bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Local Delivery of Ox40l, Cd80, and Cd86 mRNA Kindles Global Anticancer Immunity
Authors: Haabeth Ole Audun Werner , Blake Timothy R. , McKinlay Colin J. , Tveita Anders A. , Sallets Adrienne , Waymouth Robert M. , Wender Paul A. , Levy Ronald
Published: March 2023

Abstract
Localized expression of effector molecules can initiate antitumor responses through engagement of specific receptors on target cells in the tumor microenvironment. These locally induced responses may also have a systemic effect, clearing additional tumors throughout the body. In this study, to evoke systemic antitumor responses, we utilized charge-altering releasable transporters (CART) for local intratumoral delivery of mRNA coding for costimulatory and immune-modulating factors. Intratumoral injection of the CART–mRNA complexes resulted in mRNA expression at the site of administration, transfecting a substantial proportion of tumor-infiltrating dendritic cells, macrophages, and T cells in addition to the tumor cells, resulting in a local antitumor effect. Using a two-tumor model, we further show that mRNA therapy locally administered to one tumor stimulated a systemic antitumor response, curing both tumors. The combination of Ox40l-, Cd80-, and Cd86-encoding mRNA resulted in the local upregulation of proinflammatory cytokines, robust local T-cell activation, and migration of immune cells to local draining lymph node or to an anatomically distant tumor. This approach delayed tumor growth, facilitated tumor regression, and cured tumors in both A20 and CT26 tumor models. These results highlight mRNA-CART therapy as a viable approach to induce systemic antitumor immunity from a single localized injection.
Significance:
The mRNA-CART system is a highly effective delivery platform for delivering immunostimulatory genes into the tumor microenvironment for potential therapeutic development.
Data from CDK4 Regulates Lysosomal Function and mTORC1 Activation to Promote Cancer Cell Survival
Authors: Martínez-Carreres Laia , Puyal Julien , Leal-Esteban Lucía C. , Orpinell Meritxell , Castillo-Armengol Judit , Giralt Albert , Dergai Oleksandr , Moret Catherine , Barquissau Valentin , Nasrallah Anita , Pabois Angélique , Zhang Lianjun , Romero Pedro , Lopez-Mejia Isabel C. , Fajas Lluis
Published: March 2023

Abstract
Cyclin-dependent kinase 4 (CDK4) is well-known for its role in regulating the cell cycle, however, its role in cancer metabolism, especially mTOR signaling, is undefined. In this study, we established a connection between CDK4 and lysosomes, an emerging metabolic organelle crucial for mTORC1 activation. On the one hand, CDK4 phosphorylated the tumor suppressor folliculin (FLCN), regulating mTORC1 recruitment to the lysosomal surface in response to amino acids. On the other hand, CDK4 directly regulated lysosomal function and was essential for lysosomal degradation, ultimately regulating mTORC1 activity. Pharmacologic inhibition or genetic inactivation of CDK4, other than retaining FLCN at the lysosomal surface, led to the accumulation of undigested material inside lysosomes, which impaired the autophagic flux and induced cancer cell senescence in vitro and in xenograft models. Importantly, the use of CDK4 inhibitors in therapy is known to cause senescence but not cell death. To overcome this phenomenon and based on our findings, we increased the autophagic flux in cancer cells by using an AMPK activator in combination with a CDK4 inhibitor. The cotreatment induced autophagy (AMPK activation) and impaired lysosomal function (CDK4 inhibition), resulting in cell death and tumor regression. Altogether, we uncovered a previously unknown role for CDK4 in lysosomal biology and propose a novel therapeutic strategy to target cancer cells.
Significance:
These findings uncover a novel function of CDK4 in lysosomal biology, which promotes cancer progression by activating mTORC1; targeting this function offers a new therapeutic strategy for cancer treatment.
Data from Diminished AHR Signaling Drives Human Acute Myeloid Leukemia Stem Cell Maintenance
Authors: Ly Michelle , Rentas Stefan , Vujovic Ana , Wong Nicholas , Moreira Steven , Xu Joshua , Holzapfel Nicholas , Bhatia Sonam , Tran Damian , Minden Mark D. , Draper Jonathan S. , Hope Kristin J.
Published: March 2023

Abstract
Eliminating leukemic stem cells (LSC) is a sought after therapeutic paradigm for the treatment of acute myeloid leukemia (AML). While repression of aryl hydrocarbon receptor (AHR) signaling has been shown to promote short-term maintenance of primitive AML cells in culture, no work to date has examined whether altered AHR signaling plays a pathologic role in human AML or whether it contributes at all to endogenous LSC function. Here, we show AHR signaling is repressed in human AML blasts and preferentially downregulated in LSC-enriched populations within leukemias. A core set of AHR targets are uniquely repressed in LSCs across diverse genetic AML subtypes. In vitro and in vivo administration of the specific AHR agonist FICZ significantly impaired leukemic growth, promoted differentiation, and repressed self-renewal. Furthermore, LSCs suppressed a set of FICZ-responsive AHR target genes that function as tumor suppressors and promoters of differentiation. FICZ stimulation did not impair normal hematopoietic stem and progenitor (HSPC) function, and failed to upregulate a prominent LSC-specific AHR target in HSPCs, suggesting that differential mechanisms govern FICZ-induced AHR signaling manifestations in HSCs versus LSCs. Altogether, this work highlights AHR signaling suppression as a key LSC-regulating control mechanism and provides proof of concept in a preclinical model that FICZ-mediated AHR pathway activation enacts unique transcriptional programs in AML that identify it as a novel chemotherapeutic approach to selectively target human LSCs.
Significance:
The AHR pathway is suppressed in leukemic stem cells (LSC), therefore activating AHR signaling is a potential therapeutic option to target LSCs and to treat acute myeloid leukemia.
Data from Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non–Small Cell Lung Cancer
Authors: Anagnostou Valsamo , Forde Patrick M. , White James R. , Niknafs Noushin , Hruban Carolyn , Naidoo Jarushka , Marrone Kristen , Sivakumar I.K. Ashok , Bruhm Daniel C. , Rosner Samuel , Phallen Jillian , Leal Alessandro , Adleff Vilmos , Smith Kellie N. , Cottrell Tricia R. , Rhymee Lamia , Palsgrove Doreen N. , Hann Christine L. , Levy Benjamin , Feliciano Josephine , Georgiades Christos , Verde Franco , Illei Peter , Li Qing Kay , Gabrielson Edward , Brock Malcolm V. , Isbell James M. , Sauter Jennifer L. , Taube Janis , Scharpf Robert B. , Karchin Rachel , Pardoll Drew M. , Chaft Jamie E. , Hellmann Matthew D. , Brahmer Julie R. , Velculescu Victor E.
Published: March 2023

