bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft
Authors: Morton J. Jason , Alzofon Nathaniel , Keysar Stephen B. , Chimed Tugs-Saikhan , Reisinger Julie , Perrenoud Loni , Le Phuong N. , Nieto Cera , Gomez Karina , Miller Bettina , Yeager Randi , Gao Dexiang , Tan Aik-Choon , Somerset Hilary , Medina Theresa , Wang Xiao-Jing , Wang Jing H. , Robinson William , Roop Dennis R. , Gonzalez Rene , Jimeno Antonio
Published: April 2023

Abstract
Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPC) and tumors from 2 melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood–derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM, and NOD/SCID/IL2rg−/− (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non–HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFNγ)–related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated in vitro using tumor-derived cell lines.
Implications:
Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.
Data from The PI3K/mTOR Inhibitor Ompalisib Suppresses Nonhomologous End Joining and Sensitizes Cancer Cells to Radio- and Chemotherapy
Authors: Du Jie , Chen Fuqiang , Yu Jiahua , Jiang Lijun , Zhou Meijuan
Published: April 2023

Abstract
As the predominant pathway for the repair of DNA double-strand breaks (DSB), non-homologous end joining (NHEJ) attenuates the efficacy of cancer treatment which relies on the introduction of DSBs, such as radiotherapy and genotoxic drugs. Identifying novel NHEJ inhibitors is of great importance for improving the therapeutic efficiency of radio- or chemotherapy. Here we miniaturized our recently developed NHEJ detecting system into a 96-well plate-based format and interrogated an FDA approved drug library containing 1732 compounds. A collection of novel hits were considered to be potential DSB repair inhibitors at the noncytotoxic concentration. We identified omipalisib as an efficient sensitizer for DNA damage–induced cell death in vitro. Furthermore, in vitro analysis uncovered the repressive effect of omipalisib on the phosphorylation of DNA-dependent protein kinase catalytic subunit induced by ionizing radiation and doxorubicin, which led to the suppression of NHEJ pathway.
Implications:
In summary, our findings suggested the possibility for repurposing these candidates as radio- or chemosensitizers, which might extend their clinical application in cancer therapy.
Data from Genomic Alterations during the In Situ to Invasive Ductal Breast Carcinoma Transition Shaped by the Immune System
Authors: Trinh Anne , Gil Del Alcazar Carlos R. , Shukla Sachet A. , Chin Koei , Chang Young Hwan , Thibault Guillaume , Eng Jennifer , Jovanović Bojana , Aldaz C. Marcelo , Park So Yeon , Jeong Joon , Wu Catherine , Gray Joe , Polyak Kornelia
Published: April 2023

Abstract
The drivers of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) transition are poorly understood. Here, we conducted an integrated genomic, transcriptomic, and whole-slide image analysis to evaluate changes in copy-number profiles, mutational profiles, expression, neoantigen load, and topology in 6 cases of matched pure DCIS and recurrent IDC. We demonstrate through combined copy-number and mutational analysis that recurrent IDC can be genetically related to its pure DCIS despite long latency periods and therapeutic interventions. Immune “hot” and “cold” tumors can arise as early as DCIS and are subtype-specific. Topologic analysis showed a similar degree of pan-leukocyte-tumor mixing in both DCIS and IDC but differ when assessing specific immune subpopulations such as CD4 T cells and CD68 macrophages. Tumor-specific copy-number aberrations in MHC-I presentation machinery and losses in 3p, 4q, and 5p are associated with differences in immune signaling in estrogen receptor (ER)-negative IDC. Common oncogenic hotspot mutations in genes including TP53 and PIK3CA are predicted to be neoantigens yet are paradoxically conserved during the DCIS-to-IDC transition, and are associated with differences in immune signaling. We highlight both tumor and immune-specific changes in the transition of pure DCIS to IDC, including genetic changes in tumor cells that may have a role in modulating immune function and assist in immune escape, driving the transition to IDC.
Implications:
We demonstrate that the in situ to IDC evolutionary bottleneck is shaped by both tumor and immune cells.
Data from Colorectal Cancer-Associated Smad4 R361 Hotspot Mutations Boost Wnt/β-Catenin Signaling through Enhanced Smad4–LEF1 Binding
Authors: Lanauze Claudia B. , Sehgal Priyanka , Hayer Katharina , Torres-Diz Manuel , Pippin James A. , Grant Struan F.A. , Thomas-Tikhonenko Andrei
Published: April 2023

