bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from USP48 Is Upregulated by Mettl14 to Attenuate Hepatocellular Carcinoma via Regulating SIRT6 Stabilization
Authors: Du Lutao , Li Yang , Kang Min , Feng Maoxiao , Ren Yidan , Dai Hongliang , Wang Yumin , Wang Yunshan , Tang Bo
Published: March 2023

Abstract
Exploiting cancer metabolism for the clinical benefit of patients with hepatocellular carcinoma (HCC) is a topic under active investigation. Ubiquitin-specific peptidase 48 (USP48), a member of the ubiquitin-specific protease family, is involved in tumor growth, inflammation, and genome stability. However, the role of USP48 in HCC tumorigenesis remains unknown. In this study, we report that expression of USP48 is downregulated in diethylnitrosamine-induced liver tumorigenesis in mice as well as in human HCC. USP48 physically bound and stabilized SIRT6 by K48-linked deubiquitination at the K33 and K128 sites of SIRT6, which impeded metabolic reprogramming to hamper HCC tumorigenesis. Moreover, methyltransferase-like 14 (Mettl14)–induced m6A modification participated in the regulation of USP48 in HCC by maintaining USP48 mRNA stability. Our work uncovers the tumor-suppressive function of the Mettl14–USP48–SIRT6 axis via modulation of glycolysis, providing new insights into the critical roles of metabolic activities in HCC and identifying an attractive target for future treatment studies.
Significance:
These findings demonstrate that USP48 is regulated by Mettl14-induced m6A modification and stabilizes SIRT6 to attenuate HCC glycolysis and malignancy.
Data from Peripheral Nerve Resident Macrophages and Schwann Cells Mediate Cancer-Induced Pain
Authors: De Logu Francesco , Marini Matilde , Landini Lorenzo , Souza Monteiro de Araujo Daniel , Bartalucci Niccolò , Trevisan Gabriela , Bruno Gennaro , Marangoni Martina , Schmidt Brian L. , Bunnett Nigel W. , Geppetti Pierangelo , Nassini Romina
Published: March 2023

Abstract
Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of Trpa1 revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain.
Significance:
Schwann cell TRPA1 sustains cancer pain through release of M-CSF and oxidative stress, which promote the expansion and the proalgesic actions of intraneural macrophages.
Data from mTOR Activation Initiates Renal Cell Carcinoma Development by Coordinating ERK and p38MAPK
Authors: Wu Hongguang , He Dan , Biswas Soma , Shafiquzzaman Md , Zhou Xin , Charron Jean , Wang Yibin , Nayak Bijaya K. , Habib Samy L. , Liu Huijuan , Li Baojie
Published: March 2023

Abstract
Renal cell carcinoma (RCC) mainly originates from renal proximal tubules. Intriguingly, disruption of genes frequently mutated in human RCC samples thus far has only generated RCC originated from other renal tubule parts in mouse models. This hampers our understanding of the pathogenesis of RCC. Here we show that mTOR signaling, often activated in RCC samples, initiates RCC development from renal proximal tubules. Ablation of Tsc1, encoding an mTOR suppressor, in proximal tubule cells led to multiple precancerous renal cysts. mTOR activation increased MEK1 expression and ERK activation, and Mek1 ablation or inhibition diminished cyst formation in Tsc1-deficient mice. mTOR activation also increased MKK6 expression and p38MAPK activation, and ablation of the p38α-encoding gene further enhanced cyst formation and led to RCC with clear cell RCC features. Mechanistically, Tsc1 deletion induced p53 and p16 expression in a p38MAPK-dependent manner, and deleting Tsc1 and Trp53 or Cdkn2a (encoding p16) enhanced renal cell carcinogenesis. Thus, mTOR activation in combination with inactivation of the p38MAPK–p53/p16 pathway drives RCC development from renal proximal tubules. Moreover, this study uncovers previously unidentified mechanisms by which mTOR controls cell proliferation and suggests the MEK–ERK axis to be a potential target for treatment of RCC.
Significance:
Mouse modeling studies show that mTOR activation in combination with inactivation of the p38MAPK–p53/p16 axis initiates renal cell carcinoma that mimics human disease, identifying potential therapeutic targets for RCC treatment.
Data from An AIB1 Isoform Alters Enhancer Access and Enables Progression of Early-Stage Triple-Negative Breast Cancer
Authors: Sharif Ghada M. , Campbell Moray J. , Nasir Apsra , Sengupta Surojeet , Graham Garrett T. , Kushner Max H. , Kietzman William B. , Schmidt Marcel O. , Pearson Gray W. , Loudig Olivier , Fineberg Susan , Wellstein Anton , Riegel Anna T.
Published: March 2023