Abstract
Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57–18.35; P = 0.007 and HR 6.91; 95% CI, 1.37–34.97; P = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non–small cell lung cancer (N = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.

Significance: Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer.

See related commentary by Zou and Meyerson, p. 1038
Data from The Promoter-Associated Noncoding RNA pncCCND1_B Assembles a Protein–RNA Complex to Regulate Cyclin D1 Transcription in Ewing Sarcoma
Authors: Palombo Ramona , Frisone Paola , Fidaleo Marco , Mercatelli Neri , Sette Claudio , Paronetto Maria Paola
Published: March 2023

Abstract
Most Ewing sarcomas are characterized by the in-frame chromosomal translocation t(11;22) generating the EWS–FLI1 oncogene. EWS–FLI1 protein interacts with the RNA helicase DHX9 and affects transcription and processing of genes involved in neoplastic transformation, including CCND1 (the cyclin D1 gene), which contributes to cell-cycle dysregulation in cancer. In this study, we found that CCND1 expression is significantly higher in patients with Ewing sarcoma compared with other sarcomas and that the pncCCND1_B RNA, a previously uncharacterized CCND1 promoter-associated noncoding (pnc) transcript, is expressed in Ewing sarcoma cells. PncCCND1_B interacted with the RNA-binding protein Sam68 and repressed CCND1 expression. Notably, knockdown of Sam68 affected pncCCND1_B subcellular localization and cyclin D1 expression. Pharmacologic impairment of DHX9/EWS–FLI1 interaction promoted RNA-dependent association of Sam68 with DHX9 and recruitment of Sam68 to the CCND1 promoter, thus repressing it. Conversely, mitogenic stimulation of Ewing sarcoma cells with IGF1 impaired Sam68/DHX9 interaction and positively regulated CCND1 expression. These studies uncover a fine-tuned modulation of the proto-oncogene CCND1 in Ewing sarcoma cells via alternative complexes formed by DHX9 with either EWS–FLI1 or pncCCND1_B-Sam68.
Significance:
A pncRNA-based mechanism represses expression of CCND1 through the formation of a protein–RNA complex and provides new therapeutic opportunities for patients with Ewing sarcoma.
Data from MAP4K3/GLK Promotes Lung Cancer Metastasis by Phosphorylating and Activating IQGAP1
Authors: Chuang Huai-Chia , Chang Chih-Chi , Teng Chiao-Fang , Hsueh Chia-Hsin , Chiu Li-Li , Hsu Pu-Ming , Lee Ming-Ching , Hsu Chung-Ping , Chen Yi-Rong , Liu Yi-Chung , Lyu Ping-Chiang , Tan Tse-Hua
Published: March 2023

Abstract
Overexpression of the serine/threonine kinase GLK/MAP4K3 in human lung cancer is associated with poor prognosis and recurrence, however, the role of GLK in cancer recurrence remains unclear. Here, we report that transgenic GLK promotes tumor metastasis and cell migration through the scaffold protein IQ motif–containing GTPase-activating protein 1(IQGAP1). GLK transgenic mice displayed enhanced distant metastasis. IQGAP1 was identified as a GLK-interacting protein; two proline-rich regions of GLK and the WW domain of IQGAP1 mediated this interaction. GLK and IQGAP1 colocalized at the leading edge including filopodia and lamellipodia of migrating cells. GLK directly phosphorylated IQGAP1 at Ser-480 enhancing Cdc42 activation and subsequent cell migration. GLK-induced cell migration and lung cancer metastasis were abolished by IQGAP1 depletion. Consistently, human NSCLC patient tissues displayed increased phospho-IQGAP1, which correlated with poor survival. Collectively, GLK promotes lung cancer metastasis by binding to, phosphorylating, and activating IQGAP1.
Significance:
These findings show the critical role of the GLK–IQGAP cascade in cell migration and tumor metastasis, suggesting it as a potential biomarker and therapeutic target for lung cancer recurrence.
Data from A Model of Indirect Cell Death Caused by Tumor Vascular Damage after High-Dose Radiotherapy
Authors: Rodríguez-Barbeito Pedro , Díaz-Botana Pablo , Gago-Arias Araceli , Feijoo Manuel , Neira Sara , Guiu-Souto Jacobo , López-Pouso Óscar , Gómez-Caamaño Antonio , Pardo-Montero Juan
Published: March 2023

