bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from G-Protein-Coupled Estrogen Receptor 1 Promotes Gender Disparities in Hepatocellular Carcinoma via Modulation of SIN1 and mTOR Complex 2 Activity
Authors: Feng Guanying , Cai Jingshu , Huang Yunchuanxiang , Zhu Xianjun , Gong Bo , Yang Zhenglin , Yan Chunhong , Hu Zhuowei , Yang Lu , Wang Ziyan
Published: March 2024

Abstract
Due to its intricate heterogeneity and limited treatment, hepatocellular carcinoma (HCC) has been considered a major cause of cancer-related mortality worldwide. Increasing evidence indicates that G-protein-coupled estrogen receptor 1 (GPER1) can promote estrogen-dependent hepatocellular proliferation by activating AKT signaling. The mTOR complex 2 (mTORC2), whose integrity and activity are modulated by its subunit Sin1, controls the activation of AKT by phosphorylation at position S473. In this study, we investigate the modulation of Sin1 and how estrogen signaling may influence the mTORC2–AKT cascade in HCC cells and a DEN-induced mouse model. We have found that estradiol-dependent Sin1 expression is transcriptionally modulated by GPER1 as well as ERα. GPER1 is able to regulate Sin1 stability via nuclear translocation, therefore increasing Sin1–mTORC2–AKT activation. Moreover, Sin1 interacts with ERα and further enhances its transcriptional activity. Sin1 is highly expressed in acute liver injury and in cases of HCC harboring high expression of GPER1 and constitutive activation of mTORC2–AKT signaling. GPER1 inhibition using the antagonist G-15 reverses DEN-induced acute liver injury by suppressing Sin1 expression and mTORC2–AKT activation. Notably, SIN1 expression varies between male and female mice in the context of both liver injury and liver cancer. In addition, high SIN1 expression is predictive of good prognosis in both male and female patients with HCC who are free from hepatitis virus infection and who report low alcohol consumption. Hence, here we demonstrate that Sin1 can be regulated by GPER1 both through nongenomic and indirect genomic signaling.
Implications:
This study suggests that Sin1 may be a novel HCC biomarker which is gender-dependent and sensitive to particular risk factor.
Data from miR-106a Regulates Cell Proliferation and Autophagy by Targeting LKB1 in HPV-16–Associated Cervical Cancer
Authors: Cui Xiujie , Wang Xiao , Zhou Xiaoqing , Jia Jihui , Chen Hanxiang , Zhao Weiming
Published: March 2024

Abstract
miR-106a is aberrantly regulated in various tumors and plays an important role in carcinogenesis. However, the biological role and molecular mechanism by which miR-106a contributes to cervical squamous cell carcinoma (CSCC) remains elusive. In this study, we verified that miR-106a was elevated in both human papilloma virus (HPV) 16-positive CSCC tissues and cell lines. ROC curve analysis showed that miR-106a could well distinguish HPV-16–positive CSCC tissues from normal cervical squamous epithelium tissues. High expression of miR-106a was associated with malignant clinicopathologic parameters in CSCC tissues. Exogenous expression of miR-106a greatly promoted cervical cancer cell proliferation while attenuated autophagy. Furthermore, a novel target of miR-106a, liver kinase B1 (LKB1), a proven tumor suppressor in cervical cancer was verified. Here we confirmed LKB1 was negatively correlated with malignant clinicopathologic parameters in CSCC tissues. Overexpression of LKB1 neutralized the effect of miR-106a on proliferation and autophagy in cervical cancer cell lines. In addition, the role of miR-106a in cell proliferation and autophagy was via LKB1 and its downstream pathway AMP-activated protein kinase-mammalian target of rapamycin. Of note, miR-106a was upregulated by HPV-16 E7 protein. The function of HPV-16 E7 to cell proliferation was suppressed when knockdown miR-106a in HPV-16 E7–expressing cells.
Implications:
Our study highlights the tumorigenic role and regulatory mechanism of miR-106a in CSCC. miR-106a may be a potential therapeutic target in HPV-associated cervical cancer.
Data from Prostate Epithelial RON Signaling Promotes M2 Macrophage Activation to Drive Prostate Tumor Growth and Progression
Authors: Sullivan Camille , Brown Nicholas E. , Vasiliauskas Juozas , Pathrose Peterson , Starnes Sandra L. , Waltz Susan E.
Published: March 2024

Abstract
Effective treatment of advanced prostate cancer persists as a significant clinical need as only 30% of patients with distant disease survive to 5 years after diagnosis. Targeting signaling and tumor cell–immune cell interactions in the tumor microenvironment has led to the development of powerful immunotherapeutic agents, however, the prostate tumor milieu remains impermeable to these strategies highlighting the need for novel therapeutic targets. In this study, we provide compelling evidence to support the role of the RON receptor tyrosine kinase as a major regulator of macrophages in the prostate tumor microenvironment. We show that loss of RON selectively in prostate epithelial cells leads to significantly reduced prostate tumor growth and metastasis and is associated with increased intratumor infiltration of macrophages. We further demonstrate that prostate epithelial RON loss induces transcriptional reprogramming of macrophages to support expression of classical M1 markers and suppress expression of alternative M2 markers. Interestingly, our results show epithelial RON activation drives upregulation of RON expression in macrophages as a positive feed-forward mechanism to support prostate tumor growth. Using 3D coculture assays, we provide additional evidence that epithelial RON expression coordinates interactions between prostate tumor cells and macrophages to promote macrophage-mediated tumor cell growth. Taken together, our results suggest that RON receptor signaling in prostate tumor cells directs the functions of macrophages in the prostate tumor microenvironment to promote prostate cancer.
Implications:
Epithelial RON is a novel immunotherapeutic target that is responsible for directing the macrophage antitumor immune response to support prostate tumor growth and progression.
Data from Phosphorylation of PLCγ1 by EphA2 Receptor Tyrosine Kinase Promotes Tumor Growth in Lung Cancer
Authors: Song Wenqiang , Kim Laura C. , Han Wei , Hou Yuan , Edwards Deanna N. , Wang Shan , Blackwell Timothy S. , Cheng Feixiong , Brantley-Sieders Dana M. , Chen Jin
Published: March 2024