Abstract
AIB1Δ4 is an N-terminally truncated isoform of the oncogene amplified in breast cancer 1 (AIB1) with increased expression in high-grade human ductal carcinoma in situ (DCIS). However, the role of AIB1Δ4 in DCIS malignant progression has not been defined. Here we CRISPR-engineered RNA splice junctions to produce normal and early-stage DCIS breast epithelial cells that expressed only AIB1Δ4. These cells showed enhanced motility and invasion in 3D cell culture. In zebrafish, AIB1Δ4-expressing cells enabled invasion of parental cells when present in a mixed population. In mouse xenografts, a subpopulation of AIB1Δ4 cells mixed with parental cells enhanced tumor growth, recurrence, and lung metastasis. AIB1Δ4 chromatin immunoprecipitation sequencing revealed enhanced binding to regions including peroxisome proliferator-activated receptor (PPAR) and glucocorticoid receptor (GR) genomic recognition sites. H3K27ac and H3K4me1 genomic engagement patterns revealed selective activation of breast cancer-specific enhancer sites by AIB1Δ4. AIB1Δ4 cells displayed upregulated inflammatory response genes and downregulated PPAR signaling gene expression patterns. In the presence of AIB1Δ4 enabler cells, parental cells increased NF-κB and WNT signaling. Cellular cross-talk was inhibited by the PPARγ agonist efatutazone but was enhanced by treatment with the GR agonist dexamethasone. In conclusion, expression of the AIB1Δ4-selective cistrome in a small subpopulation of cells triggers an “enabler” phenotype hallmarked by an invasive transcriptional program and collective malignant progression in a heterogeneous tumor population.
Significance:
A minor subset of early-stage breast cancer cells expressing AIB1Δ4 enables bulk tumor cells to become invasive, suggesting that selective eradication of this population could impair breast cancer metastasis.
Data from Nuclear Receptor Coactivator NCOA3 Regulates UV Radiation–Induced DNA Damage and Melanoma Susceptibility
Authors: de Semir David , Bezrookove Vladimir , Nosrati Mehdi , Dar Altaf A. , Miller James R. , Leong Stanley P. , Kim Kevin B. , Liao Wilson , Soroceanu Liliana , McAllister Sean , Debs Robert J. , Schadendorf Dirk , Leachman Sancy A. , Cleaver James E. , Kashani-Sabet Mohammed
Published: March 2023