Abstract
There is increasing evidence that high doses of radiotherapy, like those delivered in stereotactic body radiotherapy (SBRT), trigger indirect mechanisms of cell death. Such effect seems to be two-fold. High doses may trigger an immune response and may cause vascular damage, leading to cell starvation and death. Development of mathematical response models, including indirect death, may help clinicians to design SBRT optimal schedules. Despite increasing experimental literature on indirect tumor cell death caused by vascular damage, efforts on modeling this effect have been limited. In this work, we present a biomathematical model of this effect. In our model, tumor oxygenation is obtained by solving the reaction–diffusion equation; radiotherapy kills tumor cells according to the linear–quadratic model, and also endothelial cells (EC), which can trigger loss of functionality of capillaries. Capillary death will affect tumor oxygenation, driving nearby tumor cells into severe hypoxia. Capillaries can recover functionality due to EC proliferation. Tumor cells entering a predetermined severe hypoxia status die according to a hypoxia-death model. This model fits recently published experimental data showing the effect of vascular damage on surviving fractions. It fits surviving fraction curves and qualitatively reproduces experimental values of percentages of functional capillaries 48 hours postirradiation, and hypoxic cells pre- and 48 hours postirradiation. This model is useful for exploring aspects of tumor and EC response to radiotherapy and constitutes a stepping stone toward modeling indirect tumor cell death caused by vascular damage and accounting for this effect during SBRT planning.
Significance:
A novel biomathematical model of indirect tumor cell death caused by vascular radiation damage could potentially help clinicians interpret experimental data and design better radiotherapy schedules.
Data from Kras/ADAM17-Dependent Jag1-ICD Reverse Signaling Sustains Colorectal Cancer Progression and Chemoresistance
Authors: Pelullo Maria , Nardozza Francesca , Zema Sabrina , Quaranta Roberta , Nicoletti Carmine , Besharat Zein Mersini , Felli Maria Pia , Cerbelli Bruna , d'Amati Giulia , Palermo Rocco , Capalbo Carlo , Talora Claudio , Di Marcotullio Lucia , Giannini Giuseppe , Checquolo Saula , Screpanti Isabella , Bellavia Diana
Published: March 2023

Abstract
Colorectal cancer is characterized by well-known genetic defects and approximately 50% of cases harbor oncogenic Ras mutations. Increased expression of Notch ligand Jagged1 occurs in several human malignancies, including colorectal cancer, and correlates with cancer progression, poor prognosis, and recurrence. Herein, we demonstrated that Jagged1 was constitutively processed in colorectal cancer tumors with mutant Kras, which ultimately triggered intrinsic reverse signaling via its nuclear-targeted intracellular domain Jag1-ICD. This process occurred when Kras/Erk/ADAM17 signaling was switched on, demonstrating that Jagged1 is a novel target of the Kras signaling pathway. Notably, Jag1-ICD promoted tumor growth and epithelial–mesenchymal transition, enhancing colorectal cancer progression and chemoresistance both in vitro and in vivo. These data highlight a novel role for Jagged1 in colorectal cancer tumor biology that may go beyond its effect on canonical Notch activation and suggest that Jag1-ICD may behave as an oncogenic driver that is able to sustain tumor pathogenesis and to confer chemoresistance through a noncanonical mechanism.
Significance:
These findings present a novel role of the transcriptionally active Jag1-ICD fragment to confer and mediate some of the activity of oncogenic KRAS.
Data from Determination of Tumor Margins with Surgical Specimen Mapping Using Near-Infrared Fluorescence
Authors: Gao Rebecca W. , Teraphongphom Nutte T. , van den Berg Nynke S. , Martin Brock A. , Oberhelman Nicholas J. , Divi Vasu , Kaplan Michael J. , Hong Steven S. , Lu Guolan , Ertsey Robert , Tummers Willemieke S.F.J. , Gomez Adam J. , Holsinger F. Christopher , Kong Christina S. , Colevas Alexander D. , Warram Jason M. , Rosenthal Eben L.
Published: March 2023

Abstract
For many solid tumors, surgical resection remains the gold standard and tumor-involved margins are associated with poor clinical outcomes. Near-infrared (NIR) fluorescence imaging using molecular agents has shown promise for in situ imaging during resection. However, for cancers with difficult imaging conditions, surgical value may lie in tumor mapping of surgical specimens. We thus evaluated a novel approach for real-time, intraoperative tumor margin assessment. Twenty-one adult patients with biopsy-confirmed squamous cell carcinoma arising from the head and neck (HNSCC) scheduled for standard-of-care surgery were enrolled. Cohort 1 (n = 3) received panitumumab-IRDye800CW at an intravenous microdose of 0.06 mg/kg, cohort 2A (n = 5) received 0.5 mg/kg, cohort 2B (n = 7) received 1 mg/kg, and cohort 3 (n = 6) received 50 mg. Patients were followed 30 days postinfusion and adverse events were recorded. Imaging was performed using several closed- and wide-field devices. Fluorescence was histologically correlated to determine sensitivity and specificity. In situ imaging demonstrated tumor-to-background ratio (TBR) of 2 to 3, compared with ex vivo specimen imaging TBR of 5 to 6. We obtained clear differentiation between tumor and normal tissue, with a 3-fold signal difference between positive and negative specimens (P < 0.05). We achieved high correlation of fluorescence intensity with tumor location with sensitivities and specificities >89%; fluorescence predicted distance of tumor tissue to the cut surface of the specimen. This novel method of detecting tumor-involved margins in surgical specimens using a cancer-specific agent provides highly sensitive and specific, real-time, intraoperative surgical navigation in resections with complex anatomy, which are otherwise less amenable to image guidance.