Abstract
EphA2 receptor tyrosine kinase (RTK) is often expressed at high levels in cancer and has been shown to regulate tumor growth and metastasis across multiple tumor types, including non–small cell lung cancer. A number of signaling pathways downstream of EphA2 RTK have been identified; however, mechanisms of EphA2 proximal downstream signals are less well characterized. In this study, we used a yeast-two-hybrid screen to identify phospholipase C gamma 1 (PLCγ1) as a novel EphA2 interactor. EphA2 interacts with PLCγ1 and the kinase activity of EphA2 was required for phosphorylation of PLCγ1. In human lung cancer cells, genetic or pharmacologic inhibition of EphA2 decreased phosphorylation of PLCγ1 and loss of PLCγ1 inhibited tumor cell growth in vitro. Knockout of PLCγ1 by CRISPR-mediated genome editing also impaired tumor growth in a KrasG12D-p53-Lkb1 murine lung tumor model. Collectively, these data show that the EphA2-PLCγ1 signaling axis promotes tumor growth of lung cancer and provides rationale for disruption of this signaling axis as a potential therapeutic option.
Implications:
The EphA2-PLCG1 signaling axis promotes tumor growth of non–small cell lung cancer and can potentially be targeted as a therapeutic option.
Data from Autocrine VEGF/VEGFR1 Signaling in a Subpopulation of Cells Associates with Aggressive Osteosarcoma
Authors: Ohba Tetsuro , Cates Justin M.M. , Cole Heather A. , Slosky David A. , Haro Hirotaka , Ando Takashi , Schwartz Herbert S. , Schoenecker Jonathan G.
Published: March 2024

Abstract
Osteosarcoma is the most common primary bone malignancy and accounts for more than half of primary skeletal malignancies in children and young adults. Although vascular endothelial growth factor (VEGF) expression in osteosarcoma has been associated with poor outcome, its role in the pathogenesis of osteosarcoma remains controversial. Here, VEGF and VEGFR1 expression in both human and murine osteosarcoma cells associated with increasing malignant potential. Autocrine VEGF/VEGFR1 signaling resulted in constitutive activation of VEGFR1 in highly aggressive osteosarcoma cells. In addition, survival and proliferation of highly aggressive osteosarcoma cells was dependent on autocrine VEGF/R1 signaling in vitro. The effect of VEGFR1 expression on in vivo tumor growth and angiogenesis was evaluated by immunoselecting subpopulations of osteosarcoma cells that express high or low levels of VEGFR1. Cell enriched for high VEGFR1 expression showed increased VEGF production, tumor growth, tumor angiogenesis, and osteolysis in vivo. In addition, it was demonstrated that VEGF and VEGFR1 are coexpressed by a subset of tumor cells in human osteosarcoma, similar to what was observed in the murine osteosarcoma cells. These results suggest that autocrine VEGF/VEGFR1 signaling in a subpopulation of tumor cells plays a pivotal role in osteosarcoma progression.

Implications: Aggressive osteosarcoma phenotypes are mediated by autocrine VEGF/VEGFR1 signaling and improved stratification measures and novel anti-angiogenic strategies may benefit this specific tumor type. Mol Cancer Res; 12(8); 1100–11. ©2014 AACR.
Data from Kinase-Dependent and -Independent Roles for PTK6 in Colon Cancer
Authors: Mathur Priya S. , Gierut Jessica J. , Guzman Grace , Xie Hui , Xicola Rosa M. , Llor Xavier , Chastkofsky Michael I. , Perekatt Ansu O. , Tyner Angela L.
Published: March 2024

Abstract
Disruption of the gene encoding Protein Tyrosine Kinase 6 (Ptk6) delayed differentiation and increased growth in the mouse intestine. However, Ptk6-null mice were also resistant to azoxymethane-induced colon tumorigenesis. To further explore functions of PTK6 in colon cancer, expression of epithelial and mesenchymal markers, as well as proliferation, migration, and xenograft tumor growth, was examined in human colon tumor cell lines with knockdown or overexpression of PTK6. PTK6 protein, transcript, and activation were also examined in a human colon tumor tissue array, using immunohistochemistry and qRT-PCR. Knockdown of PTK6 led to the epithelial–mesenchymal transition (EMT) in SW480 and HCT116 cells, whereas overexpression of PTK6 in SW620 cells restored an epithelial phenotype in a kinase-independent manner. PTK6 knockdown also increased xenograft tumor growth of SW480 cells, suggesting tumor suppressor functions. In clinical specimens, PTK6 expression was highest in normal differentiated epithelial cells and reduced in tumors. In contrast, overexpression of constitutively active PTK6 promoted STAT3 and ERK5 activation in colon cancer cells, and endogenous PTK6 promoted cell survival and oncogenic signaling in response to DNA-damaging treatments. These data indicate that PTK6 has complex, context-specific functions in colon cancer; PTK6 promotes the epithelial phenotype to antagonize the EMT in a kinase-independent manner, whereas activation of PTK6 promotes oncogenic signaling.