Abstract
About 10% to 30% of patients with colorectal cancer harbor either loss of or missense mutations in SMAD4, a critical component of the TGFβ signaling pathway. The pathophysiologic function of missense mutations in Smad4 is not fully understood. They usually map to the MH2 domain, specifically to residues that are involved in heterodimeric complex formation with regulatory Smads (such as Smad2/3) and ensuing transcriptional activation. These detrimental effects suggest that SMAD4 missense mutations can be categorized as loss-of-function. However, they tend to cluster in a few hotspots, which is more consistent with them acting by a gain-of-function mechanism. In this study, we investigated the functional role of Smad4 R361 mutants by re-expressing two R361 Smad4 variants in several Smad4-null colorectal cancer cell lines. As predicted, R361 mutations disrupted Smad2/3-Smad4 heteromeric complex formation and abolished canonical TGFβ signaling. In that, they were similar to SMAD4 loss. However, RNA sequencing and subsequent RT-PCR assays revealed that Smad4mut cells acquired a gene signature associated with enhanced Lef1 protein function and increased Wnt signaling. Mechanistically, Smad4 mutant proteins retained binding to Lef1 protein and drove a commensurate increase in downstream Wnt signaling as measured by TOP/FOP luciferase assay and Wnt-dependent cell motility. Consistent with these findings, human colorectal cancers with SMAD4 missense mutations were less likely to acquire activating mutations in the key Wnt pathway gene CTNNB1 (encoding β-catenin) than colorectal cancers with truncating SMAD4 nonsense mutations.
Implications:
Our studies suggest that in colorectal cancer hotspot mutations in Smad4 confer enhanced Wnt signaling and possibly heightened sensitivity to Wnt pathway inhibitors.
Data from LncIHAT Is Induced by Hypoxia-Inducible Factor 1 and Promotes Breast Cancer Progression
Authors: Chen Lin , Bao Lei , Niu Yanling , Wang Jennifer E. , Kumar Ashwani , Xing Chao , Wang Yingfei , Luo Weibo
Published: April 2023

Abstract
Hypoxia induces thousands of mRNAs and miRNAs to mediate tumor malignancy. However, hypoxia-induced long noncoding RNA (lncRNA) transcriptome and their role in triple-negative breast cancer (TNBC) have not been defined. Here we identified hypoxia-induced lncRNA transcriptome in two human TNBC cell lines by whole transcriptome sequencing. AC093818.1 was one of 26 validated lncRNAs and abundantly expressed in TNBC in vitro and in vivo. 5′- and 3′-rapid amplification of cDNA ends assays revealed that the isoform 2 was a dominant AC093818.1 transcript in TNBC cells and thus referred to as lncIHAT (lncRNA induced by hypoxia and abundant in TNBC). Hypoxia-inducible factor 1 (HIF1) but not HIF2 bound to the hypoxia response element at the promoter of lncIHAT to activate its transcription in hypoxic TNBC cells. LncIHAT promoted TNBC cell survival in vitro and tumor growth and lung metastasis in mice. Mechanistically, lncIHAT was required for the expression of its proximal neighboring oncogenic genes PDK1 and ITGA6 in TNBC cells and tumors. Reexpression of PDK1 and ITGA6 rescued survival and growth of lncIHAT knockdown TNBC cells in vitro. Collectively, these findings uncovered lncIHAT as a new hypoxia-induced oncogenic cis-acting lncRNA in TNBC.
Implications:
This study systematically identified hypoxia-induced lncRNA transcriptome in TNBC and sheds light on multiple layers of regulatory mechanisms of gene expression under hypoxia.
Data from Metabolomics of Prostate Cancer Gleason Score in Tumor Tissue and Serum
Authors: Penney Kathryn L. , Tyekucheva Svitlana , Rosenthal Jacob , El Fandy Habiba , Carelli Ryan , Borgstein Stephanie , Zadra Giorgia , Fanelli Giuseppe Nicolò , Stefanizzi Lavinia , Giunchi Francesca , Pomerantz Mark , Peisch Samuel , Coulson Hannah , Lis Rosina , Kibel Adam S. , Fiorentino Michelangelo , Umeton Renato , Loda Massimo
Published: April 2023

