bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Paclitaxel Reduces Tumor Growth by Reprogramming Tumor-Associated Macrophages to an M1 Profile in a TLR4-Dependent Manner
Authors: Wanderley Carlos W. , Colón David F. , Luiz João Paulo M. , Oliveira Francisco F. , Viacava Paula R. , Leite Caio A. , Pereira Janaina A. , Silva Camila M. , Silva Cassia R. , Silva Rangel L. , Speck-Hernandez Cesar A. , Mota José M. , Alves-Filho José C. , Lima-Junior Roberto C. , Cunha Thiago M. , Cunha Fernando Q.
Published: March 2023

Abstract
Paclitaxel is an antineoplastic agent widely used to treat several solid tumor types. The primary mechanism of action of paclitaxel is based on microtubule stabilization inducing cell-cycle arrest. Here, we use several tumor models to show that paclitaxel not only induces tumor cell-cycle arrest, but also promotes antitumor immunity. In vitro, paclitaxel reprogrammed M2-polarized macrophages to the M1-like phenotype in a TLR4-dependent manner, similarly to LPS. Paclitaxel also modulated the tumor-associated macrophage (TAM) profile in mouse models of breast and melanoma tumors; gene expression analysis showed that paclitaxel altered the M2-like signature of TAMs toward an M1-like profile. In mice selectively lacking TLR4 on myeloid cells, for example, macrophages (LysM-Cre+/−/TLR4fl/fl), the antitumor effect of paclitaxel was attenuated. Gene expression analysis of tumor samples from patients with ovarian cancer before and after treatment with paclitaxel detected an enrichment of genes linked to the M1 macrophage activation profile (IFNγ-stimulated macrophages). These findings indicate that paclitaxel skews TAMs toward an immunocompetent profile via TLR4, which might contribute to the antitumor effect of paclitaxel and provide a rationale for new combination regimens comprising paclitaxel and immunotherapies as an anticancer treatment.

Significance: This study provides new evidence that the antitumor effect of paclitaxel occurs in part via reactivation of the immune response against cancer, guiding tumor-associated macrophages toward the M1-like antitumor phenotype.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5891/F1.large.jpg. Cancer Res; 78(20); 5891–900. ©2018 AACR.

See related commentary by Garassino et al., p. 5729
Data from Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL
Authors: Martín-Lorenzo Alberto , Auer Franziska , Chan Lai N. , García-Ramírez Idoia , González-Herrero Inés , Rodríguez-Hernández Guillermo , Bartenhagen Christoph , Dugas Martin , Gombert Michael , Ginzel Sebastian , Blanco Oscar , Orfao Alberto , Alonso-López Diego , Rivas Javier De Las , García-Cenador Maria B. , García-Criado Francisco J. , Müschen Markus , Sánchez-García Isidro , Borkhardt Arndt , Vicente-Dueñas Carolina , Hauer Julia
Published: March 2023

Abstract
Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here, we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL–negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/− mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch toward increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR-ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells.

Significance: Loss of Pax5 drives metabolic reprogramming, which together with Sca1-restricted BCR-ABL expression enables leukemic transformation. Cancer Res; 78(10); 2669–79. ©2018 AACR.
Data from Amplification of Glyceronephosphate O-Acyltransferase and Recruitment of USP30 Stabilize DRP1 to Promote Hepatocarcinogenesis
Authors: Gu Li , Zhu Yahui , Lin Xi , Li Yajun , Cui Kaisa , Prochownik Edward V. , Li Youjun
Published: March 2023

Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and the underlying pathophysiology of HCC is highly complex. In this study, we report that, in a bioinformatic screen of 2,783 genes encoding metabolic enzymes, GNPAT, which encodes the enzyme glyceronephosphate O-acyltransferase, is amplified, upregulated, and highly correlated with poor clinical outcome in human patients with HCC. High GNPAT expression in HCC was due to its amplification and transcriptional activation by the c-Myc/KDM1A complex. GNPAT compensated the oncogenic phenotypes in c-Myc–depleted HCC cells. Mechanistically, GNPAT recruited the enzyme USP30, which deubiquitylated and stabilized dynamin-related protein 1 (DRP1), thereby facilitating regulation of mitochondrial morphology, lipid metabolism, and hepatocarcinogenesis. Inhibition of GNPAT and DRP1 dramatically attenuated lipid metabolism and hepatocarcinogenesis. Furthermore, DRP1 mediated the oncogenic phenotypes driven by GNPAT. Taken together, these results indicate that GNPAT and USP30-mediated stabilization of DRP1 play a critical role in the development of HCC.

Significance: This study identifies and establishes the role of the enzyme GNPAT in liver cancer progression, which may serve as a potential therapeutic target for liver cancer. Cancer Res; 78(20); 5808–19. ©2018 AACR.
Data from HER2/EGFR–AKT Signaling Switches TGFβ from Inhibiting Cell Proliferation to Promoting Cell Migration in Breast Cancer
Authors: Huang Fei , Shi Qiaoni , Li Yuzhen , Xu Linlin , Xu Chi , Chen Fenfang , Wang Hai , Liao Hongwei , Chang Zai , Liu Fang , Zhang Xiang H.-F. , Feng Xin-Hua , Han Jing-Dong J. , Luo Shiwen , Chen Ye-Guang
Published: March 2023

