simona , Russo Alessandro , Adamo Vincenzo , Buemi Francesco , Zullo Lodovica , Dono Mariella , De Luca Giuseppa , Longo Luca , Dal Bello Maria Giovanna , Tagliamento Marco , Alama Angela , Cittadini Giuseppe , Pronzato Paolo , Genova Carlo
Published: March 2023

Abstract
Radiomics is defined as the use of automated or semi-automated post-processing and analysis of multiple features derived from imaging exams. Extracted features might generate models able to predict the molecular profile of solid tumors. The aim of this study was to develop a predictive algorithm to define the mutational status of EGFR in treatment-naïve patients with advanced non–small cell lung cancer (NSCLC). CT scans from 109 treatment-naïve patients with NSCLC (21 EGFR-mutant and 88 EGFR-wild type) underwent radiomics analysis to develop a machine learning model able to recognize EGFR-mutant from EGFR-WT patients via CT scans. A “test–retest” approach was used to identify stable radiomics features. The accuracy of the model was tested on an external validation set from another institution and on a dataset from the Cancer Imaging Archive (TCIA). The machine learning model that considered both radiomic and clinical features (gender and smoking status) reached a diagnostic accuracy of 88.1% in our dataset with an AUC at the ROC curve of 0.85, whereas the accuracy values in the datasets from TCIA and the external institution were 76.6% and 83.3%, respectively. Furthermore, 17 distinct radiomics features detected at baseline CT scan were associated with subsequent development of T790M during treatment with an EGFR inhibitor. In conclusion, our machine learning model was able to identify EGFR-mutant patients in multiple validation sets with globally good accuracy, especially after data optimization. More comprehensive training sets might result in further improvement of radiomics-based algorithms.
Significance:
These findings demonstrate that data normalization and “test–retest” methods might improve the performance of machine learning models on radiomics images and increase their reliability when used on external validation datasets.
Data from Targeting PAK4 Inhibits Ras-Mediated Signaling and Multiple Oncogenic Pathways in High-Risk Rhabdomyosarcoma
Authors: Dasgupta Atreyi , Sierra Laura , Tsang Susan V. , Kurenbekova Lyazat , Patel Tajhal , Rajapakse Kimal , Shuck Ryan L. , Rainusso Nino , Landesman Yosef , Unger Thaddeus , Coarfa Cristian , Yustein Jason T.
Published: March 2023

Abstract
Rhabdomyosarcoma (RMS) is the most prevalent pediatric soft-tissue sarcoma. Multimodal treatment, including surgery and traditional chemotherapy with radiotherapy, has contributed to improvements in overall survival rates. However, patients with recurrent or metastatic disease have 5-year survival rates of less than 30%. One reason for the lack of therapeutic advancement is identification and targeting of critical signaling nodes. p21-activated kinases (PAK) are a family of serine/threonine kinases downstream of multiple critical tumorigenic receptor tyrosine kinase receptors and oncogenic regulators, including IGFR and RAS signaling, that significantly contribute to aggressive malignant phenotypes. Here, we report that RMS cell lines and tumors exhibit enhanced PAK4 expression levels and activity, which are further activated by growth factors involved in RMS development. Molecular perturbation of PAK4 in multiple RMS models in vitro and in vivo resulted in inhibition of RMS development and progression. Fusion-positive and -negative RMS models were sensitive to two PAK4 small-molecule inhibitors, PF-3758309 and KPT-9274, which elicited significant antitumor and antimetastatic potential in several primary and metastatic in vivo models, including a relapsed RMS patient-derived xenograft model. Transcriptomic analysis of PAK4-targeted tumors revealed inhibition of the RAS-GTPase, Hedgehog, and Notch pathways, along with evidence of activation of antitumor immune response signatures. This PAK4-targeting gene signature showed prognostic significance for patients with sarcoma. Overall, our results show for the first time that PAK4 is a novel and viable therapeutic target for the treatment of high-risk RMS.
Significance:
These data demonstrate a novel oncogenic role for PAK4 in rhabdomyosarcoma and show that targeting PAK4 activity is a promising viable therapeutic option for advanced rhabdomyosarcoma.