Abstract
Gleason score, a measure of prostate tumor differentiation, is the strongest predictor of lethal prostate cancer at the time of diagnosis. Metabolomic profiling of tumor and of patient serum could identify biomarkers of aggressive disease and lead to the development of a less-invasive assay to perform active surveillance monitoring. Metabolomic profiling of prostate tissue and serum samples was performed. Metabolite levels and metabolite sets were compared across Gleason scores. Machine learning algorithms were trained and tuned to predict transformation or differentiation status from metabolite data. A total of 135 metabolites were significantly different (Padjusted < 0.05) in tumor versus normal tissue, and pathway analysis identified one sugar metabolism pathway (Padjusted = 0.03). Machine learning identified profiles that predicted tumor versus normal tissue (AUC of 0.82 ± 0.08). In tumor tissue, 25 metabolites were associated with Gleason score (unadjusted P < 0.05), 4 increased in high grade while the remainder were enriched in low grade. While pyroglutamine and 1,5-anhydroglucitol were correlated (0.73 and 0.72, respectively) between tissue and serum from the same patient, no metabolites were consistently associated with Gleason score in serum. Previously reported as well as novel metabolites with differing abundance were identified across tumor tissue. However, a “metabolite signature” for Gleason score was not obtained. This may be due to study design and analytic challenges that future studies should consider.
Implications:
Metabolic profiling can distinguish benign and neoplastic tissues. A novel unsupervised machine learning method can be utilized to achieve this distinction.
Data from N-Glycosylation Patterns Correlate with Hepatocellular Carcinoma Genetic Subtypes
Authors: DelaCourt Andrew , Black Alyson , Angel Peggi , Drake Richard , Hoshida Yujin , Singal Amit , Lewin David , Taouli Bachir , Lewis Sara , Schwarz Myron , Fiel M. Isabel , Mehta Anand S.
Published: April 2023

Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths globally, and the incidence rate in the United States is increasing. Studies have identified inter- and intratumor heterogeneity as histologic and/or molecular subtypes/variants associated with response to certain molecular targeted therapies. Spatial HCC tissue profiling of N-linked glycosylation by matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) may serve as a new method to evaluate the tumor heterogeneity. Previous work has identified significant changes in the N-linked glycosylation of HCC tumors but has not accounted for the heterogeneous genetic and molecular nature of HCC. To determine the correlation between HCC-specific N-glycosylation changes and genetic/molecular tumor features, we profiled HCC tissue samples with MALDI-IMS and correlated the spatial N-glycosylation with a widely used HCC molecular classification (Hoshida subtypes). MALDI-IMS data displayed trends that could approximately distinguish between subtypes, with subtype 1 demonstrating significantly dysregulated N-glycosylation versus adjacent nontumor tissue. Although there were no individual N-glycan structures that could identify specific subtypes, trends emerged regarding the correlation of branched glycan expression to HCC as a whole and fucosylated glycan expression to subtype 1 tumors specifically.
Implications:
Correlating N-glycosylation to specific subtypes offers the specific detection of subtypes of HCC, which could both enhance early HCC sensitivity and guide targeted clinical therapies.
Data from Genomic and Transcriptomic Correlates of Thyroid Carcinoma Evolution after BRAF Inhibitor Therapy
Authors: Lee Mark , Untch Brian R. , Xu Bin , Ghossein Ronald , Han Catherine , Kuo Fengshen , Valero Cristina , Nadeem Zaineb , Patel Neal , Makarov Vladimir , Dogan Snjezana , Wong Richard J. , Sherman Eric J. , Ho Alan L. , Chan Timothy A. , Fagin James A. , Morris Luc G.T.
Published: April 2023

Abstract
Targeted inhibition of BRAF V600E achieves tumor control in a subset of advanced thyroid tumors. Nearly all tumors develop resistance, and some have been observed to subsequently undergo dedifferentiation. The molecular alterations associated with thyroid cancer dedifferentiation in the setting of BRAF inhibition are unknown. We analyzed targeted next-generation sequencing data from 639 advanced, recurrent and/or metastatic thyroid carcinomas, including 15 tumors that were treated with BRAF inhibitor drugs and had tissue sampled during or posttreatment, 8 of which had matched pretherapy samples. Pre- and posttherapy tissues from one additional patient were profiled with whole-exome sequencing and RNA expression profiling. Mutations in genes comprising the SWI/SNF chromatin remodeling complex and the PI3K–AKT–mTOR, MAPK, and JAK–STAT pathways all increased in prevalence across more dedifferentiated thyroid cancer histologies. Of 7 thyroid cancers that dedifferentiated after BRAF inhibition, 6 had mutations in these pathways. These mutations were mostly absent from matched pretreatment samples and were rarely detected in tumors that did not dedifferentiate. Additional analyses in one of the vemurafenib-treated tumors before and after anaplastic transformation revealed the emergence of an oncogenic PIK3CA mutation, activation of ERK signaling, dedifferentiation, and development of an immunosuppressive tumor microenvironment. These findings validate earlier preclinical data implicating these genetic pathways in resistance to BRAF inhibitors, and suggest that genetic alterations mediating acquired drug resistance may also promote thyroid tumor dedifferentiation.
Implications:
The possibility that thyroid cancer dedifferentiation may be attributed to selective pressure applied by BRAF inhibitor–targeted therapy should be investigated further.
Data from Qa-1b Modulates Resistance to Anti–PD-1 Immune Checkpoint Blockade in Tumors with Defects in Antigen Processing
Authors: Zhang Xiao , Sabio Erich , Krishna Chirag , Ma Xiaoxiao , Wang Jingming , Jiang Hui , Havel Jonathan J. , Chan Timothy A.
Published: April 2023