Implications: Understanding context-specific functions of PTK6 is important, because although it promotes cell survival and oncogenic signaling after DNA damage, expression of PTK6 in established tumors may maintain the epithelial phenotype, preventing tumor progression. Mol Cancer Res; 14(6); 563–73. ©2016 AACR.
Data from Constitutive CHK1 Expression Drives a pSTAT3–CIP2A Circuit that Promotes Glioblastoma Cell Survival and Growth
Authors: Khanna Anchit , Thoms Julie A.I. , Stringer Brett W. , Chung Sylvia A. , Ensbey Kathleen S. , Jue Toni Rose , Jahan Zeenat , Subramanian Shruthi , Anande Govardhan , Shen Han , Unnikrishnan Ashwin , McDonald Kerrie L. , Day Bryan W. , Pimanda John E.
Published: March 2024

Abstract
High-constitutive activity of the DNA damage response protein checkpoint kinase 1 (CHK1) has been shown in glioblastoma (GBM) cell lines and in tissue sections. However, whether constitutive activation and overexpression of CHK1 in GBM plays a functional role in tumorigenesis or has prognostic significance is not known. We interrogated multiple glioma patient cohorts for expression levels of CHK1 and the oncogene cancerous inhibitor of protein phosphatase 2A (CIP2A), a known target of high-CHK1 activity, and examined the relationship between these two proteins in GBM. Expression levels of CHK1 and CIP2A were independent predictors for reduced overall survival across multiple glioma patient cohorts. Using siRNA and pharmacologic inhibitors we evaluated the impact of their depletion using both in vitro and in vivo models and sought a mechanistic explanation for high CIP2A in the presence of high-CHK1 levels in GBM and show that; (i) CHK1 and pSTAT3 positively regulate CIP2A gene expression; (ii) pSTAT3 and CIP2A form a recursively wired transcriptional circuit; and (iii) perturbing CIP2A expression induces GBM cell senescence and retards tumor growth in vitro and in vivo. Taken together, we have identified an oncogenic transcriptional circuit in GBM that can be destabilized by targeting CIP2A.
Implications:
High expression of CIP2A in gliomas is maintained by a CHK1-dependent pSTAT3–CIP2A recursive loop; interrupting CIP2A induces cell senescence and slows GBM growth adding impetus to the development of CIP2A as an anticancer drug target.
Data from A YAP/TAZ-Regulated Molecular Signature Is Associated with Oral Squamous Cell Carcinoma
Authors: Hiemer Samantha E. , Zhang Liye , Kartha Vinay K. , Packer Trevor S. , Almershed Munirah , Noonan Vikki , Kukuruzinska Maria , Bais Manish V. , Monti Stefano , Varelas Xaralabos
Published: March 2024

Abstract
Oral squamous cell carcinoma (OSCC) is a prevalent form of cancer that develops from the epithelium of the oral cavity. OSCC is on the rise worldwide, and death rates associated with the disease are particularly high. Despite progress in understanding the mutational and expression landscape associated with OSCC, advances in deciphering these alterations for the development of therapeutic strategies have been limited. Further insight into the molecular cues that contribute to OSCC is therefore required. Here, we show that the transcriptional regulators YAP (YAP1) and TAZ (WWTR1), which are key effectors of the Hippo pathway, drive protumorigenic signals in OSCC. Regions of premalignant oral tissues exhibit aberrant nuclear YAP accumulation, suggesting that dysregulated YAP activity contributes to the onset of OSCC. Supporting this premise, we determined that nuclear YAP and TAZ activity drives OSCC cell proliferation, survival, and migration in vitro, and is required for OSCC tumor growth and metastasis in vivo. Global gene expression profiles associated with YAP and TAZ knockdown revealed changes in the control of gene expression implicated in protumorigenic signaling, including those required for cell cycle progression and survival. Notably, the transcriptional signature regulated by YAP and TAZ significantly correlates with gene expression changes occurring in human OSCCs identified by The Cancer Genome Atlas (TCGA), emphasizing a central role for YAP and TAZ in OSCC biology.

Implications: This study defines a YAP/TAZ-regulated transcriptional program in OSCC and reveals novel roles for nuclear YAP/TAZ activity in the onset and progression of this cancer. Mol Cancer Res; 13(6); 957–68. ©2015 AACR.
Data from Combined Src/EGFR Inhibition Targets STAT3 Signaling and Induces Stromal Remodeling to Improve Survival in Pancreatic Cancer
Authors: Dosch Austin R. , Dai Xizi , Reyzer Michelle L. , Mehra Siddharth , Srinivasan Supriya , Willobee Brent A. , Kwon Deukwoo , Kashikar Nilesh , Caprioli Richard , Merchant Nipun B. , Nagathihalli Nagaraj S.
Published: March 2024