Significance: This study demonstrates that fluorescence can be used as a sensitive and specific method of guiding surgeries for head and neck cancers and potentially other cancers with challenging imaging conditions, increasing the probability of complete resections and improving oncologic outcomes. Cancer Res; 78(17); 5144–54. ©2018 AACR.
Data from A Genetic Vaccine Encoding Shared Cancer Neoantigens to Treat Tumors with Microsatellite Instability
Authors: Leoni Guido , D'Alise Anna Morena , Cotugno Gabriella , Langone Francesca , Garzia Irene , De Lucia Maria , Fichera Imma , Vitale Rosa , Bignone Veronica , Tucci Fabio Giovanni , Mori Federica , Leuzzi Adriano , Di Matteo Elena , Troise Fulvia , Abbate Adele , Merone Rossella , Ruzza Valentino , Diodoro Maria Grazia , Yadav Mahesh , Gordon-Alonso Monica , Vanhaver Cristophe , Panigada Maddalena , Soprana Elisa , Siccardi Antonio , Folgori Antonella , Colloca Stefano , van der Bruggen Pierre , Nicosia Alfredo , Lahm Armin , Catanese Maria Teresa , Scarselli Elisa
Published: March 2023

Abstract
Tumors with microsatellite instability (MSI) are caused by a defective DNA mismatch repair system that leads to the accumulation of mutations within microsatellite regions. Indels in microsatellites of coding genes can result in the synthesis of frameshift peptides (FSP). FSPs are tumor-specific neoantigens shared across patients with MSI. In this study, we developed a neoantigen-based vaccine for the treatment of MSI tumors. Genetic sequences from 320 MSI tumor biopsies and matched healthy tissues in The Cancer Genome Atlas database were analyzed to select shared FSPs. Two hundred nine FSPs were selected and cloned into nonhuman Great Ape Adenoviral and Modified Vaccinia Ankara vectors to generate a viral-vectored vaccine, referred to as Nous-209. Sequencing tumor biopsies of 20 independent patients with MSI colorectal cancer revealed that a median number of 31 FSPs out of the 209 encoded by the vaccine was detected both in DNA and mRNA extracted from each tumor biopsy. A relevant number of peptides encoded by the vaccine were predicted to bind patient HLA haplotypes. Vaccine immunogenicity was demonstrated in mice with potent and broad induction of FSP-specific CD8 and CD4 T-cell responses. Moreover, a vaccine-encoded FSP was processed in vitro by human antigen-presenting cells and was subsequently able to activate human CD8 T cells. Nous-209 is an “off-the-shelf” cancer vaccine encoding many neoantigens shared across sporadic and hereditary MSI tumors. These results indicate that Nous-209 can induce the optimal breadth of immune responses that might achieve clinical benefit to treat and prevent MSI tumors.
Significance:
These findings demonstrate the feasibility of an “off-the-shelf” vaccine for treatment and prevention of tumors harboring frameshift mutations and neoantigenic peptides as a result of microsatellite instability.
Data from Bisphosphonate Use and Breast Cancer Risk among Women with Ductal Carcinoma In Situ
Authors: Li Christopher I. , Flanagan Meghan R. , Tang Mei-Tzu C. , Porter Peggy L. , Malone Kathleen E.
Published: March 2023

Abstract
Women with a history of ductal carcinoma in situ (DCIS) have an elevated risk of a subsequent invasive breast cancer, but there are few established potentially modifiable factors known to lower this risk. Bisphosphonates are a commonly used treatment for patients with osteoporosis and have been shown to lower risks of recurrence and mortality in patients with invasive breast cancer; however, their use has not previously been investigated within the context of DCIS. Utilizing a population-based nested case–control design, we compared 301 cases of women diagnosed with DCIS and a subsequent breast cancer and 587 individually matched controls (on age, DCIS diagnosis year, primary treatment, histology, grade, and disease-free survival time) who were diagnosed with DCIS but never a subsequent breast cancer. Information on recency and duration of bisphosphonate use was ascertained from patient interviews and medical record reviews. Current users of bisphosphonates had a reduced risk of developing an invasive breast cancer compared with never users [OR = 0.50; 95% confidence interval (CI): 0.26–0.99]. Users of bisphosphonates for ≥48 months had a similar reduction in risk (OR = 0.45; 95% CI, 0.24–1.06). This is the first study to document that bisphosphonate use is associated with a lower risk of subsequent invasive breast cancer among women with a history of DCIS. This finding is consistent with the protective effect of bisphosphonates observed in other breast cancer settings. If validated by others, bisphosphonates may be an effective risk-reducing approach with the potential added benefits of its positive impacts on bone health and fracture risk.
Significance:
This study finds that bisphosphonate use among women with a history of DCIS is associated with lower risk of subsequent invasive breast cancer, providing a potential preventative approach for this high-risk population.
Data from Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer
Authors: Smalley Munisha , Natarajan Siva Kumar , Mondal Jayanta , Best Douglas , Goldman David , Shanthappa Basavaraja , Pellowe Moriah , Dash Chinmayee , Saha Tanmoy , Khiste Sachin , Ramadurai Nithya , Eton Elliot O. , Smalley Joshua L. , Brown Andrew , Thayakumar Allen , Rahman Mamunur , Arai Kazuya , Kohandel Mohammad , Sengupta Shiladitya , Goldman Aaron
Published: March 2023