Abstract
Melanoma occurs as a consequence of inherited susceptibility to the disease and exposure to UV radiation (UVR) and is characterized by uncontrolled cellular proliferation and a high mutational load. The precise mechanisms by which UVR contributes to the development of melanoma remain poorly understood. Here we show that activation of nuclear receptor coactivator 3 (NCOA3) promotes melanomagenesis through regulation of UVR sensitivity, cell-cycle progression, and circumvention of the DNA damage response (DDR). Downregulation of NCOA3 expression, either by genetic silencing or small-molecule inhibition, significantly suppressed melanoma proliferation in melanoma cell lines and patient-derived xenografts. NCOA3 silencing suppressed expression of xeroderma pigmentosum C and increased melanoma cell sensitivity to UVR. Suppression of NCOA3 expression led to activation of DDR effectors and reduced expression of cyclin B1, resulting in G2–M arrest and mitotic catastrophe. A SNP in NCOA3 (T960T) reduced NCOA3 protein expression and was associated with decreased melanoma risk, given a significantly lower prevalence in a familial melanoma cohort than in a control cohort without cancer. Overexpression of wild-type NCOA3 promoted melanocyte survival following UVR and was accompanied by increased levels of UVR-induced DNA damage, both of which were attenuated by overexpression of NCOA3 (T960T). These results describe NCOA3-regulated pathways by which melanoma can develop, with germline NCOA3 polymorphisms enabling enhanced melanocyte survival in the setting of UVR exposure, despite an increased mutational burden. They also identify NCOA3 as a novel therapeutic target for melanoma.
Significance:
This study explores NCOA3 as a regulator of the DDR and a therapeutic target in melanoma, where activation of NCOA3 contributes to melanoma development following exposure to ultraviolet light.
Data from Gene Fusions Create Partner and Collateral Dependencies Essential to Cancer Cell Survival
Authors: Gillani Riaz , Seong Bo Kyung A. , Crowdis Jett , Conway Jake R. , Dharia Neekesh V. , Alimohamed Saif , Haas Brian J. , Han Kyuho , Park Jihye , Dietlein Felix , He Meng Xiao , Imamovic Alma , Ma Clement , Bassik Michael C. , Boehm Jesse S. , Vazquez Francisca , Gusev Alexander , Liu David , Janeway Katherine A. , McFarland James M. , Stegmaier Kimberly , Van Allen Eliezer M.
Published: March 2023

Abstract
Gene fusions frequently result from rearrangements in cancer genomes. In many instances, gene fusions play an important role in oncogenesis; in other instances, they are thought to be passenger events. Although regulatory element rearrangements and copy number alterations resulting from these structural variants are known to lead to transcriptional dysregulation across cancers, the extent to which these events result in functional dependencies with an impact on cancer cell survival is variable. Here we used CRISPR-Cas9 dependency screens to evaluate the fitness impact of 3,277 fusions across 645 cell lines from the Cancer Dependency Map. We found that 35% of cell lines harbored either a fusion partner dependency or a collateral dependency on a gene within the same topologically associating domain as a fusion partner. Fusion-associated dependencies revealed numerous novel oncogenic drivers and clinically translatable alterations. Broadly, fusions can result in partner and collateral dependencies that have biological and clinical relevance across cancer types.
Significance:
This study provides insights into how fusions contribute to fitness in different cancer contexts beyond partner-gene activation events, identifying partner and collateral dependencies that may have direct implications for clinical care.
Data from Loss of KMT5C Promotes EGFR Inhibitor Resistance in NSCLC via LINC01510-Mediated Upregulation of MET
Authors: Pal Arpita S. , Agredo Alejandra , Lanman Nadia A. , Son Jihye , Sohal Ikjot Singh , Bains Manvir , Li Chennan , Clingerman Jenna , Gates Kayla , Kasinski Andrea L.
Published: March 2023