Abstract
Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics which hinder the delivery of chemotherapeutic drugs into PDAC tumors and mediate resistance to therapy. Previously, we have shown that STAT3 is a key biomarker of therapeutic resistance to gemcitabine treatment in PDAC, which can be overcome by combined inhibition of the Src and EGFR pathways. Although it is well-established that concurrent EGFR and Src inhibition exert these antineoplastic properties through direct inhibition of mitogenic pathways in tumor cells, the influence of this combined therapy on stromal constituents in PDAC tumors remains unknown. In this study, we demonstrate in both orthotopic tumor xenograft and Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mouse models that concurrent EGFR and Src inhibition abrogates STAT3 activation, increases microvessel density, and prevents tissue fibrosis in vivo. Furthermore, the stromal changes induced by parallel EGFR and Src pathway inhibition resulted in improved overall survival in PKT mice when combined with gemcitabine. As a phase I clinical trial utilizing concurrent EGFR and Src inhibition with gemcitabine has recently concluded, these data provide timely translational insight into the novel mechanism of action of this regimen and expand our understanding into the phenomenon of stromal-mediated therapeutic resistance.
Implications:
These findings demonstrate that Src/EGFR inhibition targets STAT3, remodels the tumor stroma, and results in enhanced delivery of gemcitabine to improve overall survival in a mouse model of PDAC.
Data from p53–Pirh2 Complex Promotes Twist1 Degradation and Inhibits EMT
Authors: Yang-Hartwich Yang , Tedja Roslyn , Roberts Cai M. , Goodner-Bingham Jamie , Cardenas Carlos , Gurea Marta , Sumi Natalia J. , Alvero Ayesha B. , Glackin Carlotta A. , Mor Gil
Published: March 2024

Abstract
Epithelial–mesenchymal transition (EMT) is a critical process involved in cancer metastasis and chemoresistance. Twist1 is a key EMT-inducing transcription factor, which is upregulated in multiple types of cancers and has been shown to promote tumor cell invasiveness and support tumor progression. Conversely, p53 is a tumor suppressor gene that is frequently mutated in cancers. This study demonstrates the ability of wild-type (WT) p53 to promote the degradation of Twist1 protein. By forming a complex with Twist1 and the E3 ligase Pirh2, WT p53 promotes the ubiquitination and proteasomal degradation of Twist1, thus inhibiting EMT and maintaining the epithelial phenotype. The ability of p53 to induce Twist1 degradation is abrogated when p53 is mutated. Consequently, the loss of p53-induced Twist1 degradation leads to EMT and the acquisition of a more invasive cancer phenotype.

Implication: These data provide new insight into the metastatic process at the molecular level and suggest a signaling pathway that can potentially be used to develop new prognostic markers and therapeutic targets to curtail cancer progression.
Data from Bone Microenvironment Changes in Latexin Expression Promote Chemoresistance
Authors: Zhang Mi , Osisami Mary , Dai Jinlu , Keller Jill M. , Escara-Wilke June , Mizokami Atsushi , Keller Evan T.
Published: March 2024

Abstract
Although docetaxel is the standard of care for advanced prostate cancer, most patients develop resistance to docetaxel. Therefore, elucidating the mechanism that underlies resistance to docetaxel is critical to enhance therapeutic intervention. Mining cDNA microarray from the PC-3 prostate cancer cell line and its docetaxel-resistant derivative (PC3-TxR) revealed decreased latexin (LXN) expression in the resistant cells. LXN expression was inversely correlated with taxane resistance in a panel of prostate cancer cell lines. LXN knockdown conferred docetaxel resistance to prostate cancer cells in vitro and in vivo, whereas LXN overexpression reduced docetaxel resistance in several prostate cancer cell lines. A mouse model of prostate cancer demonstrated that prostate cancer cells developed resistance to docetaxel in the bone microenvironment, but not the soft tissue microenvironment. This was associated with decreased LXN expression in prostate cancer cells in the bone microenvironment compared with the soft tissue microenvironment. It was identified that bone stromal cells decreased LXN expression through methylation and induced chemoresistance in prostate cancer in vitro. These findings reveal that a subset of prostate cancer develops docetaxel resistance through loss of LXN expression associated with methylation and that the bone microenvironment promotes this drug resistance phenotype.

Implications: This study suggests that the LXN pathway should be further explored as a viable target for preventing or reversing taxane resistance in prostate cancer. Mol Cancer Res; 15(4); 457–66. ©2017 AACR.
Data from Comparative Genomics Reveals Shared Mutational Landscape in Canine Hemangiosarcoma and Human Angiosarcoma
Authors: Megquier Kate , Turner-Maier Jason , Swofford Ross , Kim Jong-Hyuk , Sarver Aaron L. , Wang Chao , Sakthikumar Sharadha , Johnson Jeremy , Koltookian Michele , Lewellen Mitzi , Scott Milcah C. , Schulte Ashley J. , Borst Luke , Tonomura Noriko , Alfoldi Jessica , Painter Corrie , Thomas Rachael , Karlsson Elinor K. , Breen Matthew , Modiano Jaime F. , Elvers Ingegerd , Lindblad-Toh Kerstin
Published: March 2024

Abstract
Angiosarcoma is a highly aggressive cancer of blood vessel–forming cells with few effective treatment options and high patient mortality. It is both rare and heterogenous, making large, well-powered genomic studies nearly impossible. Dogs commonly suffer from a similar cancer, called hemangiosarcoma, with breeds like the golden retriever carrying heritable genetic factors that put them at high risk. If the clinical similarity of canine hemangiosarcoma and human angiosarcoma reflects shared genomic etiology, dogs could be a critically needed model for advancing angiosarcoma research. We assessed the genomic landscape of canine hemangiosarcoma via whole-exome sequencing (47 golden retriever hemangiosarcomas) and RNA sequencing (74 hemangiosarcomas from multiple breeds). Somatic coding mutations occurred most frequently in the tumor suppressor TP53 (59.6% of cases) as well as two genes in the PI3K pathway: the oncogene PIK3CA (29.8%) and its regulatory subunit PIK3R1 (8.5%). The predominant mutational signature was the age-associated deamination of cytosine to thymine. As reported in human angiosarcoma, CDKN2A/B was recurrently deleted and VEGFA, KDR, and KIT recurrently gained. We compared the canine data to human data recently released by The Angiosarcoma Project, and found many of the same genes and pathways significantly enriched for somatic mutations, particularly in breast and visceral angiosarcomas. Canine hemangiosarcoma closely models the genomic landscape of human angiosarcoma of the breast and viscera, and is a powerful tool for investigating the pathogenesis of this devastating disease.
Implications:
We characterize the genomic landscape of canine hemangiosarcoma and demonstrate its similarity to human angiosarcoma.
Data from Calcium Sensor, NCS-1, Promotes Tumor Aggressiveness and Predicts Patient Survival
Authors: Moore Lauren M. , England Allison , Ehrlich Barbara E. , Rimm David L.
Published: March 2024