Abstract
Immune checkpoint blockade (ICB) has improved cancer care, but ICB is only effective in some patients. The molecular mechanisms that influence ICB therapy response are not completely understood. The non-classical MHC class I molecule HLA-E and its mouse ortholog, Qa-1b, present a limited set of peptides in a TAP1-dependent manner to the NKG2A/CD94 heterodimer to transduce an inhibitory signal to natural killer (NK) and CD8+ T cells. However, deficiency of TAP1 allows Qa-1b to present an alternative peptidome to Qa-1b–restricted T-cell receptors of cytotoxic T cells. In this study, we used CRISPR–Cas9 to study the relationship between TAP1, Qa-1b, and response to anti-PD1 therapy. We hypothesized that immunotherapy response in TAP1-deficient tumors would be influenced by Qa-1b. Strikingly, using a syngeneic orthotopic mouse model, we found that although TAP1-deficient tumors were resistant to anti-PD1 treatment, anti-PD1 response was significantly enhanced in tumors lacking both TAP1 and Qa-1b. This increased sensitivity is partially dependent on NK cells. TAP1-deficient tumors were associated with an increase of intratumoral regulatory T cells (Treg) and neutrophils, whereas tumors lacking both TAP1 and Qa-1b exhibited an increased CD8+ T-cell to Treg ratio. These data suggest that direct inhibition of Qa-1b may alter the immune microenvironment to reverse resistance to anti-PD1 therapy, particularly in the context of antigen-processing defects.
Implications:
This study reveals important functional crosstalk between classical TAP-dependent MHC complexes and Qa-1b/HLA-E, particularly in tumors with impaired antigen-processing machinery. This can dramatically influence immunotherapy efficacy.
Data from Stromal-Derived Extracellular Vesicles Suppress Proliferation of Bone Metastatic Cancer Cells Mediated by ERK2
Authors: Shupp Alison B. , Neupane Manish , Agostini Lebaron C. , Ning Gang , Brody Jonathan R. , Bussard Karen M.
Published: April 2023

Abstract
Bone is a common site of cancer metastasis, including cancers such as breast, prostate, and multiple myeloma. Disseminated tumor cells (DTC) shed from a primary tumor may travel to bone and can survive undetected for years before proliferating to form overt metastatic lesions. This period of time can be defined as metastatic latency. Once in the metastatic microenvironment, DTCs engage in intercellular communication with surrounding stromal cells, which can influence cancer cell survival, proliferation, and ultimately disease progression. The role of the surrounding tumor microenvironment in regulating DTC fate is becoming increasingly recognized. We have previously shown that in the bone microenvironment, osteoblasts are “educated” by interactions with breast cancer cells, and these “educated” osteoblasts (EO) produce soluble factors that regulate cancer cell proliferation. In this study, we provide evidence indicating that EOs produce small extracellular vesicles (sEV) that suppress breast cancer proliferation, in part through regulation of ERK1/2 signaling. In addition, using EdU-incorporation assays and propidium iodide staining we demonstrate that exposure to EO-derived sEVs decreases breast cancer cell entry to S-phase of cell cycle. We also have evidence that particular microRNAs, including miR-148a-3p, are enriched in EO-derived sEVs, and that miR-148a-3p is capable of regulating breast cancer proliferation.
Implications:
These findings underscore the importance of sEV-mediated communication in the earlier stages of cancer progression, and suggest that EO-derived sEVs may be one mechanism by which the bone microenvironment suppresses breast cancer cell proliferation.
Data from L-Plastin Promotes Gastric Cancer Growth and Metastasis in a Helicobacter pylori cagA-ERK-SP1–Dependent Manner
Authors: Teng Yong-Sheng , Chen Wan-Yan , Yan Zong-Bao , Lv Yi-Pin , Liu Yu-Gang , Mao Fang-Yuan , Zhao Yong-Liang , Peng Liu-Sheng , Cheng Ping , Duan Mu-Bing , Chen Weisan , Wang Yu , Luo Ping , Zou Quan-Ming , Chen Jun , Zhuang Yuan
Published: April 2023