Abstract
TGFβ signaling inhibits cell proliferation to block cancer initiation, yet it also enhances metastasis to promote malignancy during breast cancer development. The mechanisms underlying these differential effects are still unclear. Here, we report that HER2/EGFR signaling switches TGFβ function in breast cancer cells from antiproliferation to cancer promotion. Inhibition of HER2/EGFR activity attenuated TGFβ–induced epithelial–mesenchymal transition and migration but enhanced the antiproliferative activity of TGFβ. Activation of HER2/EGFR induced phosphorylation of Smad3 at Ser208 of the linker region through AKT, which promoted the nuclear accumulation of Smad3 and subsequent expression of the genes related to EMT and cell migration. In contrast, HER2/EGFR signaling had no effects on the nuclear localization of Smad2. Knockdown of Smad3, but not Smad2, blocked TGFβ–induced breast cancer cell migration. We observed a positive correlation between the nuclear localization of Smad3 and HER2 activation in advanced human breast cancers. Our results demonstrate a key role for HER2/EGFR in differential regulation of Smad3 activity to shift TGFβ function from antitumorigenic to protumorigenic during breast cancer development.

Significance: TGFβ signaling can shift from inhibiting to promoting breast cancer development via HER2/EGFR AKT-mediated phosphorylation of Smad3 at S208, enhancing its nuclear accumulation and upregulation of EMT-related genes.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6073/F1.large.jpg. Cancer Res; 78(21); 6073–85. ©2018 AACR.
Data from CDKN2A/p16 Deletion in Head and Neck Cancer Cells Is Associated with CDK2 Activation, Replication Stress, and Vulnerability to CHK1 Inhibition
Authors: Gadhikar Mayur A. , Zhang Jiexin , Shen Li , Rao Xiayu , Wang Jing , Zhao Mei , Kalu Nene N. , Johnson Faye M. , Byers Lauren A. , Heymach John , Hittelman Walter N. , Udayakumar Durga , Pandita Raj K. , Pandita Tej K. , Pickering Curtis R. , Redwood Abena B. , Piwnica-Worms Helen , Schlacher Katharina , Frederick Mitchell J. , Myers Jeffrey N.
Published: March 2023

Abstract
Checkpoint kinase inhibitors (CHKi) exhibit striking single-agent activity in certain tumors, but the mechanisms accounting for hypersensitivity are poorly understood. We screened a panel of 49 established human head and neck squamous cell carcinoma (HNSCC) cell lines and report that nearly 20% are hypersensitive to CHKi monotherapy. Hypersensitive cells underwent early S-phase arrest at drug doses sufficient to inhibit greater than 90% of CHK1 activity. Reduced rate of DNA replication fork progression and chromosomal shattering were also observed, suggesting replication stress as a root causative factor in CHKi hypersensitivity. To explore genomic underpinnings of CHKi hypersensitivity, comparative genomic analysis was performed between hypersensitive cells and cells categorized as least sensitive because they showed drug IC50 value greater than the cell panel median and lacked early S-phase arrest. Novel association between CDKN2A/p16 copy number loss, CDK2 activation, replication stress, and hypersensitivity of HNSCC cells to CHKi monotherapy was found. Restoring p16 in cell lines harboring CDKN2A/p16 genomic deletions alleviated CDK2 activation and replication stress, attenuating CHKi hypersensitivity. Taken together, our results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from CHKi therapy.

Significance: These results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from therapy with CHK inhibitors. Cancer Res; 78(3); 781–97. ©2017 AACR.
Data from SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma
Authors: Sakthikumar Sharadha , Elvers Ingegerd , Kim Jaegil , Arendt Maja L. , Thomas Rachael , Turner-Maier Jason , Swofford Ross , Johnson Jeremy , Schumacher Steven E. , Alföldi Jessica , Axelsson Erik , Couto C. Guillermo , Kisseberth William C. , Pettersson Mats E. , Getz Gad , Meadows Jennifer R.S. , Modiano Jaime F. , Breen Matthew , Kierczak Marcin , Forsberg-Nilsson Karin , Marinescu Voichita D. , Lindblad-Toh Kerstin
Published: March 2023

Abstract
Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species.

Significance: Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease. Cancer Res; 78(13); 3421–31. ©2018 AACR.
Data from Dual Inhibition of DNA and Histone Methyltransferases Increases Viral Mimicry in Ovarian Cancer Cells
Authors: Liu Minmin , Thomas Stacey L. , DeWitt Ashley K. , Zhou Wanding , Madaj Zachary B. , Ohtani Hitoshi , Baylin Stephen B. , Liang Gangning , Jones Peter A.
Published: March 2023

Abstract
Ovarian cancer ranks as the most deadly gynecologic cancer, and there is an urgent need to develop more effective therapies. Previous studies have shown that G9A, a histone methyltransferase that catalyzes mono- and dimethylation of histone H3 lysine9, is highly expressed in ovarian cancer tumors, and its overexpression is associated with poor prognosis. Here we report that pharmacologic inhibition of G9A in ovarian cancer cell lines with high levels of G9A expression induces synergistic antitumor effects when combined with the DNA methylation inhibitor (DNMTi) 5-aza-2′-deoxycytidine (5-aza-CdR). These antitumor effects included upregulation of endogenous retroviruses (ERV), activation of the viral defense response, and induction of cell death, which have been termed "viral mimicry" effects induced by DNMTi. G9Ai treatment further reduced H3K9me2 levels within the long terminal repeat regions of ERV, resulting in further increases of ERV expression and enhancing "viral mimicry" effects. In contrast, G9Ai and 5-aza-CdR were not synergistic in cell lines with low basal G9A levels. Taken together, our results suggest that the synergistic effects of combination treatment with DNMTi and G9Ai may serve as a novel therapeutic strategy for patients with ovarian cancer with high levels of G9A expression.