Abstract
Neuronal Calcium Sensor 1 (NCS-1) is a multi-functional Ca2+-binding protein that affects a range of cellular processes beyond those related to neurons. Functional characterization of NCS-1 in neuronal model systems suggests that NCS-1 may influence oncogenic processes. To this end, the biological role of NCS-1 was investigated by altering its endogenous expression in MCF-7 and MB-231 breast cancer cells. Overexpression of NCS-1 resulted in a more aggressive tumor phenotype demonstrated by a marked increase in invasion and motility, and a decrease in cell-matrix adhesion to collagen IV. Overexpression of NCS-1 was also shown to increase the efficacy of paclitaxel-induced cell death in a manner that was independent of cellular proliferation. To determine the association between NCS-1 and clinical outcome, NCS-1 expression was measured in two independent breast cancer cohorts by the Automated Quantitative Analysis method of quantitative immunofluorescence. Elevated levels of NCS-1 were significantly correlated with shorter survival rates. Furthermore, multivariate analysis demonstrated that NCS-1 status was prognostic, independent of estrogen receptor, progesterone receptor, HER2, and lymph node status. These findings indicate that NCS-1 plays a role in the aggressive behavior of a subset of breast cancers and has therapeutic or biomarker potential.

Implications: NCS-1, a calcium-binding protein, is associated with clinicopathologic features of aggressiveness in breast cancer cells and worse outcome in two breast cancer patient cohorts. Mol Cancer Res; 15(7); 942–52. ©2017 AACR.
Data from Proinflammatory Macrophages Promote Multiple Myeloma Resistance to Bortezomib Therapy
Authors: Beyar-Katz Ofrat , Magidey Ksenia , Reiner-Benaim Anat , Barak Noga , Avivi Irit , Cohen Yael , Timaner Michael , Avraham Shimrit , Hayun Michal , Lavi Noa , Bersudsky Marina , Voronov Elena , Apte Ron N. , Shaked Yuval
Published: March 2024

Abstract
Multiple myeloma (MM) is a plasma cell neoplasia commonly treated with proteasome inhibitors such as bortezomib. Although bortezomib has demonstrated enhanced survival benefit, some patients relapse and subsequently develop resistance to such therapy. Here, we investigate the mechanisms underlying relapse and refractory MM following bortezomib treatment. We show that bortezomib-exposed proinflammatory macrophages promote an enrichment of MM-tumor-initiating cells (MM-TIC) both in vitro and in vivo. These effects are regulated in part by IL1β, as blocking the IL1β axis by a pharmacologic or genetic approach abolishes bortezomib-induced MM-TIC enrichment. In MM patients treated with bortezomib, high proinflammatory macrophages in the bone marrow negatively correlate with survival rates (HR, 1.722; 95% CI, 1.138–2.608). Furthermore, a positive correlation between proinflammatory macrophages and TICs in the bone marrow was also found. Overall, our results uncover a protumorigenic cross-talk involving proinflammatory macrophages and MM cells in response to bortezomib therapy, a process that enriches the MM-TIC population.
Implications:
Our findings suggest that proinflammatory macrophages in bone marrow biopsies represent a potential prognostic biomarker for acquired MM resistance to bortezomib therapy.
Data from Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism
Authors: Valli Alessandro , Morotti Matteo , Zois Christos E. , Albers Patrick K. , Soga Tomoyoshi , Feldinger Katharina , Fischer Roman , Frejno Martin , McIntyre Alan , Bridges Esther , Haider Syed , Buffa Francesca M. , Baban Dilair , Rodriguez Miguel , Yanes Oscar , Whittington Hannah J. , Lake Hannah A. , Zervou Sevasti , Lygate Craig A. , Kessler Benedikt M. , Harris Adrian L.
Published: March 2024

Abstract
Hypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1α is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways. We analyzed pathways that allow cells to survive hypoxic stress in the absence of HIF1α, using the HCT116 colon cancer cell line with deleted HIF1α versus control. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, and proteomic analysis and integrated the results. These showed surprisingly that in three-dimensional growth, a key regulatory step of glycolysis is Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained in hypoxia through upregulation of GLUT14, not previously recognized in this role. Finally, there was a marked adaptation and change of phosphocreatine energy pathways, which made the cells susceptible to inhibition of creatine metabolism in hypoxic conditions. Overall, our studies show a complex adaptation to hypoxia that can bypass HIF1α, but it is targetable and it provides new insight into the key metabolic pathways involved in cancer growth.
Implications:
Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting.
Data from BMP7 Signaling in TGFBR2-Deficient Stromal Cells Provokes Epithelial Carcinogenesis
Authors: Eikesdal Hans Petter , Becker Lisa M. , Teng Yingqi , Kizu Akane , Carstens Julienne L. , Kanasaki Keizo , Sugimoto Hikaru , LeBleu Valerie S. , Kalluri Raghu
Published: March 2024