Abstract
Actin cytoskeleton dynamic rearrangement is required for tumor cell metastasis and is a key characteristic of Helicobacter pylori (H. pylori)-infected host cells. Actin cytoskeleton modulation is coordinated by multiple actin-binding proteins (ABP). Through Kyoto encyclopedia of gene and genomes database, GEPIA website, and real-time PCR data, we found that H. pylori infection significantly induced L-plastin, a key ABP, in gastric cancer cells. We further explored the regulation and function of L-plastin in H. pylori–associated gastric cancer and found that, mechanistically, H. pylori infection induced gastric cancer cells to express L-plastin via cagA-activated ERK signaling pathway to mediate SP1 binding to L-plastin promoter. Moreover, this increased L-plastin promoted gastric cancer cell proliferation and migration in vitro and facilitated the growth and metastasis of gastric cancer in vivo. Finally, we detected the expression pattern of L-plastin in gastric cancer tissues, and found that L-plastin was increased in gastric cancer tissues and that this increase of L-plastin positively correlated with cagA+ H. pylori infection status. Overall, our results elucidate a novel mechanism of L-plastin expression induced by H. pylori, and a new function of L-plastin–facilitated growth and metastasis of gastric cancer, and thereby implicating L-plastin as a potential therapeutic target against gastric cancer.
Implications:
Our results elucidate a novel mechanism of L-plastin expression induced by H. pylori in gastric cancer, and a new function of L-plastin–facilitated gastric cancer growth and metastasis, implicating L-plastin as a potential therapeutic target against gastric cancer.
Data from KRAS Mutants Upregulate Integrin β4 to Promote Invasion and Metastasis in Colorectal Cancer
Authors: Choi Seo-Hyun , Kim Jin K. , Chen Chin-Tung , Wu Chao , Marco Michael R. , Barriga Francisco M. , O'Rourke Kevin , Pelossof Raphael , Qu Xuan , Chang Qing , de Stanchina Elisa , Shia Jinru , Smith J. Joshua , Sanchez-Vega Francisco , Garcia-Aguilar Julio
Published: April 2023

Abstract
KRAS mutation in colorectal cancer is associated with aggressive tumor behavior through increased invasiveness and higher rates of lung metastases, but the biological mechanisms behind these features are not fully understood. In this study, we show that KRAS-mutant colorectal cancer upregulates integrin α6β4 through ERK/MEK signaling. Knocking-out integrin β4 (ITGB4) specifically depleted the expression of integrin α6β4 and this resulted in a reduction in the invasion and migration ability of the cancer cells. We also observed a reduction in the number and area of lung metastatic foci in mice that were injected with ITGB4 knockout KRAS-mutant colorectal cancer cells compared with the mice injected with ITGB4 wild-type KRAS-mutant colorectal cancer cells, while no difference was observed in liver metastases. Inhibiting integrin α6β4 in KRAS-mutant colorectal cancer could be a potential therapeutic target to diminish the KRAS-invasive phenotype and associated pulmonary metastasis rate.
Implications:
Knocking-out ITGB4, which is overexpressed in KRAS-mutant colorectal cancer and promotes tumor aggressiveness, diminishes local invasiveness and rates of pulmonary metastasis.
Data from Comprehensive Viral Genotyping Reveals Prognostic Viral Phylogenetic Groups in HPV16-Associated Squamous Cell Carcinoma of the Oropharynx
Authors: Schrank Travis P. , Landess Lee , Stepp Wesley H. , Rehmani Hina , Weir William H. , Lenze Nicholas , Lal Asim , Wu Di , Kothari Aditi , Hackman Trevor G. , Sheth Siddharth , Patel Shetal , Jefferys Stuart R. , Issaeva Natalia , Yarbrough Wendell G.
Published: April 2023

Abstract
Human papillomavirus–positive (HPV+) squamous cell carcinoma of the oropharynx (OPSCC) is the most prevalent HPV-associated malignancy in the United States and is primarily caused by HPV subtype 16 (HPV16). Favorable treatment outcomes have led to increasing interest in treatment deescalation to reduce treatment-related morbidity. Prognostic biomarkers are needed to identify appropriately low-risk patients for reduced treatment intensity. Targeted DNA sequencing including all HPV16 open reading frames was performed on tumors from 104 patients with HPV16+ OPSCC treated at a single center. Genotypes closely related to the HPV16-A1 reference were associated with increased numbers of somatic copy-number variants in the human genome and poor recurrence-free survival (RFS). Genotypes divergent from HPV16-A1 were associated with favorable RFS. These findings were independent of tobacco smoke exposure. Total RNA sequencing was performed on a second independent cohort of 89 HPV16+ OPSCC cases. HPV16 genotypes divergent from HPV16-A1 were again validated in this independent cohort, to be prognostic of improved RFS in patients with moderate (less than 30 pack-years) or low (no more than 10 pack-years) of tobacco smoke exposure. In summary, we show in two independent cohorts that viral sequence divergence from the HPV16-A1 reference is correlated with improved RFS in patients with moderate or low tobacco smoke exposure.
Implications:
HPV16 genotype is a potential biomarker that could be easily adopted to guide therapeutic decision-making related to deescalation therapy.
Data from MIRO2 Regulates Prostate Cancer Cell Growth via GCN1-Dependent Stress Signaling
Authors: Furnish Madison , Boulton Dillon P. , Genther Victoria , Grofova Denisa , Ellinwood Mitchell Lee , Romero Lina , Lucia M. Scott , Cramer Scott D. , Caino M. Cecilia
Published: April 2023