Significance: Dual inhibition of DNA methylation and histone H3 lysine 9 dimethylation by 5-aza-CdR and G9Ai results in synergistic upregulation of ERV and induces an antiviral response, serving as a basis for exploring this novel combination treatment in patients with ovarian cancer. Cancer Res; 78(20); 5754–66. ©2018 AACR.
Data from RNF6 Promotes Colorectal Cancer by Activating the Wnt/β-Catenin Pathway via Ubiquitination of TLE3
Authors: Liu Lei , Zhang Yanquan , Wong Chi Chun , Zhang Jingwan , Dong Yujuan , Li Xiangchun , Kang Wei , Chan Francis K.L. , Sung Joseph J.Y. , Yu Jun
Published: March 2023

Abstract
Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer. Previous whole-genome sequencing of colorectal cancer clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we showed that RNF6 is upregulated in 73.5% (147/200) of patients with colorectal cancer and was positively associated with RNF6 gene amplification. Furthermore, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of patients with colorectal cancer. RNF6 promoted cell growth, cell-cycle progression, and epithelial-to-mesenchymal transition in colorectal cancer cells; RNF6 also promoted colorectal tumor growth and lung metastasis in mouse models. Mechanistic investigations revealed that RNF6 bound and ubiquitylated transducin-like enhancer of split 3 (TLE3), a transcriptional repressor of the β-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of β-catenin to TCF4/LEF, triggering Wnt/β-catenin activation. Restoration of TLE3 expression abolished the oncogenic effects of RNF6. Taken together, these results demonstrate that RNF6 plays a pivotal oncogenic role in colorectal tumorigenesis.

Significance: RNF6-mediated ubiquitination and degradation of TLE3 activates the Wnt/β-catenin pathway in colorectal carcinogenesis. Cancer Res; 78(8); 1958–71. ©2018 AACR.
Data from UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling
Authors: Dikshit Anushka , Jin Yingai J. , Degan Simone , Hwang Jihwan , Foster Matthew W. , Li Chuan-Yuan , Zhang Jennifer Y.
Published: March 2023

Abstract
UBE2N is a K63-specific ubiquitin conjugase linked to various immune disorders and cancer. Here, we demonstrate that UBE2N and its partners UBE2V1 and UBE2V2 are highly expressed in malignant melanoma. Silencing of UBE2N and its partners significantly decreased melanoma cell proliferation and subcutaneous tumor growth. This was accompanied by increased expression of E-cadherin, p16, and MC1R and decreased expression of melanoma malignancy markers including SOX10, Nestin, and ABCB5. Mass spectrometry–based phosphoproteomic analysis revealed that UBE2N loss resulted in distinct alterations to the signaling landscape: MEK/ERK signaling was impaired, FRA1 and SOX10 gene regulators were downregulated, and p53 and p16 tumor suppressors were upregulated. Similar to inhibition of UBE2N and MEK, silencing FRA1 decreased SOX10 expression and cell proliferation. Conversely, exogenous expression of active FRA1 increased pMEK and SOX10 expression, and restored anchorage-independent cell growth of cells with UBE2N loss. Systemic delivery of NSC697923, a small-molecule inhibitor of UBE2N, significantly decreased melanoma xenograft growth. These data indicate that UBE2N is a novel regulator of the MEK/FRA1/SOX10 signaling cascade and is indispensable for malignant melanoma growth. Our findings establish the basis for targeting UBE2N as a potential treatment strategy for melanoma.

Significance: These findings identify ubiquitin conjugase UBE2N and its variant partners as novel regulators of MAPK signaling and potential therapeutic targets in melanoma. Cancer Res; 78(22); 6462–72. ©2018 AACR.
Data from IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer
Authors: He Weizhi , Wu Jinghua , Shi Juanjuan , Huo Yan-Miao , Dai Wentao , Geng Jing , Lu Ping , Yang Min-Wei , Fang Yuan , Wang Wei , Zhang Zhi-Gang , Habtezion Aida , Sun Yong-Wei , Xue Jing
Published: March 2023

Abstract
Chronic inflammation is a feature of pancreatic cancer, but little is known about how immune cells or immune cell–related signals affect pancreatic cancer stemness and development. Our previous work showed that IL22/IL22RA1 plays a vital role in acute and chronic pancreatitis progression by mediating cross-talk between immune cells and acinar cells or stellate cells, respectively. Here, we find IL22RA1 is highly but heterogeneously expressed in pancreatic cancer cells, with high expression associated with poor prognosis of patients with pancreatic cancer. The IL22RA1hi population from pancreatic cancer harbored higher stemness potential and tumorigenicity. Notably, IL22 promoted pancreatic cancer stemness via IL22RA1/STAT3 signaling, establishing the mechanism of regulation of cancer stemness by microenvironmental factors. Moreover, STAT3 was indispensable for the maintenance of IL22RA1hi cells. Overall, these findings provide a therapeutic strategy for patients with PDAC with high expression of IL22RA1.