Abstract
Deregulated transforming growth factor-β (TGFβ) signaling is a common feature of many epithelial cancers. Deletion of TGFβ receptor type 2 (TGFBR2) in fibroblast specific protein-1 (FSP1)-positive stromal cells induces squamous cell carcinoma in the murine forestomach, implicating fibroblast-derived hepatocyte growth factor (HGF) as the major driver of the epithelium carcinogenesis. Prior to cancer development, hyperproliferative FSP1+ fibroblasts lacking TGFBR2 accumulate in the forestomach, disrupting the regulatory signaling cross-talk with the forestomach epithelium. Here, concurrent loss in TGFBR2 and SMAD4 completely abrogates the development of forestomach cancer. Bone morphogenic protein-7 (BMP7) was highly upregulated in forestomach cancer tissue, activating Smad1/5/8 signaling, cell proliferation, and HGF production in TGFBR2-deficient FSP1+ fibroblasts. This stimulation by BMP7 was lost in the combined TGFBR2 and SMAD4 double knockout fibroblasts, which included a profound decrease in HGF expression. Thus, Smad4-mediated signaling is required to initiate epithelial carcinogenesis subsequent to TGFBR2 deletion in FSP1+ fibroblasts.

Implications: These findings reveal a complex cross-talk between epithelial cells and the stroma, wherein Smad4 is required to elicit squamous cell carcinomas in the forestomach of mice with TGFBR2-deficient stromal cells. Mol Cancer Res; 16(10); 1568–78. ©2018 AACR.
Data from YAP Tyrosine Phosphorylation and Nuclear Localization in Cholangiocarcinoma Cells Are Regulated by LCK and Independent of LATS Activity
Authors: Sugihara Takaaki , Werneburg Nathan W. , Hernandez Matthew C. , Yang Lin , Kabashima Ayano , Hirsova Petra , Yohanathan Lavanya , Sosa Carlos , Truty Mark J. , Vasmatzis George , Gores Gregory J. , Smoot Rory L.
Published: March 2024

Abstract
The Hippo pathway effector, Yes-associated protein (YAP), is a transcriptional coactivator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2–LATS1/2) culminating in phosphorylation of YAP at Serine 127 and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression, including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models. Mol Cancer Res; 16(10); 1556–67. ©2018 AACR.
Data from Multiclonality and Marked Branched Evolution of Low-Grade Endometrioid Endometrial Carcinoma
Authors: Lazo de la Vega Lorena , Samaha Mia C. , Hu Kevin , Bick Nolan R. , Siddiqui Javed , Hovelson Daniel H. , Liu Chia-Jen , Carter Cody S. , Cho Kathleen R. , Sciallis Andrew P. , Tomlins Scott A.
Published: March 2024

Abstract
The molecular events driving low-grade endometrioid endometrial carcinoma (LGEC) development—like in many cancers—are incompletely understood. Hence, here we performed multiregion, comprehensive somatic molecular profiling of routinely processed formalin-fixed, paraffin-embedded (FFPE) material from 13 cases of LGEC totaling 64 minute, spatially defined cell populations ranging from presumed precursor lesions through invasive LGEC. Shared driving PTEN, PIK3R1, or PIK3CA mutations support clonal origin of the samples in each case, except for two cases with two clonally distinct neoplastic populations, consistent with unexpected multiclonality in LGEC development. Although substantial heterogeneity in driving somatic alterations was present across populations in nearly all cases, these alterations were usually clonal in a given population, supporting continued selection and clonal sweeping of driving alterations in populations with both precursor and LGEC histology. Importantly, CTNNB1 mutational status, which has been proposed as both prognostic and predictive in LGEC, was frequently heterogeneous and subclonal, occurring both exclusively in precursor or cancer populations in different cases. Whole-transcriptome profiling of coisolated RNA from 12 lesions (from 5 cases) was robust and confirmed histologic and molecular heterogeneity, including activated Wnt signaling in CTNNB1-mutant versus wild-type populations. Taken together, we demonstrate clinically relevant multiclonality and intratumoral heterogeneity during LGEC development with important implications for diagnosis, prognosis, and therapeutic prediction. More broadly, our methodology is broadly scalable to enable high-throughput genomic and transcriptomic characterization of precursor and invasive cancer populations from routine FFPE specimens.
Implications:
Multiregion profiling of LGEC populations using a highly scalable approach demonstrates clinically relevant multiclonality and intratumoral heterogeneity.
Data from Molecular Signature and Mechanisms of Hepatitis D Virus–Associated Hepatocellular Carcinoma
Authors: Diaz Giacomo , Engle Ronald E. , Tice Ashley , Melis Marta , Montenegro Stephanie , Rodriguez-Canales Jaime , Hanson Jeffrey , Emmert-Buck Michael R. , Bock Kevin W. , Moore Ian N. , Zamboni Fausto , Govindarajan Sugantha , Kleiner David E. , Farci Patrizia
Published: March 2024