Abstract
There is a continued need to identify novel therapeutic targets to prevent the mortality associated with prostate cancer. In this context, mitochondrial Rho GTPase 2 (MIRO2) mRNA was upregulated in metastatic prostate cancer compared with localized tumors, and higher MIRO2 levels were correlated with poor patient survival. Using human cell lines that represent androgen-independent or -sensitive prostate cancer, we showed that MIRO2 depletion impaired cell growth, colony formation, and tumor growth in mice. Network analysis of MIRO2′s binding partners identified metabolism and cellular responses to extracellular stimuli as top overrepresented pathways. The top hit on our screen, General Control Nonderepressible 1 (GCN1), was overexpressed in prostate cancer, and interacted with MIRO2 in prostate cancer cell lines and in primary prostate cancer cells. Functional analysis of MIRO2 mutations present in patients with prostate cancer led to the identification of MIRO2 159L, which increased GCN1 binding. Importantly, MIRO2 was necessary for efficient GCN1-mediated GCN2 kinase signaling and induction of the transcription factor activating transcription factor 4 (ATF4) levels. Further, MIRO2′s effect on regulating prostate cancer cell growth was mediated by ATF4. Finally, levels of activated GCN2 and ATF4 were correlated with MIRO2 expression in prostate cancer xenografts. Both MIRO2 and activated GCN2 levels were higher in hypoxic areas of prostate cancer xenografts. Overall, we propose that targeting the MIRO2-GCN1 axis may be a valuable strategy to halt prostate cancer growth.
Implications:
MIRO2/GCN1/GCN2 constitute a novel mitochondrial signaling pathway that controls androgen-independent and androgen-sensitive prostate cancer cell growth.
Data from DNA-PK Inhibitor Peposertib Amplifies Radiation-Induced Inflammatory Micronucleation and Enhances TGFβ/PD-L1 Targeted Cancer Immunotherapy
Authors: Carr Michael I. , Chiu Li-Ya , Guo Yige , Xu Chunxiao , Lazorchak Adam S. , Yu Huakui , Qin Guozhong , Qi Jin , Marelli Bo , Lan Yan , Sun Qing , Czauderna Frank , Zenke Frank T. , Blaukat Andree , Vassilev Lyubomir T.
Published: April 2023

Abstract
Radiotherapy is the most widely used cancer treatment and improvements in its efficacy and safety are highly sought-after. Peposertib (also known as M3814), a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, effectively suppresses the repair of radiation-induced DNA double-strand breaks (DSB) and regresses human xenograft tumors in preclinical models. Irradiated cancer cells devoid of p53 activity are especially sensitive to the DNA-PK inhibitor, as they lose a key cell-cycle checkpoint circuit and enter mitosis with unrepaired DSBs, leading to catastrophic consequences. Here, we show that inhibiting the repair of DSBs induced by ionizing radiation with peposertib offers a powerful new way for improving radiotherapy by simultaneously enhancing cancer cell killing and response to a bifunctional TGFβ “trap”/anti-PD-L1 cancer immunotherapy. By promoting chromosome misalignment and missegregation in p53-deficient cancer cells with unrepaired DSBs, DNA-PK inhibitor accelerated micronuclei formation, a key generator of cytosolic DNA and activator of cGAS/STING-dependent inflammatory signaling as it elevated PD-L1 expression in irradiated cancer cells. Triple combination of radiation, peposertib, and bintrafusp alfa, a fusion protein simultaneously inhibiting the profibrotic TGFβ and immunosuppressive PD-L1 pathways was superior to dual combinations and suggested a novel approach to more efficacious radioimmunotherapy of cancer.
Implications:
Selective inhibition of DNA-PK in irradiated cancer cells enhances inflammatory signaling and activity of dual TGFβ/PD-L1 targeted therapy and may offer a more efficacious combination option for the treatment of locally advanced solid tumors.
Supplementary Figure 1 from Effect of Orally Administered Bovine Lactoferrin on the Growth of Adenomatous Colorectal Polyps in a Randomized, Placebo-Controlled Clinical Trial
Authors: Kozu Takahiro , Iinuma Gen , Ohashi Yasuo , Saito Yutaka , Akasu Takayuki , Saito Daizo , Alexander David B. , Iigo Masaaki , Kakizoe Tadao , Tsuda Hiroyuki
Published: April 2023