Significance: IL22RA1/STAT3 signaling enhances stemness and tumorigenicity in pancreatic cancer. Cancer Res; 78(12); 3293–305. ©2018 AACR.
Data from LIFEx: A Freeware for Radiomic Feature Calculation in Multimodality Imaging to Accelerate Advances in the Characterization of Tumor Heterogeneity
Authors: Nioche Christophe , Orlhac Fanny , Boughdad Sarah , Reuzé Sylvain , Goya-Outi Jessica , Robert Charlotte , Pellot-Barakat Claire , Soussan Michael , Frouin Frédérique , Buvat Irène
Published: March 2023

Abstract
Textural and shape analysis is gaining considerable interest in medical imaging, particularly to identify parameters characterizing tumor heterogeneity and to feed radiomic models. Here, we present a free, multiplatform, and easy-to-use freeware called LIFEx, which enables the calculation of conventional, histogram-based, textural, and shape features from PET, SPECT, MR, CT, and US images, or from any combination of imaging modalities. The application does not require any programming skills and was developed for medical imaging professionals. The goal is that independent and multicenter evidence of the usefulness and limitations of radiomic features for characterization of tumor heterogeneity and subsequent patient management can be gathered. Many options are offered for interactive textural index calculation and for increasing the reproducibility among centers. The software already benefits from a large user community (more than 800 registered users), and interactions within that community are part of the development strategy.

Significance: This study presents a user-friendly, multi-platform freeware to extract radiomic features from PET, SPECT, MR, CT, and US images, or any combination of imaging modalities. Cancer Res; 78(16); 4786–9. ©2018 AACR.
Data from p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4
Authors: Kajiwara Chihiro , Fumoto Katsumi , Kimura Hirokazu , Nojima Satoshi , Asano Keita , Odagiri Kazuki , Yamasaki Makoto , Hikita Hayato , Takehara Tetsuo , Doki Yuichiro , Morii Eiichi , Kikuchi Akira
Published: March 2023

Abstract
Dickkopf3 (DKK3) is a secretory protein that belongs to the DKK family, but exhibits structural divergence from other family members, and its corresponding receptors remain to be identified. Although DKK3 has been shown to have oncogenic functions in certain cancer types, the underlying mechanism by which DKK3 promotes tumorigenesis remains to be clarified. We show here that DKK3 stimulates esophageal cancer cell proliferation via cytoskeleton-associated protein 4 (CKAP4), which acts as a receptor for DKK3. DKK3 was expressed in approximately 50% of tumor lesions of esophageal squamous cell carcinoma (ESCC) cases; simultaneous expression of DKK3 and CKAP4 was associated with poor prognosis. Anti-CKAP4 antibody inhibited both binding of DKK3 to CKAP4 and xenograft tumor formation induced by ESCC cells. p63, a p53-related transcriptional factor frequently amplified in ESCC, bound to the upstream region of the DKK3 gene. Knockdown of p63 decreased DKK3 expression in ESCC cells, and reexpression of DKK3 partially rescued cell proliferation in p63-depleted ESCC cells. Expression of ΔNp63α and DKK3 increased the size of tumor-like esophageal organoids, and anti-CKAP4 antibody inhibited growth of esophageal organoids. Taken together, these results suggest that the DKK3-CKAP4 axis might serve as a novel molecular target for ESCC.

Significance: In esophageal cancer, findings identify DKK3 as a poor prognostic indicator and demonstrate CKAP4 inhibition as an effective therapeutic strategy. Cancer Res; 78(21); 6107–20. ©2018 AACR.
Data from Activation of the Unfolded Protein Response via Inhibition of Protein Disulfide Isomerase Decreases the Capacity for DNA Repair to Sensitize Glioblastoma to Radiotherapy
Authors: Liu Yajing , Ji Wenbin , Shergalis Andrea , Xu Jiaqi , Delaney Amy M. , Calcaterra Andrew , Pal Anupama , Ljungman Mats , Neamati Nouri , Rehemtulla Alnawaz
Published: March 2023

Abstract
Patients with glioblastoma multiforme (GBM) survive on average 12 to 14 months after diagnosis despite surgical resection followed by radiotheraphy and temozolomide therapy. Intrinsic or acquired resistance to chemo- and radiotherapy is common and contributes to a high rate of recurrence. To investigate the therapeutic potential of protein disulfide isomerase (PDI) as a target to overcome resistance to chemoradiation, we developed a GBM tumor model wherein conditional genetic ablation of prolyl 4-hydroxylase subunit beta (P4HB), the gene that encodes PDI, can be accomplished. Loss of PDI expression induced the unfolded protein response (UPR) and decreased cell survival in two independent GBM models. Nascent RNA Bru-seq analysis of PDI-depleted cells revealed a decrease in transcription of genes involved in DNA repair and cell-cycle regulation. Activation of the UPR also led to a robust decrease in RAD51 protein expression as a result of its ubiquitination-mediated proteosomal degradation. Clonogenic survival assays demonstrated enhanced killing of GBM cells in response to a combination of PDI knockdown and ionizing radiation (IR) compared with either modality alone, which correlated with a decreased capacity to repair IR-induced DNA damage. Synergistic tumor control was also observed with the combination of PDI inhibition and IR in a mouse xenograft model compared with either single agent alone. These findings provide a strong rationale for the development of PDI inhibitors and their use in combination with DNA damage-inducing, standard-of-care therapies such as IR.
Significance:
These findings identify PDIA1 as a therapeutic target in GBM by demonstrating efficacy of its inhibition in combination with radiotherapy through a novel mechanism involving downregulation of DNA repair genes.
Data from Psychologic Distress Is Associated with Cancer-Specific Mortality among Patients with Cervical Cancer
Authors: Lu Donghao , Andrae Bengt , Valdimarsdóttir Unnur , Sundström Karin , Fall Katja , Sparén Pär , Fang Fang
Published: March 2023