Abstract
Drug-induced resistance, or tolerance, is an emerging yet poorly understood failure of anticancer therapy. The interplay between drug-tolerant cancer cells and innate immunity within the tumor, the consequence on tumor growth, and therapeutic strategies to address these challenges remain undescribed. Here, we elucidate the role of taxane-induced resistance on natural killer (NK) cell tumor immunity in triple-negative breast cancer (TNBC) and the design of spatiotemporally controlled nanomedicines, which boost therapeutic efficacy and invigorate “disabled” NK cells. Drug tolerance limited NK cell immune surveillance via drug-induced depletion of the NK-activating ligand receptor axis, NK group 2 member D, and MHC class I polypeptide-related sequence A, B. Systems biology supported by empirical evidence revealed the heat shock protein 90 (Hsp90) simultaneously controls immune surveillance and persistence of drug-treated tumor cells. On the basis of this evidence, we engineered a “chimeric” nanotherapeutic tool comprising taxanes and a cholesterol-tethered Hsp90 inhibitor, radicicol, which targets the tumor, reduces tolerance, and optimally reprimes NK cells via prolonged induction of NK-activating ligand receptors via temporal control of drug release in vitro and in vivo. A human ex vivo TNBC model confirmed the importance of NK cells in drug-induced death under pressure of clinically approved agents. These findings highlight a convergence between drug-induced resistance, the tumor immune contexture, and engineered approaches that consider the tumor and microenvironment to improve the success of combinatorial therapy.
Significance:
This study uncovers a molecular mechanism linking drug-induced resistance and tumor immunity and provides novel engineered solutions that target these mechanisms in the tumor and improve immunity, thus mitigating off-target effects.
Data from The Microbiome and Cancer: Creating Friendly Neighborhoods and Removing the Foes Within
Authors: Parida Sheetal , Sharma Dipali
Published: March 2023

Abstract
The human body is colonized by the microbial cells that are estimated to be as abundant as human cells, yet their genome is roughly 100 times the human genome, providing significantly more genetic diversity. The past decade has observed an explosion of interest in examining the existence of microbiota in the human body and understanding its role in various diseases including inflammatory bowel disease, neurologic diseases, cardiovascular disorders, and cancer. Many studies have demonstrated differential community composition between normal tissue and cancerous tissue, paving the way for investigations focused on deciphering the cause-and-effect relationships between specific microbes and initiation and progression of various cancers. Also, evolving are the strategies to alter tumor-associated dysbiosis and move it toward eubiosis with holistic approaches to change the entire neighborhood or to neutralize pathogenic strains. In this review, we discuss important pathogenic bacteria and the underlying mechanisms by which they affect cancer progression. We summarize key microbiota alterations observed in multiple tumor niches, their association with clinical stages, and their potential use in cancer diagnosis and management. Finally, we discuss microbiota-based therapeutic approaches.
Data from PKCϵ Is Required for KRAS-Driven Lung Tumorigenesis
Authors: Garg Rachana , Cooke Mariana , Benavides Fernando , Abba Martín C. , Cicchini Michelle , Feldser David M. , Kazanietz Marcelo G.
Published: March 2023

Abstract
Non–small cell lung cancer (NSCLC) is the most frequent subtype of lung cancer and remains a highly lethal malignancy and one of the leading causes of cancer-related deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histologic form of NSCLC. In this study, we examined the role of PKCε, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Database analysis revealed an association between PKCε expression and poor outcome in patients with lung adenocarcinoma specifically harboring KRAS mutations. A PKCε-deficient, conditionally activatable allele of oncogenic Kras (LSL-KrasG12D;PKCε−/− mice) demonstrated the requirement of PKCε for Kras-driven lung tumorigenesis in vivo, which was consistent with impaired transformed growth reported in PKCε-deficient KRAS-dependent NSCLC cells. Moreover, PKCε-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA sequencing revealed little overlap for PKCε and KRAS in the control of genes and biological pathways relevant in NSCLC, suggesting that a permissive role of PKCε in KRAS-driven lung tumorigenesis may involve nonredundant mechanisms. Our results thus, highlight the relevance and potential of targeting PKCε for lung cancer therapeutics.
Significance:
These findings demonstrate that KRAS-mediated tumorigenesis requires PKCε expression and highlight the potential for developing PKCε-targeted therapies for oncogenic RAS-driven malignancies.
Data from Glutamine-Directed Migration of Cancer-Activated Fibroblasts Facilitates Epithelial Tumor Invasion
Authors: Mestre-Farrera Aida , Bruch-Oms Marina , Peña Raúl , Rodríguez-Morató José , Alba-Castellón Lorena , Comerma Laura , Quintela-Fandino Miguel , Duñach Mireia , Baulida Josep , Pozo Óscar J. , García de Herreros Antonio
Published: March 2023

Abstract
Tumors are complex tissues composed of transformed epithelial cells as well as cancer-activated fibroblasts (CAF) that facilitate epithelial tumor cell invasion. We show here that CAFs and other mesenchymal cells rely much more on glutamine than epithelial tumor cells; consequently, they are more sensitive to inhibition of glutaminase. Glutamine dependence drove CAF migration toward this amino acid when cultured in low glutamine conditions. CAFs also invaded a Matrigel matrix following a glutamine concentration gradient and enhanced the invasion of tumor cells when both cells were cocultured. Accordingly, glutamine directed invasion of xenografted tumors in immunocompromised mice. Stimulation of glutamine-driven epithelial tumor invasion by fibroblasts required previous CAF activation, which involved the TGFβ/Snail1 signaling axis. CAFs moving toward Gln presented a polarized Akt2 distribution that was modulated by the Gln-dependent activity of TRAF6 and p62 in the migrating front, and depletion of these proteins prevented Akt2 polarization and Gln-driven CAF invasion. Our results demonstrate that glutamine deprivation promotes CAF migration and invasion, which in turn facilitates the movement of tumor epithelial cells toward nutrient-rich territories. These results provide a novel molecular mechanism for how metabolic stress enhances invasion and metastasis.
Significance:
Cancer-associated fibroblasts migrate and invade toward free glutamine and facilitate invasion of tumor epithelial cells, accounting for their movement away from the hostile conditions of the tumor towards nutrient-rich adjacent tissues.
Data from The Cytidine Deaminase APOBEC3G Contributes to Cancer Mutagenesis and Clonal Evolution in Bladder Cancer
Authors: Liu Weisi , Newhall Kevin P. , Khani Francesca , Barlow LaMont , Nguyen Duy , Gu Lilly , Eng Ken , Bhinder Bhavneet , Uppal Manik , Récapet Charlotte , Sboner Andrea , Ross Susan R. , Elemento Olivier , Chelico Linda , Faltas Bishoy M.
Published: March 2023