Abstract
EGFR inhibitors (EGFRi) are standard-of-care treatments administered to patients with non–small cell lung cancer (NSCLC) that harbor EGFR alterations. However, development of resistance posttreatment remains a major challenge. Multiple mechanisms can promote survival of EGFRi-treated NSCLC cells, including secondary mutations in EGFR and activation of bypass tracks that circumvent the requirement for EGFR signaling. Nevertheless, the mechanisms involved in bypass signaling activation are understudied and require further elucidation. In this study, we identify that loss of an epigenetic factor, lysine methyltransferase 5C (KMT5C), drives resistance of NSCLC to multiple EGFRis, including erlotinib, gefitinib, afatinib, and osimertinib. KMT5C catalyzed trimethylation of histone H4 lysine 20 (H4K20), a modification required for gene repression and maintenance of heterochromatin. Loss of KMT5C led to upregulation of an oncogenic long noncoding RNA, LINC01510, that promoted transcription of the oncogene MET, a component of a major bypass mechanism involved in EGFRi resistance. These findings underscore the loss of KMT5C as a critical event in driving EGFRi resistance by promoting a LINC01510/MET axis, providing mechanistic insights that could help improve NSCLC treatment.
Significance:
Dysregulation of the epigenetic modifier KMT5C can drive MET-mediated EGFRi resistance, implicating KMT5C loss as a putative biomarker of resistance and H4K20 methylation as a potential target in EGFRi-resistant lung cancer.
Data from PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer
Authors: Chabanon Roman M. , Morel Daphné , Eychenne Thomas , Colmet-Daage Léo , Bajrami Ilirjana , Dorvault Nicolas , Garrido Marlène , Meisenberg Cornelia , Lamb Andrew , Ngo Carine , Hopkins Suzanna R. , Roumeliotis Theodoros I. , Jouny Samuel , Hénon Clémence , Kawai-Kawachi Asuka , Astier Clémence , Konde Asha , Del Nery Elaine , Massard Christophe , Pettitt Stephen J. , Margueron Raphaël , Choudhary Jyoti S. , Almouzni Geneviève , Soria Jean-Charles , Deutsch Eric , Downs Jessica A. , Lord Christopher J. , Postel-Vinay Sophie
Published: March 2023

Abstract
Inactivation of Polybromo 1 (PBRM1), a specific subunit of the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% of clear cell renal cell carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used a series of orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with PBRM1 deficiency. The PBRM1/PARP inhibitor synthetic lethality was recapitulated using several clinical PARP inhibitors in a series of in vitro model systems and in vivo in a xenograft model of ccRCC. In the absence of exogenous DNA damage, PBRM1-defective cells exhibited elevated levels of replication stress, micronuclei, and R-loops. PARP inhibitor exposure exacerbated these phenotypes. Quantitative mass spectrometry revealed that multiple R-loop processing factors were downregulated in PBRM1-defective tumor cells. Exogenous expression of the R-loop resolution enzyme RNase H1 reversed the sensitivity of PBRM1-deficient cells to PARP inhibitors, suggesting that excessive levels of R-loops could be a cause of this synthetic lethality. PARP and ATR inhibitors also induced cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) innate immune signaling in PBRM1-defective tumor cells. Overall, these findings provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers.
Significance:
This study demonstrates that PARP and ATR inhibitors are synthetic lethal with the loss of PBRM1, a PBAF-specific subunit, thus providing the rationale for assessing these inhibitors in patients with PBRM1-defective cancer.
Data from Combined Inhibition of p38MAPK and PIKfyve Synergistically Disrupts Autophagy to Selectively Target Cancer Cells
Authors: O'Connell Constandina E. , Vassilev Alex
Published: March 2023

Abstract
In nutrient-poor conditions, autophagy buffers metabolic stress and counteracts the effects of chemotherapy and radiation on cancer cells, which depend on autophagy for survival. However, clinical trials targeting autophagy have failed to produce successful anticancer treatments using currently available inhibitors. Recent studies have shown that PIKfyve kinase inhibitors disrupt lysosome function in autophagy and can selectively kill certain cancer cells. Analysis of biochemical changes caused by PIKfyve inhibition revealed that resistant cells contain significantly higher levels of cellular p38MAPK protein and phosphorylation. Expression of the lysosomal protein, lysosomal-associated membrane protein 2, carrying phosphomimetic mutations of the p38MAPK phosphorylation sites prevented all effects caused by PIKfyve inhibition–induced lysosome dysfunction. Thus, the activation of p38MAPK in response to PIKfyve inhibition revealed a novel compensatory role in maintaining lysosome function in autophagy. The functional cooperation between the cellular PIKfyve and p38MAPK pathways in regulating lysosome homeostasis was especially important in cancer cells. Combined inhibition of PIKfyve and p38MAPK activities synergistically blocked autophagy-mediated protein degradation, prevented cathepsin maturation, and markedly reduced the viability of multiple cancer cell types without affecting the viability of normal cells. Furthermore, combined PIKfyve and p38MAPK inhibitors synergistically reduced tumor growth in mice bearing xenografts of human colorectal adenocarcinoma, suggesting a novel way to target cancer cells by prolonged inhibition of autophagy using lower drug concentrations.
Significance:
This study demonstrates that PIKfyve and p38MAPK cooperate to regulate lysosome homeostasis and their combined inhibition synergistically blocks autophagy to reduce cancer cell viability in vitro and in vivo.
Data from CRISPR-Mediated Kinome Editing Prioritizes a Synergistic Combination Therapy for FGFR1-Amplified Lung Cancer
Authors: Yang Zhang , Liang Shun-Qing , Yang Haitang , Xu Duo , Bruggmann Rémy , Gao Yanyun , Deng Haibin , Berezowska Sabina , Hall Sean R.R. , Marti Thomas M. , Kocher Gregor J. , Zhou Qinghua , Schmid Ralph A. , Peng Ren-Wang
Published: March 2023