Abstract
Emerging evidence suggests a role of psychologic factors in the progression of different cancer types. However, it is unclear whether psychologic distress around the time of diagnosis of invasive cervical cancer places patients at a higher risk of cancer-specific mortality, independently of tumor characteristics and treatment modalities. We conducted a nationwide cohort study, including 4,245 patients with newly diagnosed cervical cancer during 2002–2011 in Sweden. Psychologic distress was indicated by a clinical diagnosis of depression, anxiety, or stress reaction and adjustment disorders, or the experience of a stressful life event, including death or severe illness of a family member, divorce, or between jobs, from one year before cancer diagnosis and onwards. We calculated the HRs of cancer-specific mortality among the patients exposed to psychologic distress, compared with unexposed patients, controlling for socioeconomic characteristics and other known prognostic indicators such as tumor and treatment characteristics. We found that patients exposed to psychologic distress had an increased risk of cancer-specific mortality (HR 1.33; 95% CI, 1.14–1.54). The association was primarily driven by distress experienced within one year before or after diagnosis (HR 1.30; 95% CI, 1.11–1.52), but not thereafter (HR 1.12; 95% CI, 0.84–1.49). In summary, our study shows that psychiatric disorders and stressful life events around cancer diagnosis are associated with increased cancer-specific mortality among patients with cervical cancer, independent of tumor characteristics and treatment modality.
Significance:
These findings support the integration of psychologic screening and intervention in the clinical management of patients with cervical cancer, particularly around the time of cancer diagnosis.
Data from SF3B2-Mediated RNA Splicing Drives Human Prostate Cancer Progression
Authors: Kawamura Norihiko , Nimura Keisuke , Saga Kotaro , Ishibashi Airi , Kitamura Koji , Nagano Hiromichi , Yoshikawa Yusuke , Ishida Kyoso , Nonomura Norio , Arisawa Mitsuhiro , Luo Jun , Kaneda Yasufumi
Published: March 2023

Abstract
Androgen receptor splice variant-7 (AR-V7) is a constitutively active AR variant implicated in castration-resistant prostate cancers. Here, we show that the RNA splicing factor SF3B2, identified by in silico and CRISPR/Cas9 analyses, is a critical determinant of AR-V7 expression and is correlated with aggressive cancer phenotypes. Transcriptome and PAR-CLIP analyses revealed that SF3B2 controls the splicing of target genes, including AR, to drive aggressive phenotypes. SF3B2-mediated aggressive phenotypes in vivo were reversed by AR-V7 knockout. Pladienolide B, an inhibitor of a splicing modulator of the SF3b complex, suppressed the growth of tumors addicted to high SF3B2 expression. These findings support the idea that alteration of the splicing pattern by high SF3B2 expression is one mechanism underlying prostate cancer progression and therapeutic resistance. This study also provides evidence supporting SF3B2 as a candidate therapeutic target for treating patients with cancer.
Significance:
RNA splicing factor SF3B2 is essential for the generation of an androgen receptor (AR) variant that renders prostate cancer cells resistant to AR-targeting therapy.
Data from Disruption of the Scaffolding Function of mLST8 Selectively Inhibits mTORC2 Assembly and Function and Suppresses mTORC2-Dependent Tumor Growth In Vivo
Authors: Hwang Yoonha , Kim Laura C. , Song Wenqiang , Edwards Deanna N. , Cook Rebecca S. , Chen Jin
Published: March 2023

Abstract
mTOR is a serine/threonine kinase that acts in two distinct complexes, mTORC1 and mTORC2, and is dysregulated in many diseases including cancer. mLST8 is a shared component of both mTORC1 and mTORC2, yet little is known regarding how mLST8 contributes to assembly and activity of the mTOR complexes. Here we assessed mLST8 loss in a panel of normal and cancer cells and observed little to no impact on assembly or activity of mTORC1. However, mLST8 loss blocked mTOR association with mTORC2 cofactors RICTOR and SIN1, thus abrogating mTORC2 activity. Similarly, a single pair of mutations on mLST8 with a corresponding mutation on mTOR interfered with mTORC2 assembly and activity without affecting mTORC1. We also discovered a direct interaction between mLST8 and the NH2-terminal domain of the mTORC2 cofactor SIN1. In PTEN-null prostate cancer xenografts, mLST8 mutations disrupting the mTOR interaction motif inhibited AKT S473 phosphorylation and decreased tumor cell proliferation and tumor growth in vivo. Together, these data suggest that the scaffolding function of mLST8 is critical for assembly and activity of mTORC2, but not mTORC1, an observation that could enable therapeutic mTORC2-selective inhibition as a therapeutic strategy.
Significance:
These findings show that mLST8 functions as a scaffold to maintain mTORC2 integrity and kinase activity, unveiling a new avenue for development of mTORC2-specific inhibitors.
Data from APE1 Upregulates MMP-14 via Redox-Sensitive ARF6-Mediated Recycling to Promote Cell Invasion of Esophageal Adenocarcinoma
Authors: Lu Heng , Bhat Ajaz A. , Peng Dunfa , Chen Zheng , Zhu Shoumin , Hong Jun , Maacha Selma , Yan Jin , Robbins David J. , Washington M. Kay , Belkhiri Abbes , El-Rifai Wael
Published: March 2023