Abstract
Mutagenic processes leave distinct signatures in cancer genomes. The mutational signatures attributed to APOBEC3 cytidine deaminases are pervasive in human cancers. However, data linking individual APOBEC3 proteins to cancer mutagenesis in vivo are limited. Here, we showed that transgenic expression of human APOBEC3G promotes mutagenesis, genomic instability, and kataegis, leading to shorter survival in a murine bladder cancer model. Acting as mutagenic fuel, APOBEC3G increased the clonal diversity of bladder cancer, driving divergent cancer evolution. Characterization of the single-base substitution signature induced by APOBEC3G in vivo established the induction of a mutational signature distinct from those caused by APOBEC3A and APOBEC3B. Analysis of thousands of human cancers revealed the contribution of APOBEC3G to the mutational profiles of multiple cancer types, including bladder cancer. Overall, this study dissects the mutagenic impact of APOBEC3G on the bladder cancer genome, identifying that it contributes to genomic instability, tumor mutational burden, copy-number loss events, and clonal diversity.
Significance:
APOBEC3G plays a role in cancer mutagenesis and clonal heterogeneity, which can potentially inform future therapeutic efforts that restrict tumor evolution.

See related commentary by Caswell and Swanton, p. 487
Data from Long-Chain Acylcarnitines Induce Senescence of Invariant Natural Killer T Cells in Hepatocellular Carcinoma
Authors: Cheng Xue , Tan Xiaosheng , Wang Wei , Zhang Ziyao , Zhu Rongfei , Wu Mi , Li Mingyu , Chen Yiqing , Liang Zhihui , Zhu Peng , Wu Xiongwen , Weng Xiufang
Published: March 2023

Abstract
CD1d-restricted invariant natural killer T (iNKT) cells actively patrol the liver and possess valuable antitumor potential. However, clinical trials evaluating administration of iNKT cell–specific agonist α-galactosylceramide (α-GalCer) have failed to achieve obvious tumor regression. Improving the efficacy of iNKT cell–based immunotherapy requires a better understanding of the factors restraining the clinical benefits. In the context of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we found circulating and hepatic iNKT cells were hyperactivated but demonstrated imbalances in ratio and defective α-GalCer responsiveness. Exogenous IL2 helped to expand residual α-GalCer–responsive clones with reduced T-cell receptor diversity. However, transcriptome-wide analysis revealed activation of the senescence-associated secretory phenotype and dampened cytotoxicity in iNKT cells, weakening their immune surveillance capacity. The senescent status of iNKT cells from the patients was further illustrated by cell-cycle arrest, impaired telomere maintenance, perturbed calcium transport-related biological processes, and altered metabolism. Lipidomic profiling revealed the accumulation of long-chain acylcarnitines (LCAC) and aberrant lipid metabolism in HCC tissue. Exogenous LCACs, especially palmitoyl-carnitine and stearoyl-carnitine, inhibited iNKT cell expansion and promoted senescence. Collectively, our results provide deeper insights into iNKT cell dysregulation and identify a cell senescence–associated challenge for iNKT cell–based immunotherapy in HBV-related HCC. The mechanistic links between iNKT cell senescence and accumulated LCACs suggest new targets for anti-HCC immunotherapies.
Significance:
Patients with HBV-related HCC exhibit a cell senescence–associated dysregulation of invariant natural killer cells that is related to altered lipid metabolism and accumulated LCACs in tumor tissue.
Data from Olig1/2-Expressing Intermediate Lineage Progenitors Are Predisposed to PTEN/p53-Loss–Induced Gliomagenesis and Harbor Specific Therapeutic Vulnerabilities
Authors: Verma Ravinder , Chen Xiameng , Xin Dazhuan , Luo Zaili , Ogurek Sean , Xin Mei , Rao Rohit , Berry Kalen , Lu Q. Richard
Published: March 2023

Abstract
Malignant gliomas such as glioblastoma are highly heterogeneous with distinct cells of origin and varied genetic alterations. It remains elusive whether the specific states of neural cell lineages are differentially susceptible to distinct genetic alterations during malignant transformation. Here, an analysis of The Cancer Genome Atlas databases revealed that comutations of PTEN and TP53 are most significantly enriched in human high-grade gliomas. Therefore, we selectively ablated Pten and Trp53 in different progenitors to determine which cell lineage states are susceptible to malignant transformation. Mice with PTEN/p53 ablation mediated by multilineage-expressing human GFAP (hGFAP) promoter–driven Cre developed glioma but with incomplete penetrance and long latency. Unexpectedly, ablation of Pten and Trp53 in Nestin+ neural stem cells (NSC) or Pdgfra+/NG2+ committed oligodendrocyte precursor cells (OPC), two major cells of origin in glioma, did not induce glioma formation in mice. Strikingly, mice lacking Pten and Trp53 in Olig1+/Olig2+ intermediate precursors (pri-OPC) prior to the committed OPCs developed high-grade gliomas with 100% penetrance and short latency. The resulting tumors exhibited distinct tumor phenotypes and drug sensitivities from NSC- or OPC-derived glioma subtypes. Integrated transcriptomic and epigenomic analyses revealed that PTEN/p53-loss induced activation of oncogenic pathways, including HIPPO-YAP and PI3K signaling, to promote malignant transformation. Targeting the core regulatory circuitries YAP and PI3K signaling effectively inhibited tumor cell growth. Thus, our multicell state in vivo mutagenesis analyses suggests that transit-amplifying states of Olig1/2 intermediate lineage precursors are predisposed to PTEN/p53-loss–induced transformation and gliomagenesis, pointing to subtype-specific treatment strategies for gliomas with distinct genetic alterations.
Significance:
Multiple progenitor-state mutagenesis reveal that Olig1/2-expressing intermediate precursors are highly susceptible to PTEN/p53-loss–mediated transformation and impart differential drug sensitivity, indicating tumor-initiating cell states and genetic drivers dictate glioma phenotypes and drug responses.