Abstract
There is limited data on the molecular mechanisms whereby hepatitis D virus (HDV) promotes liver cancer. Therefore, serum and liver specimens obtained at the time of liver transplantation from well-characterized patients with HDV-HCC (n = 5) and with non-HCC HDV cirrhosis (n = 7) were studied using an integrated genomic approach. Transcriptomic profiling was performed using laser capture–microdissected (LCM) malignant and nonmalignant hepatocytes, tumorous and nontumorous liver tissue from patients with HDV-HCC, and liver tissue from patients with non-HCC HDV cirrhosis. HDV-HCC was also compared with hepatitis B virus (HBV) HBV-HCC alone, and hepatitis C virus (HCV) HCV-HCC. HDV malignant hepatocytes were characterized by an enrichment of upregulated transcripts associated with pathways involved in cell-cycle/DNA replication, damage, and repair (Sonic Hedgehog, GADD45, DNA-damage-induced 14-3-3σ, cyclins and cell-cycle regulation, cell cycle: G2–M DNA-damage checkpoint regulation, and hereditary breast cancer). Moreover, a large network of genes identified functionally relate to DNA repair, cell cycle, mitotic apparatus, and cell division, including 4 cancer testis antigen genes, attesting to the critical role of genetic instability in this tumor. Besides being overexpressed, these genes were also strongly coregulated. Gene coregulation was high not only when compared with nonmalignant hepatocytes, but also to malignant hepatocytes from HBV-HCC alone or HCV-HCC. Activation and coregulation of genes critically associated with DNA replication, damage, and repair point to genetic instability as an important mechanism of HDV hepatocarcinogenesis. This specific HDV-HCC trait emerged also from the comparison of the molecular pathways identified for each hepatitis virus–associated HCC. Despite the dependence of HDV on HBV, these findings suggest that HDV and HBV promote carcinogenesis by distinct molecular mechanisms.

Implications: This study identifies a molecular signature of HDV-associated hepatocellular carcinoma and suggests the potential for new biomarkers for early diagnostics. Mol Cancer Res; 16(9); 1406–19. ©2018 AACR.
Data from Chromosome 20q Amplification Defines a Subtype of Microsatellite Stable, Left-Sided Colon Cancers with Wild-type RAS/RAF and Better Overall Survival
Authors: Ptashkin Ryan N. , Pagan Carlos , Yaeger Rona , Middha Sumit , Shia Jinru , O'Rourke Kevin P. , Berger Michael F. , Wang Lu , Cimera Robert , Wang Jiajing , Klimstra David S. , Saltz Leonard , Ladanyi Marc , Zehir Ahmet , Hechtman Jaclyn F.
Published: March 2024

Abstract
Here, comprehensive analysis was performed on the molecular and clinical features of colorectal carcinoma harboring chromosome 20q amplification. Tumor and normal DNA from patients with advanced colorectal carcinoma underwent next-generation sequencing via MSK-IMPACT, and a subset of case samples was subjected to high-resolution microarray (Oncoscan). Relationships between genomic copy number and transcript expression were assessed with The Cancer Genome Atlas (TCGA) colorectal carcinoma data. Of the colorectal carcinoma patients sequenced (n = 401) with MSK-IMPACT, 148 (37%) had 20q gain, and 30 (7%) had 20q amplification. In both the MSK-IMPACT and TCGA datasets, BCL2L1 was the most frequently amplified 20q oncogene. However, SRC was the only recognized 20q oncogene with a significant inverse relationship between mRNA upregulation and RAS/RAF mutation (OR, −0.4 ± 0.2, P = 0.02). In comparison with 20q diploid colorectal carcinoma, 20q gain/amplification was associated with wild-type KRAS (P < 0.001) and BRAF (P = 0.01), microsatellite stability (P < 0.001), distal primary tumors (P < 0.001), and mutant TP53 (P < 0.001), but not stage. On multivariate analysis, longer overall survival from the date of metastasis was observed with chromosome 20q gain (P = 0.02) or amplification (P = 0.04) compared with diploid 20q.

Implications: 20q amplification defines a subset of colorectal cancer patients with better overall survival from the date of metastasis, and further studies are warranted to assess whether the inhibition of 20q oncogenes, such as SRC, may benefit this subset of patients. Mol Cancer Res; 15(6); 708–13. ©2017 AACR.
Data from Identification and Characterization of Oncogenic SOS1 Mutations in Lung Adenocarcinoma
Authors: Cai Diana , Choi Peter S. , Gelbard Maya , Meyerson Matthew
Published: March 2024

Abstract
Lung adenocarcinomas are characterized by mutations in the receptor tyrosine kinase (RTK)/Ras/Raf pathway, with up to 75% of cases containing mutations in known driver genes. However, the driver alterations in the remaining cases are yet to be determined. Recent exome sequencing analysis has identified SOS1, encoding a guanine nucleotide exchange factor, as significantly mutated in lung adenocarcinomas lacking canonical oncogenic RTK/Ras/Raf pathway mutations. Here, we demonstrate that ectopic expression of lung adenocarcinoma–derived mutants of SOS1 induces anchorage-independent cell growth in vitro and tumor formation in vivo. Biochemical experiments suggest that these mutations lead to overactivation of the Ras pathway, which can be suppressed by mutations that disrupt either the Ras-GEF or putative Rac-GEF activity of SOS1. Transcriptional profiling reveals that the expression of mutant SOS1 leads to the upregulation of MYC target genes and genes associated with Ras transformation. Furthermore, we demonstrate that an AML cancer cell line harboring a lung adenocarcinoma–associated mutant SOS1 is dependent on SOS1 for survival and is also sensitive to MEK inhibition. Our work provides experimental evidence for the role of SOS1 as an oncogene and suggests a possible therapeutic strategy to target SOS1-mutated cancers.
Implications:
This study demonstrates that SOS1 mutations found in lung adenocarcinoma are oncogenic and that MEK inhibition may be a therapeutic avenue for the treatment of SOS1-mutant cancers.
Data from Inhibition of Ciliogenesis Promotes Hedgehog Signaling, Tumorigenesis, and Metastasis in Breast Cancer
Authors: Hassounah Nadia B. , Nunez Martha , Fordyce Colleen , Roe Denise , Nagle Ray , Bunch Thomas , McDermott Kimberly M.
Published: March 2024