Supplementary Figure 1 from Effect of Orally Administered Bovine Lactoferrin on the Growth of Adenomatous Colorectal Polyps in a Randomized, Placebo-Controlled Clinical Trial
Perspective on this Article from Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice
Authors: Johnson Thomas E. , Kassie Fekadu , O'Sullivan M. Gerard , Negia Mesfin , Hanson Timothy E. , Upadhyaya Pramod , Ruvolo Peter P. , Hecht Stephen S. , Xing Chengguo
Published: April 2023

Perspective on this Article from Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice
Supplementary Materials 3 from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
Authors: Abba Martín C. , Hu Yuhui , Levy Carla C. , Gaddis Sally , Kittrell Frances S. , Hill Jamal , Bissonnette Reid P. , Brown Powel H. , Medina Daniel , Aldaz C. Marcelo
Published: April 2023

Supplementary Materials 3 from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
Related Article from Long-term Follow-up in Cancer Prevention Trials (It Ain't Over 'Til It's Over)
Authors: Cuzick Jack
Published: April 2023

Related Article from Long-term Follow-up in Cancer Prevention Trials (It Ain't Over 'Til It's Over)
Supplementary Materials from Phase IIA Trial Testing Erlotinib as an Intervention against Intraductal Pancreatic Mucinous Neoplasms
Authors: Lipkin Steven , Lee John , Imagawa David , Hewitt Stephen M. , Tucker Chris , Zell Jason A. , Wong Vanessa , Garcia Angela , Gonzalez Rachel , Zanna Gary Della , Richmond Ellen , Rodriguez L.M. , Bigg M , Schnoll-Sussmans F , Meyskens Frank
Published: April 2023

Supplementary Materials from Phase IIA Trial Testing Erlotinib as an Intervention against Intraductal Pancreatic Mucinous Neoplasms
Press Coverage from Racial Survival Disparity in Head and Neck Cancer Results from Low Prevalence of Human Papillomavirus Infection in Black Oropharyngeal Cancer Patients
Authors: Settle Kathleen , Posner Marshall R. , Schumaker Lisa M. , Tan Ming , Suntharalingam Mohan , Goloubeva Olga , Strome Scott E. , Haddad Robert I. , Patel Shital S. , Cambell Earl V. , Sarlis Nicholas , Lorch Jochen , Cullen Kevin J.
Published: April 2023

Press Coverage from Racial Survival Disparity in Head and Neck Cancer Results from Low Prevalence of Human Papillomavirus Infection in Black Oropharyngeal Cancer Patients
Supplementary Tables S1-S4 from NSAID Use and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: The Liver Cancer Pooling Project
Authors: Petrick Jessica L. , Sahasrabuddhe Vikrant V. , Chan Andrew T. , Alavanja Michael C. , Beane-Freeman Laura E. , Buring Julie E. , Chen Jie , Chong Dawn Q. , Freedman Neal D. , Fuchs Charles S. , Gaziano John Michael , Giovannucci Edward , Graubard Barry I. , Hollenbeck Albert R. , Hou Lifang , Jacobs Eric J. , King Lindsay Y. , Koshiol Jill , Lee I-Min , Linet Martha S. , Palmer Julie R. , Purdue Mark P. , Rosenberg Lynn , Schairer Catherine , Sesso Howard D. , Sigurdson Alice J. , Wactawski-Wende Jean , Zeleniuch-Jacquotte Anne , Campbell Peter T. , McGlynn Katherine A.
Published: April 2023

Supplementary Table S1. Cohorts Participating in the Liver Cancer Pooling Project with Information on Aspirin Use. Supplementary Table S2. Assessment of aspirin and ibuprofen use, Liver Cancer Pooling Project. Supplemental Table S3. Adjusted* Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between NSAID Use and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex, Cigarette Use, Alcohol Consumption, and Ibuprofen Use, Liver Cancer Pooling Project. Supplemental Table S4. Adjusted* Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between NSAID Use and Confirmed or Suspected Hepatocellular Carcinoma, Liver Cancer Pooling Project.
Related Article from Brush-based Cytology Screening in the Tonsils and Cervix: There Is a Difference!
Authors: Lingen Mark W.
Published: April 2023