See related commentary by Zamler and Hu, p. 807
Data from Androgen Signaling Contributes to Sex Differences in Cancer by Inhibiting NF-κB Activation in T Cells and Suppressing Antitumor Immunity
Authors: Zhang Xiaomin , Cheng Limin , Gao Chengqi , Chen Jing , Liao Shuangye , Zheng Yongqiang , Xu Liping , He Jingjing , Wang Danyang , Fang Ziqian , Zhang Jianeng , Yan Min , Luan Yi , Chen Siyu , Chen Likun , Xia Xiaojun , Deng Chunhao , Chen Guokai , Li Wende , Liu Zexian , Zhou Penghui
Published: March 2023

Abstract
Sex is known to be an important factor in the incidence, progression, and outcome of cancer. A better understanding of the underlying mechanisms could help improve cancer prevention and treatment. Here, we demonstrated a crucial role of antitumor immunity in the sex differences in cancer. Consistent with observations in human cancers, male mice showed accelerated tumor progression compared with females, but these differences were not observed in immunodeficient mice. Androgen signaling suppressed T-cell immunity against cancer in males. Mechanistically, androgen-activated androgen receptor upregulated expression of USP18, which inhibited TAK1 phosphorylation and the subsequent activation of NF-κB in antitumor T cells. Reduction of testosterone synthesis by surgical castration or using the small-molecular inhibitor abiraterone significantly enhanced the antitumor activity of T cells in male mice and improved the efficacy of anti–PD-1 immunotherapy. Together, this study revealed a novel mechanism contributing to sex differences in cancer. These results indicate that inhibition of androgen signaling is a promising approach to improve the efficacy of immunotherapy in males.
Significance:
Androgen signaling induces immunosuppression in cancer by blocking T-cell activity through upregulation of USP18 and subsequent inhibition of NF-κB activity, providing a targetable axis to improve antitumor immunity in males.
Data from Reimagining Cancer: Moving from the Cellular to the Tissue Level
Authors: Demicheli Romano , Hrushesky William J.M.
Published: March 2023

Abstract
The current universally accepted explanation of cancer origin and behavior, the somatic mutation theory, is cell-centered and rooted in perturbation of gene function independent of the external environmental context. However, tumors consist of various epithelial and stromal cell populations temporally and spatially organized into an integrated neoplastic community, and they can have properties similar to normal tissues. Accordingly, we review specific normal cellular and tissue traits and behaviors with adaptive temporal and spatial self-organization that result in ordered patterns and structures. A few recent theories have described these tissue-level cancer behaviors, invoking a conceptual shift from the cellular level and highlighting the need for methodologic approaches based on the analysis of complex systems. We propose extending the analytical approach of regulatory networks to the tissue level and introduce the concept of "cancer attractors." These concepts require reevaluation of cancer imaging and investigational approaches and challenge the traditional reductionist approach of cancer molecular biology.
Data from Single-Cell Analysis in Lung Adenocarcinoma Implicates RNA Editing in Cancer Innate Immunity and Patient Prognosis
Authors: Chan Tracey W. , Dodson Jack P. , Arbet Jaron , Boutros Paul C. , Xiao Xinshu
Published: March 2023

Abstract
RNA editing modifies single nucleotides of RNAs, regulating primary protein structure and protein abundance. In recent years, the diversity of proteins and complexity of gene regulation associated with RNA editing dysregulation has been increasingly appreciated in oncology. Large-scale shifts in editing have been observed in bulk tumors across various cancer types. However, RNA editing in single cells and individual cell types within tumors has not been explored. By profiling editing in single cells from lung adenocarcinoma biopsies, we found that the increased editing trend of bulk lung tumors was unique to cancer cells. Elevated editing levels were observed in cancer cells resistant to targeted therapy, and editing sites associated with drug response were enriched. Consistent with the regulation of antiviral pathways by RNA editing, higher editing levels in cancer cells were associated with reduced antitumor innate immune response, especially levels of natural killer cell infiltration. In addition, the level of RNA editing in cancer cells was positively associated with somatic point mutation burden. This observation motivated the definition of a new metric, RNA editing load, reflecting the amount of RNA mutations created by RNA editing. Importantly, in lung cancer, RNA editing load was a stronger predictor of patient survival than DNA mutations. This study provides the first single cell dissection of editing in cancer and highlights the significance of RNA editing load in cancer prognosis.
Significance:
RNA editing analysis in single lung adenocarcinoma cells uncovers RNA mutations that correlate with tumor mutation burden and cancer innate immunity and reveals the amount of RNA mutations that strongly predicts patient survival.