Abstract
Primary cilia are chemosensors that play a dual role to either activate or repress Hedgehog signaling, depending on presence or absence of ligand, respectively. While inhibition of ciliogenesis has been shown to be characteristic of breast cancers, the functional consequence is unknown. Here, for the first time, inhibition of ciliogenesis led to earlier tumor formation, faster tumor growth rate, higher grade tumor formation, and increased metastasis in the polyoma middle T (PyMT) mouse model of breast cancer. In in vitro model systems, inhibition of ciliogenesis resulted in increased expression of Hedgehog-target genes through a mechanism involving loss of the repressor form of the GLI transcription factor (GLIR) and activation of Hedgehog target gene expression through cross-talk with TGF-alpha (TGFA) signaling. Bioinformatics analysis revealed that increased Hedgehog signaling is frequently associated with increased TGFA; signaling in patients with triple-negative breast cancers (TNBC), a particularly aggressive breast cancer subtype. These results identify a previously unrecognized role for inhibition of ciliogenesis in breast cancer progression. This study identifies inhibition of ciliogenesis as an important event for activation of Hedgehog signaling and progression of breast cancer to a more aggressive, metastatic disease.

Implications: These findings change the way we understand how cancer cells turn on a critical signaling pathways and a provide rationale for developing novel therapeutic approaches to target noncanonical Hedgehog signaling for the treatment of breast cancer. Mol Cancer Res; 15(10); 1421–30. ©2017 AACR.
Data from Pharmacologic Ascorbate Primes Pancreatic Cancer Cells for Death by Rewiring Cellular Energetics and Inducing DNA Damage
Authors: Buranasudja Visarut , Doskey Claire M. , Gibson Adrienne R. , Wagner Brett A. , Du Juan , Gordon David J. , Koppenhafer Stacia L. , Cullen Joseph J. , Buettner Garry R.
Published: March 2024

Abstract
The clinical potential of pharmacologic ascorbate (P-AscH−; intravenous delivery achieving mmol/L concentrations in blood) as an adjuvant in cancer therapy is being reevaluated. At mmol/L concentrations, P-AscH− is thought to exhibit anticancer activity via generation of a flux of H2O2 in tumors, which leads to oxidative distress. Here, we use cell culture models of pancreatic cancer to examine the effects of P-AscH− on DNA damage, and downstream consequences, including changes in bioenergetics. We have found that the high flux of H2O2 produced by P-AscH− induces DNA damage. In response to this DNA damage, we observed that PARP1 is hyperactivated. Using our unique absolute quantitation, we found that P-AscH− mediated the overactivation of PARP1, which results in consumption of NAD+, and subsequently depletion of ATP leading to mitotic cell death. We have also found that Chk1 plays a major role in the maintenance of genomic integrity following treatment with P-AscH−. Hyperactivation of PARP1 and DNA repair are ATP-consuming processes. Using a Seahorse XF96 analyzer, we demonstrated that the severe decrease in ATP after challenging with P-AscH− is because of increased demand, not changes in the rate of production. Genetic deletion and pharmacologic inhibition of PARP1 preserved both NAD+ and ATP; however, the toxicity of P-AscH− remained. These data indicate that disruption of bioenergetics is a secondary factor in the toxicity of P-AscH−; damage to DNA appears to be the primary factor.
Implications:
Efforts to leverage P-AscH− in cancer therapy should first focus on DNA damage.
Data from Therapeutic Effect of Y-27632 on Tumorigenesis and Cisplatin-Induced Peripheral Sensory Loss through RhoA–NF-κB
Authors: Zhu Yi , Howard George A. , Pittman Keith , Boykin Christi , Herring Laura E. , Wilkerson Emily M. , Verbanac Kathryn , Lu Qun
Published: March 2024

Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer therapy that frequently requires a reduction or cessation of treatments and negatively impacts the patient's quality of life. There is currently no effective means to prevent or treat CIPN. In this study, we developed and applied CIPN in an immunocompetent, syngeneic murine Lewis Lung Carcinoma (LLCab) model that enabled the elucidation of both tumor and host responses to cisplatin and treatments of Y-27632, a selective inhibitor of Rho kinase/p160ROCK. Y-27632 not only preserved cisplatin's efficacy toward tumor suppression but also the combination treatment inhibited tumor cell proliferation and increased cellular apoptosis. By alleviating the cisplatin-induced loss of epidermal nerve fibers (ENFs), Y-27632 protected tumor-bearing mice from cisplatin-induced reduction of touch sensation. Furthermore, quantitative proteomic analysis revealed the striking cisplatin-induced dysregulation in cellular stress (inflammation, mitochondrial deficiency, DNA repair, etc.)–associated proteins. Y-27632 was able to reverse the changes of these proteins that are associated with Rho GTPase and NF-κB signaling network, and also decreased cisplatin-induced NF-κB hyperactivation in both footpad tissues and tumor. Therefore, Y-27632 is an effective adjuvant in tumor suppression and peripheral neuroprotection. These studies highlight the potential of targeting the RhoA–NF-κB axis as a combination therapy to treat CIPN.
Implications:
This study, for the first time, demonstrated the dual antineoplastic and neuroprotective effects of Rho kinase/p160ROCK inhibition in a syngeneic immunocompetent tumor-bearing mouse model, opening the door for further clinical adjuvant development of RhoA–NF-κB axis to improve chemotherapeutic outcomes.