Abstract
Oncogenic activation of the FGFR pathway is frequent in lung and other cancers. However, due to drug resistance, pharmacological blockage of aberrant FGFR signaling has provided little clinical benefit in patients with FGFR-amplified tumors. The determining factors for the limited efficacy of FGFR-targeted therapy remain incompletely understood. In this study, we performed kinome-wide CRISPR/Cas9 loss-of-function screens in FGFR1-amplified lung cancer cells treated with an FGFR inhibitor. These screens identified PLK1 as a potent synthetic lethal target that mediates a resistance mechanism by overriding DNA damage and cell-cycle arrest upon FGFR1 inhibition. Genetic and pharmacological antagonism of PLK1 in combination with FGFR inhibitor therapy synergized to enhance antiproliferative effects and drove cancer cell death in vitro and in vivo through activation of the γH2AX–CHK–E2F1 axis. These findings suggest a previously unappreciated role for PLK1 in modulating FGFR1 inhibitor sensitivity and demonstrate a synergistic drug combination for treating FGFR1-amplified lung cancer.
Significance:
The identification of PLK1 as a potent synthetic lethal target for FGFR-targeted therapy provides an innovative rationale for the treatment of lung and other FGFR1-amplified cancers.
Data from Characterization of Peptides Targeting Metastatic Tumor Cells as Probes for Cancer Detection and Vehicles for Therapy Delivery
Authors: Subramanian Shraddha , Daquinag Alexes C. , AghaAmiri Solmaz , Ghosh Sukhen C. , Azhdarinia Ali , Kolonin Mikhail G.
Published: March 2023

Abstract
Metastasis is the leading cause of cancer-related deaths, and metastatic cancers remain largely incurable due to chemoresistance. Biomarkers of metastatic cells are lacking, and probes that could be used to detect and target metastases would be highly valuable. Here we hypothesize that metastatic cancer cells express cell-surface receptors that can be harnessed for identification of molecules homing to metastases. Screening a combinatorial library in a mouse mammary tumor model of spontaneous metastasis identified cyclic peptides with tropism for cancer cells disseminated to the lungs. Two lead peptides, CLRHSSKIC and CRAGVGRGC, bound murine and human cells derived from breast carcinoma and melanoma in culture and were selective for metastatic cells in vivo. In mice, peptide CRAGVGRGC radiolabeled with 67Ga for biodistribution analysis demonstrated selective probe homing to lung metastases. Moreover, systemic administration of 68Ga-labeled CRAGVGRGC enabled noninvasive imaging of lung metastases in mice by PET. A CRAGVGRGC-derived peptide induced apoptosis upon cell internalization in vitro and suppressed metastatic burden in vivo. Colocalization of CLRHSSKIC and CRAGVGRGC with N-cadherin+/E-cadherin− cells indicated that both peptides are selective for cancer cells that have undergone the epithelial-to-mesenchymal transition. We conclude that CRAGVGRGC is useful as a probe to facilitate the development of imaging modalities and therapies targeting metastases.
Significance:
This study identifies new molecules that bind metastatic cells and demonstrates their application as noninvasive imaging probes and vehicles for cytotoxic therapy delivery in preclinical cancer models.
Data from Genomic Alterations in PIK3CA-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Kα Inhibitors
Authors: Cai Yanyan , Xu Guotai , Wu Fan , Michelini Flavia , Chan Carmen , Qu Xuan , Selenica Pier , Ladewig Erik , Castel Pau , Cheng Yuanming , Zhao Alison , Jhaveri Komal , Toska Eneda , Jimenez Marta , Jacquet Alexandra , Tran-Dien Alicia , Andre Fabrice , Chandarlapaty Sarat , Reis-Filho Jorge S. , Razavi Pedram , Scaltriti Maurizio
Published: March 2023