See related commentary by Luo and Liang, p. 351
Supplementary Figure 3 from Polymorphisms in the TOX3/LOC643714 Locus and Risk of Breast Cancer in African-American Women
Authors: Ruiz-Narváez Edward A. , Rosenberg Lynn , Cozier Yvette C. , Cupples L. Adrienne , Adams-Campbell Lucile L. , Palmer Julie R.
Published: March 2023

Supplementary Figure 3 from Polymorphisms in the TOX3/LOC643714 Locus and Risk of Breast Cancer in African-American Women
Supplementary Table 2 from Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women
Authors: Lu Tzu-Pin , Tsai Mong-Hsun , Lee Jang-Ming , Hsu Chung-Ping , Chen Pei-Chun , Lin Chung-Wu , Shih Jin-Yuan , Yang Pan-Chyr , Hsiao Chuhsing Kate , Lai Liang-Chuan , Chuang Eric Y.
Published: March 2023

Supplementary Table 2 from Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women
Supplementary Table 1 from Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women
Authors: Lu Tzu-Pin , Tsai Mong-Hsun , Lee Jang-Ming , Hsu Chung-Ping , Chen Pei-Chun , Lin Chung-Wu , Shih Jin-Yuan , Yang Pan-Chyr , Hsiao Chuhsing Kate , Lai Liang-Chuan , Chuang Eric Y.
Published: March 2023

Supplementary Table 1 from Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women
Supplementary Figure 1 from Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women
Authors: Lu Tzu-Pin , Tsai Mong-Hsun , Lee Jang-Ming , Hsu Chung-Ping , Chen Pei-Chun , Lin Chung-Wu , Shih Jin-Yuan , Yang Pan-Chyr , Hsiao Chuhsing Kate , Lai Liang-Chuan , Chuang Eric Y.
Published: March 2023

Supplementary Figure 1 from Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women
Supplementary Table 2 from Elevated Systemic Levels of Inflammatory Cytokines in Older Women with Persistent Cervical Human Papillomavirus Infection
Authors: Kemp Troy J. , Hildesheim Allan , García-Piñeres Alfonso , Williams Marcus C. , Shearer Gene M. , Rodriguez Ana Cecilia , Schiffman Mark , Burk Robert , Freer Enrique , Bonilla Jose , Herrero Rolando , Pinto Ligia A.
Published: March 2023

Supplementary Table 2 from Elevated Systemic Levels of Inflammatory Cytokines in Older Women with Persistent Cervical Human Papillomavirus Infection
Supplementary Table 1 from Evaluation of Multiplexed Cytokine and Inflammation Marker Measurements: a Methodologic Study
Authors: Chaturvedi Anil K. , Kemp Troy J. , Pfeiffer Ruth M. , Biancotto Angelique , Williams Marcus , Munuo Stella , Purdue Mark P. , Hsing Ann W. , Pinto Ligia , McCoy J. Philip , Hildesheim Allan
Published: March 2023

Supplementary Table 1 from Evaluation of Multiplexed Cytokine and Inflammation Marker Measurements: a Methodologic Study
Supplementary Appendix 3 from Screening for Colorectal Cancer in a Safety-Net Health Care System: Access to Care Is Critical and Has Implications for Screening Policy
Authors: Gupta Samir , Tong Liyue , Allison James E. , Carter Elizabeth , Koch Mark , Rockey Don C. , Anderson Paula , Ahn Chul , Argenbright Keith , Skinner Celette Sugg
Published: March 2023

Supplementary Appendix 3 from Screening for Colorectal Cancer in a Safety-Net Health Care System: Access to Care Is Critical and Has Implications for Screening Policy
Supplementary Table 2 from State Disparities in Colorectal Cancer Mortality Patterns in the United States
Authors: Naishadham Deepa , Lansdorp-Vogelaar Iris , Siegel Rebecca , Cokkinides Vilma , Jemal Ahmedin
Published: March 2023

PDF file - 62K
Supplementary Table 2 from CYP19A1 Genetic Variation in Relation to Prostate Cancer Risk and Circulating Sex Hormone Concentrations in Men from the Breast and Prostate Cancer Cohort Consortium
Authors: Travis Ruth C. , Schumacher Fredrick , Hirschhorn Joel N. , Kraft Peter , Allen Naomi E. , Albanes Demetrius , Berglund Goran , Berndt Sonja I. , Boeing Heiner , Bueno-de-Mesquita H. Bas , Calle Eugenia E. , Chanock Stephen , Dunning Alison M. , Hayes Richard , Feigelson Heather Spencer , Gaziano J. Michael , Giovannucci Edward , Haiman Christopher A. , Henderson Brian E. , Kaaks Rudolf , Kolonel Laurence N. , Ma Jing , Rodriguez Laudina , Riboli Elio , Stampfer Meir , Stram Daniel O. , Thun Michael J. , Tjønneland Anne , Trichopoulos Dimitrios , Vineis Paolo , Virtamo Jarmo , Le Marchand Loïc , Hunter David J.
Published: March 2023

Supplementary Table 2 from CYP19A1 Genetic Variation in Relation to Prostate Cancer Risk and Circulating Sex Hormone Concentrations in Men from the Breast and Prostate Cancer Cohort Consortium
Supplementary Table 1A from State Disparities in Colorectal Cancer Mortality Patterns in the United States
Authors: Naishadham Deepa , Lansdorp-Vogelaar Iris , Siegel Rebecca , Cokkinides Vilma , Jemal Ahmedin
Published: March 2023

PDF file - 85K, Mortality rates and trends in Colorectal Cancer, by State, US, 1990-2007, Non-Hispanic Whites
Data Supplement from Are HIV-Infected Men Vulnerable to Prostate Cancer Treatment Disparities?
Authors: Murphy Adam B. , Bhatia Ramona , Martin Iman K. , Klein David A. , Hollowell Courtney M.P. , Nyame Yaw , Dielubanza Elodi , Achenbach Chad , Kittles Rick A.
Published: March 2023

Supplemental Table 1: National Comprehensive Cancer Network guidelines for risk-appropriate therapy for prostate cancer. We have described appropriate treatments for low, intermediate, high, and very high risk categories, along with metastatic disease.