Abstract
Esophageal adenocarcinoma (EAC) is an aggressive malignancy with poor clinical outcome. The incidence of EAC has been rising rapidly in the past three decades. Here, we showed that apurinic/apyrimidinic endonuclease (APE1) is overexpressed in EAC cell lines, and patients' samples of dysplasia and EAC. Downregulation of APE1 or inhibition of its redox function significantly repressed invasion. Overexpression of a redox-defective mutant, C65A, abrogated the proinvasive phenotype of APE1. APE1 regulated invasion via upregulation of matrix metalloproteinase 14 (MMP-14), which subsequently activated MMP-2, leading to degradation of the extracellular matrix in a redox-dependent manner. Downregulation of APE1 or inhibition of its redox function decreased the rate of endocytosis and recycling of MMP-14 protein. APE1 interacted with ARF6, a key regulator of MMP-14 recycling, which maintained ARF6 activity in an APE1-redox–dependent manner, promoting its ability to regulate MMP-14 recycling to the cell surface. In summary, these findings identify a novel redox-sensitive APE1–ARF6–MMP-14 signaling axis that mediates cellular invasion in esophageal carcinogenesis.
Significance:
This study demonstrates the association between oxidative stress and the development and metastatic behavior of esophageal adenocarcinoma.
Data from The Hippo Pathway Component TAZ Promotes Immune Evasion in Human Cancer through PD-L1
Authors: Janse van Rensburg Helena J. , Azad Taha , Ling Min , Hao Yawei , Snetsinger Brooke , Khanal Prem , Minassian Lori M. , Graham Charles H. , Rauh Michael J. , Yang Xiaolong
Published: March 2023

Abstract
The Hippo pathway component WW domain-containing transcription regulator 1 (TAZ) is a transcriptional coactivator and an oncogene in breast and lung cancer. Transcriptional targets of TAZ that modulate immune cell function in the tumor microenvironment are poorly understood. Here, we perform a comprehensive screen for immune-related genes regulated by TAZ and its paralog YAP using NanoString gene expression profiling. We identify the immune checkpoint molecule PD-L1 as a target of Hippo signaling. The upstream kinases of the Hippo pathway, mammalian STE20-like kinase 1 and 2 (MST1/2), and large tumor suppressor 1 and 2 (LATS1/2), suppress PD-L1 expression while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines. PD-L1 expression in cancer cell lines is determined by TAZ activity and TAZ/YAP/TEAD increase PD-L1 promoter activity. Critically, TAZ-induced PD-L1 upregulation in human cancer cells is sufficient to inhibit T-cell function. The relationship between TAZ and PD-L1 is not conserved in multiple mouse cell lines, likely due to differences between the human and mouse PD-L1 promoters. To explore the extent of divergence in TAZ immune-related targets between human and mouse cells, we performed a second NanoString screen using mouse cell lines. We show that many targets of TAZ may be differentially regulated between these species. These findings highlight the role of Hippo signaling in modifying human/murine physiologic/pathologic immune responses and provide evidence implicating TAZ in human cancer immune evasion.

Significance: Human-specific activation of PD-L1 by a novel Hippo signaling pathway in cancer immune evasion may have a significant impact on research in immunotherapy. Cancer Res; 78(6); 1457–70. ©2018 AACR.
Data from Integrative Pharmacogenomics Analysis of Patient-Derived Xenografts
Authors: Mer Arvind S. , Ba-Alawi Wail , Smirnov Petr , Wang Yi X. , Brew Ben , Ortmann Janosch , Tsao Ming-Sound , Cescon David W. , Goldenberg Anna , Haibe-Kains Benjamin
Published: March 2023

Abstract
Identifying robust biomarkers of drug response constitutes a key challenge in precision medicine. Patient-derived tumor xenografts (PDX) have emerged as reliable preclinical models that more accurately recapitulate tumor response to chemo- and targeted therapies. However, the lack of computational tools makes it difficult to analyze high-throughput molecular and pharmacologic profiles of PDX. We have developed Xenograft Visualization & Analysis (Xeva), an open-source software package for in vivo pharmacogenomic datasets that allows for quantification of variability in gene expression and pathway activity across PDX passages. We found that only a few genes and pathways exhibited passage-specific alterations and were therefore not suitable for biomarker discovery. Using the largest PDX pharmacogenomic dataset to date, we identified 87 pathways that are significantly associated with response to 51 drugs (FDR < 0.05). We found novel biomarkers based on gene expressions, copy number aberrations, and mutations predictive of drug response (concordance index > 0.60; FDR < 0.05). Our study demonstrates that Xeva provides a flexible platform for integrative analysis of preclinical in vivo pharmacogenomics data to identify biomarkers predictive of drug response, representing a major step forward in precision oncology.
Significance:
A computational platform for PDX data analysis reveals consistent gene and pathway activity across passages and confirms drug response prediction biomarkers in PDX.

See related commentary by Meehan, p. 4324
Data from A Direct Podocalyxin–Dynamin-2 Interaction Regulates Cytoskeletal Dynamics to Promote Migration and Metastasis in Pancreatic Cancer Cells
Authors: Wong Bin Sheng , Shea Daniel J. , Mistriotis Panagiotis , Tuntithavornwat Soontorn , Law Robert A. , Bieber Jake M. , Zheng Lei , Konstantopoulos Konstantinos
Published: March 2023