Abstract
PI3Kα inhibitors have shown clinical activity in PIK3CA-mutated estrogen receptor-positive (ER+) patients with breast cancer. Using whole genome CRISPR/Cas9 sgRNA knockout screens, we identified and validated several negative regulators of mTORC1 whose loss confers resistance to PI3Kα inhibition. Among the top candidates were TSC1, TSC2, TBC1D7, AKT1S1, STK11, MARK2, PDE7A, DEPDC5, NPRL2, NPRL3, C12orf66, SZT2, and ITFG2. Loss of these genes invariably results in sustained mTOR signaling under pharmacologic inhibition of the PI3K–AKT pathway. Moreover, resistance could be prevented or overcome by mTOR inhibition, confirming the causative role of sustained mTOR activity in limiting the sensitivity to PI3Kα inhibition. Cumulatively, genomic alterations affecting these genes are identified in about 15% of PIK3CA-mutated breast tumors and appear to be mutually exclusive. This study improves our understanding of the role of mTOR signaling restoration in leading to resistance to PI3Kα inhibition and proposes therapeutic strategies to prevent or revert this resistance.
Significance:
These findings show that genetic lesions of multiple negative regulators of mTORC1 could limit the efficacy of PI3Kα inhibitors in breast cancer, which may guide patient selection strategies for future clinical trials.
Data from miR-31 Displays Subtype Specificity in Lung Cancer
Authors: Davenport Mackenzie L. , Echols John B. , Silva Austin D. , Anderson Joshua C. , Owens Philip , Yates Clayton , Wei Qing , Harada Shuko , Hurst Douglas R. , Edmonds Mick D.
Published: March 2023

Abstract
miRNA rarely possess pan-oncogenic or tumor-suppressive properties. Most miRNAs function under tissue-specific contexts, acting as either tumor suppressors in one tissue, promoting oncogenesis in another, or having no apparent role in the regulation of processes associated with the hallmarks of cancer. What has been less clear is the role of miRNAs within cell types of the same tissue and the ability within each cell type to contribute to oncogenesis. In this study, we characterize the role of one such tissue-specific miRNA, miR-31, recently identified as the most oncogenic miRNA in lung adenocarcinoma, across the histologic spectrum of human lung cancer. Compared with normal lung tissue, miR-31 was overexpressed in patient lung adenocarcinoma, squamous cell carcinoma, and large-cell neuroendocrine carcinoma, but not small-cell carcinoma or carcinoids. miR-31 promoted tumor growth in mice of xenografted human adenocarcinoma and squamous cell carcinoma cell lines, but not in large- or small-cell carcinoma lines. While miR-31 did not promote primary tumor growth of large- and small-cell carcinoma, it did promote spontaneous metastasis. Mechanistically, miR-31 altered distinct cellular signaling programs within each histologic subtype, resulting in distinct phenotypic differences. This is the first report distinguishing diverse functional roles for this miRNA across the spectrum of lung cancers and suggests that miR-31 has broad clinical value in human lung malignancy.
Significance:
These findings demonstrate the oncogenic properties of miR-31 in specific subtypes of lung cancer and highlight it as a potential therapeutic target in these subtypes.
Data from Genetic Risk for Overall Cancer and the Benefit of Adherence to a Healthy Lifestyle
Authors: Zhu Meng , Wang Tianpei , Huang Yanqian , Zhao Xiaoyu , Ding Yuqing , Zhu Mengyi , Ji Mengmeng , Wang Cheng , Dai Juncheng , Yin Rong , Xu Lin , Ma Hongxia , Wei Qingyi , Jin Guangfu , Hu Zhibin , Shen Hongbing
Published: March 2023