Related Article from Brush-based Cytology Screening in the Tonsils and Cervix: There Is a Difference!
Supplementary Table 6 from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
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Supplementary Table 6 from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
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Supplementary Table 4 from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
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Supplementary Figure 1 from Meat Consumption, Nonsteroidal Anti-Inflammatory Drug Use, and Mortality among Colorectal Cancer Patients in the California Teachers Study
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PDF file - 79KB, Effect of RES on the protein levels of p4E-BP1 and FOXO-3 in prostate cancer cells
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Supplementary Table 3 from A Hexane Fraction of American Ginseng Suppresses Mouse Colitis and Associated Colon Cancer: Anti-inflammatory and Proapoptotic Mechanisms
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Supplementary Figure 2 from Transcriptional Attenuation in Colon Carcinoma Cells in Response to Butyrate
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PDF file - 409K, ANA-1 Murine Macrophage cells exposed to the Hexane Fraction of AG undergo apoptosis in vitro. ANA-1 cells were exposed to the Hexane Fraction of AG (260 μg/ml) for indicated times. Fluorescent TUNEL assay was performed to determine apoptosis post-treatment and analyzed by flow-cytometry. Percentage of apoptotic cells were depicted in each histogram. A minimum of 20,000 cells were counted for each treatment.
Supplementary Figure 5 from A Hexane Fraction of American Ginseng Suppresses Mouse Colitis and Associated Colon Cancer: Anti-inflammatory and Proapoptotic Mechanisms
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PDF file - 1.1MB, Expression of apoptotic markers in TK6 cells following exposure to the Hexane Fraction of AG. TK6 cells were exposed to indicated concentrations of the Hexane Fraction of AG for 24 hr. A. Western blot analysis of p53, Phospho-p53-Serine-15, p53 Up-regulator and Mediator of Apoptosis (PUMA) and β-actin. C-, indicates the negative control, which were HCT116 p53-/- cells. C+, indicates the positive control, which was a purified p53 peptide. Numbers under the bands indicate densitometry values as a ratio relative to control (concentration 0 �g/ml) for each treatment. B. Densitometric analysis of the expression of p53, Phospho-p53-Serine-15 and PUMA, adjusted for β-actin.
Supplementary Figure 4 from A Hexane Fraction of American Ginseng Suppresses Mouse Colitis and Associated Colon Cancer: Anti-inflammatory and Proapoptotic Mechanisms
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PDF file - 3.2MB, Inflammatory cells exposed to the whole AG extract and the Hexane Fraction of AG undergo apoptosis in vitro. A. TK6 cells were exposed to indicated doses of AG or the Hexane Fraction of AG dissolved in media for 24 hours. The Annexin V assay was performed to determine apoptosis post-treatment and analyzed using flow cytometry. Percentage of apoptotic cells are depicted in each histogram. A minimum of 10,000 cells were counted from three separate plates for each time and dose indicated. B. Primary CD4+/CD25- T-lymphocytes from untreated C57BL/6 mice exposed to indicated doses of AG or the Hexane Fraction of AG dissolved in media for 24 hours undergo apoptosis (assessed by Annexin V staining). CD4+/CD25- T-lymphocytes were isolated from the spleens of four different mice. Purified (>90% T-cell purity) non-activated or Con A-activated T lymphocytes (1 � 106) were exposed to indicated doses of AG or the Hexane Fraction of AG dissolved in media for 24 hours. The Annexin V assay was performed to determine apoptosis post-treatment and analyzed using flow cytometry. Percentage of apoptotic cells are depicted in each histogram. A minimum of 10,000 cells were counted from three separate plates (n = 3) for each time and dose indicated.
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PDF file - 2.6MB, Effect of whole AG extract and different fractions of AG on IFN-γ-induced iNOS expression. The murine macrophage cell line (ANA-1 cells) was incubated for 12 hr with No AG (media only), the whole AG extract (260 �g/ml), or the indicated AG Fraction (260 �g/ml), washed, then exposed to IFN-γ (100 U/ml) for 0, 2, 4 and 8 hrs. Cell lysates were analyzed by Western blot analysis. C+, indicates the positive control, which was an archived ANA-1 cell lysate previously induced by IFN-γ, and known to have iNOS induction. The treatment was repeated 3 times to ensure consistency.
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Supplementary Table S4 from Constitutional Methylation of the BRCA1 Promoter Is Specifically Associated with BRCA1 Mutation-Associated Pathology in Early-Onset Breast Cancer
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