Abstract
The sialoglycoprotein podocalyxin is absent in normal pancreas but is overexpressed in pancreatic cancer and is associated with poor clinical outcome. Here, we investigate the role of podocalyxin in migration and metastasis of pancreatic adenocarcinomas using SW1990 and Pa03c as cell models. Although ezrin is regarded as a cytoplasmic binding partner of podocalyxin that regulates actin polymerization via Rac1 or RhoA, we did not detect podocalyxin–ezrin association in pancreatic cancer cells. Moreover, depletion of podocalyxin did not alter actin dynamics or modulate Rac1 and RhoA activities in pancreatic cancer cells. Using mass spectrometry, bioinformatics analysis, coimmunoprecipitation, and pull-down assays, we discovered a novel, direct binding interaction between the cytoplasmic tail of podocalyxin and the large GTPase dynamin-2 at its GTPase, middle, and pleckstrin homology domains. This podocalyxin–dynamin-2 interaction regulated microtubule growth rate, which in turn modulated focal adhesion dynamics and ultimately promoted efficient pancreatic cancer cell migration via microtubule- and Src-dependent pathways. Depletion of podocalyxin in a hemispleen mouse model of pancreatic cancer diminished liver metastasis without altering primary tumor size. Collectively, these findings reveal a novel mechanism by which podocalyxin facilitates pancreatic cancer cell migration and metastasis.
Significance:
These findings reveal that a novel interaction between podocalyxin and dynamin-2 promotes migration and metastasis of pancreatic cancer cells by regulating microtubule and focal adhesion dynamics.
Data from PIN1 Maintains Redox Balance via the c-Myc/NRF2 Axis to Counteract Kras-Induced Mitochondrial Respiratory Injury in Pancreatic Cancer Cells
Authors: Liang Chen , Shi Si , Liu Mingyang , Qin Yi , Meng Qingcai , Hua Jie , Ji Shunrong , Zhang Yuqing , Yang Jingxuan , Xu Jin , Ni Quanxing , Li Min , Yu Xianjun
Published: March 2023

Abstract
Kras is a decisive oncogene in pancreatic ductal adenocarcinoma (PDAC). PIN1 is a key effector involved in the Kras/ERK axis, synergistically mediating various cellular events. However, the underlying mechanism by which PIN1 promotes the development of PDAC remains unclear. Here we sought to elucidate the effect of PIN1 on redox homeostasis in Kras-driven PDAC. PIN1 was prevalently upregulated in PDAC and predicted the prognosis of the disease, especially Kras-mutant PDAC. Downregulation of PIN1 inhibited PDAC cell growth and promoted apoptosis, partially due to mitochondrial dysfunction. Silencing of PIN1 damaged basal mitochondrial function by significantly increasing intracellular ROS. Furthermore, PIN1 maintained redox balance via synergistic activation of c-Myc and NRF2 to upregulate expression of antioxidant response element driven genes in PDAC cells. This study elucidates a new mechanism by which Kras/ERK/NRF2 promotes tumor growth and identifies PIN1 as a decisive target in therapeutic strategies aimed at disturbing the redox balance in pancreatic cancer.
Significance:
This study suggests that antioxidation protects Kras-mutant pancreatic cancer cells from oxidative injury, which may contribute to development of a targeted therapeutic strategy for Kras-driven PDAC by impairing redox homeostasis.
Data from ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17–Mutant KIT
Authors: Apsel Winger Beth , Cortopassi Wilian A. , Garrido Ruiz Diego , Ding Lucky , Jang Kibeom , Leyte-Vidal Ariel , Zhang Na , Esteve-Puig Rosaura , Jacobson Matthew P. , Shah Neil P.
Published: March 2023

Abstract
KIT is a type-3 receptor tyrosine kinase that is frequently mutated at exon 11 or 17 in a variety of cancers. First-generation KIT tyrosine kinase inhibitors (TKI) are ineffective against KIT exon 17 mutations, which favor an active conformation that prevents these TKIs from binding. The ATP-competitive inhibitors, midostaurin and avapritinib, which target the active kinase conformation, were developed to inhibit exon 17–mutant KIT. Because secondary kinase domain mutations are a common mechanism of TKI resistance and guide ensuing TKI design, we sought to define problematic KIT kinase domain mutations for these emerging therapeutics. Midostaurin and avapritinib displayed different vulnerabilities to secondary kinase domain substitutions, with the T670I gatekeeper mutation being selectively problematic for avapritinib. Although gatekeeper mutations often directly disrupt inhibitor binding, we provide evidence that T670I confers avapritinib resistance indirectly by inducing distant conformational changes in the phosphate-binding loop. These findings suggest combining midostaurin and avapritinib may forestall acquired resistance mediated by secondary kinase domain mutations.
Significance:
This study identifies potential problematic kinase domain mutations for next-generation KIT inhibitors midostaurin and avapritinib.
Data from SCFFBXW7/GSK3β-Mediated GFI1 Degradation Suppresses Proliferation of Gastric Cancer Cells
Authors: Kuai Xiaoling , Li Long , Chen Ran , Wang Kangjunjie , Chen Min , Cui Binghai , Zhang Yuxue , Li Junqiang , Zhu Hongwen , Zhou Hu , Huang Jianfei , Qin Jun , Wang Zhiwei , Wei Wenyi , Gao Daming
Published: March 2023

Abstract
Gastric cancer is the third leading cause of cancer-related death worldwide. The regulatory mechanisms underlying gastric cancer cell proliferation are largely unclear. Here, we show that the transcription factor GFI1 is associated with advanced clinical gastric cancer progression and promoted gastric cancer cell proliferation partially through inhibition of gastrokine-2 (GKN2) transcription. GFI1 was a degrading substrate of FBXW7, whose loss was observed in gastric cancer. Mechanistically, GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. A nondegradable GFI1 S94A/S98A mutant was more potent in driving gastric cancer cell proliferation and tumorigenesis than wild-type GFI1. Overall, this study reveals the oncogenic role of GFI1 in gastric cancer and provides mechanistic insights into the tumor suppressor function of FBXW7.
Significance:
These findings demonstrate the oncogenic role of the transcription factor GFI1 and the tumor suppressive function of FBXW7 in gastric cancer.
Data from LKB1 and KEAP1/NRF2 Pathways Cooperatively Promote Metabolic Reprogramming with Enhanced Glutamine Dependence in KRAS-Mutant Lung Adenocarcinoma
Authors: Galan-Cobo Ana , Sitthideatphaiboon Piyada , Qu Xiao , Poteete Alissa , Pisegna Marlese A. , Tong Pan , Chen Pei-Hsuan , Boroughs Lindsey K. , Rodriguez Mirna L.M. , Zhang Winter , Parlati Francesco , Wang Jing , Gandhi Varsha , Skoulidis Ferdinandos , DeBerardinis Ralph J. , Minna John D. , Heymach John V.
Published: March 2023

Abstract
In KRAS-mutant lung adenocarcinoma, tumors with LKB1 loss (KL) are highly enriched for concurrent KEAP1 mutations, which activate the KEAP1/NRF2 pathway (KLK). Here, we investigated the biological consequences of these cooccurring alterations and explored whether they conferred specific therapeutic vulnerabilities. Compared with KL tumors, KLK tumors exhibited increased expression of genes involved in glutamine metabolism, the tricarboxylic acid cycle, and the redox homeostasis signature. Using isogenic pairs with knockdown or overexpression of LKB1, KEAP1, and NRF2, we found that LKB1 loss results in increased energetic and redox stress marked by increased levels of intracellular reactive oxygen species and decreased levels of ATP, NADPH/NADP+ ratio, and glutathione. Activation of the KEAP1/NRF2 axis in LKB1-deficient cells enhanced cell survival and played a critical role in the maintenance of energetic and redox homeostasis in a glutamine-dependent manner. LKB1 and the KEAP1/NRF2 pathways cooperatively drove metabolic reprogramming and enhanced sensitivity to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, these findings elucidate the adaptive advantage provided by KEAP1/NRF2 pathway activation in KL tumors and support clinical testing of glutaminase inhibitor in subsets of KRAS-mutant lung adenocarcinoma.
Significance:
In KRAS-mutant non–small cell lung cancer, LKB1 loss results in enhanced energetic/redox stress, which is tolerated, in part, through cooccurring KEAP1/NRF2–dependent metabolic adaptations, thus enhancing glutamine dependence and vulnerability to glutaminase inhibition.
Data from Sphingosine Kinase 1 Signaling Promotes Metastasis of Triple-Negative Breast Cancer
Authors: Acharya Sunil , Yao Jun , Li Ping , Zhang Chenyu , Lowery Frank J. , Zhang Qingling , Guo Hua , Qu Jingkun , Yang Fei , Wistuba Ignacio I. , Piwnica-Worms Helen , Sahin Aysegul A. , Yu Dihua
Published: March 2023

Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. To identify TNBC therapeutic targets, we performed integrative bioinformatics analysis of multiple breast cancer patient-derived gene expression datasets and focused on kinases with FDA-approved or in-pipeline inhibitors. Sphingosine kinase 1 (SPHK1) was identified as a top candidate. SPHK1 overexpression or downregulation in human TNBC cell lines increased or decreased spontaneous metastasis to lungs in nude mice, respectively. SPHK1 promoted metastasis by transcriptionally upregulating the expression of the metastasis-promoting gene FSCN1 via NFκB activation. Activation of the SPHK1/NFκB/FSCN1 signaling pathway was associated with distance metastasis and poor clinical outcome in patients with TNBC. Targeting SPHK1 and NFκB using clinically applicable inhibitors (safingol and bortezomib, respectively) significantly inhibited aggressive mammary tumor growth and spontaneous lung metastasis in orthotopic syngeneic TNBC mouse models. These findings highlight SPHK1 and its downstream target, NFκB, as promising therapeutic targets in TNBC.
Significance:
SPHK1 is overexpressed in TNBC and promotes metastasis, targeting SPHK1 or its downstream target NFκB with clinically available inhibitors could be effective for inhibiting TNBC metastasis.
Data from Glucocorticoid Receptor Signaling Activates TEAD4 to Promote Breast Cancer Progression
Authors: He Lingli , Yuan Liang , Sun Yang , Wang Pingyang , Zhang Hailin , Feng Xue , Wang Zuoyun , Zhang Wenxiang , Yang Chuanyu , Zeng Yi Arial , Zhao Yun , Chen Ceshi , Zhang Lei
Published: March 2023

Abstract
The Hippo pathway plays a critical role in cell growth and tumorigenesis. The activity of TEA domain transcription factor 4 (TEAD4) determines the output of Hippo signaling; however, the regulation and function of TEAD4 has not been explored extensively. Here, we identified glucocorticoids (GC) as novel activators of TEAD4. GC treatment facilitated glucocorticoid receptor (GR)-dependent nuclear accumulation and transcriptional activation of TEAD4. TEAD4 positively correlated with GR expression in human breast cancer, and high expression of TEAD4 predicted poor survival of patients with breast cancer. Mechanistically, GC activation promoted GR interaction with TEAD4, forming a complex that was recruited to the TEAD4 promoter to boost its own expression. Functionally, the activation of TEAD4 by GC promoted breast cancer stem cells maintenance, cell survival, metastasis, and chemoresistance both in vitro and in vivo. Pharmacologic inhibition of TEAD4 inhibited GC-induced breast cancer chemoresistance. In conclusion, our study reveals a novel regulation and functional role of TEAD4 in breast cancer and proposes a potential new strategy for breast cancer therapy.
Significance:
This study provides new insight into the role of glucocorticoid signaling in breast cancer, with potential for clinical translation.