Abstract
Cancer site–specific polygenic risk scores (PRS) effectively identify individuals at high risk of individual cancers, but the effectiveness of PRS on overall cancer risk assessment and the extent to which a high genetic risk of overall cancer can be offset by a healthy lifestyle remain unclear. Here, we constructed an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific PRSs. Lifestyle was determined according to smoking, alcohol consumption, physical activity, body mass index, and diet. Cox regression by sex was used to analyze associations of genetic and lifestyle factors with cancer incidence using UK Biobank data (N = 442,501). Compared with participants at low genetic risk (bottom quintile of CPRS), those at intermediate (quintiles 2 to 4) or high (top quintile) genetic risk had HRs of 1.27 (95% confidence interval, 1.21–1.34) or 1.91 (1.81–2.02) for overall cancer, respectively, for men, and 1.21 (1.16–1.27) or 1.62 (1.54–1.71), respectively, for women. A joint effect of genetic and lifestyle factors on overall cancer risk was observed, with HRs reaching 2.99 (2.45–3.64) for men and 2.38 (2.05–2.76) for women with high genetic risk and unfavorable lifestyle compared with those with low genetic risk and favorable lifestyle. Among participants at high genetic risk, the standardized 5-year cancer incidence was significantly reduced from 7.23% to 5.51% for men and from 5.77% to 3.69% for women having a favorable lifestyle. In summary, individuals at high genetic risk of overall cancer can be identified by CPRS, and risk can be attenuated by adopting a healthy lifestyle.
Significance:
A new indicator of cancer polygenic risk score measures genetic risk for overall cancer, which could identify individuals with high cancer risk to facilitate decision-making about lifestyle modifications for personalized prevention.
Data from Human Endogenous Retrovirus Type K Promotes Proliferation and Confers Sensitivity to Antiretroviral Drugs in Merlin-Negative Schwannoma and Meningioma
Authors: Maze Emmanuel A. , Agit Bora , Reeves Shona , Hilton David A. , Parkinson David B. , Laraba Liyam , Ercolano Emanuela , Kurian Kathreena M. , Hanemann C. Oliver , Belshaw Robert D. , Ammoun Sylwia
Published: March 2023

Abstract
Deficiency of the tumor suppressor Merlin causes development of schwannoma, meningioma, and ependymoma tumors, which can occur spontaneously or in the hereditary disease neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Surgery and radiotherapy are current first-line treatments; however, tumors frequently recur with limited treatment options. Here, we use human Merlin-negative schwannoma and meningioma primary cells to investigate the involvement of the endogenous retrovirus HERV-K in tumor development. HERV-K proteins previously implicated in tumorigenesis were overexpressed in schwannoma and all meningioma grades, and disease-associated CRL4DCAF1 and YAP/TEAD pathways were implicated in this overexpression. In normal Schwann cells, ectopic overexpression of HERV-K Env increased proliferation and upregulated expression of c-Jun and pERK1/2, which are key components of known tumorigenic pathways in schwannoma, JNK/c-Jun, and RAS/RAF/MEK/ERK. Furthermore, FDA-approved retroviral protease inhibitors ritonavir, atazanavir, and lopinavir reduced proliferation of schwannoma and grade I meningioma cells. These results identify HERV-K as a critical regulator of progression in Merlin-deficient tumors and offer potential strategies for therapeutic intervention.
Significance:
The endogenous retrovirus HERV-K activates oncogenic signaling pathways and promotes proliferation of Merlin-deficient schwannomas and meningiomas, which can be targeted with antiretroviral drugs and TEAD inhibitors.
Data from A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair
Authors: Pulver Emilia M. , Mukherjee Chirantani , van de Kamp Gerarda , Roobol Stefan J. , Rother Magdalena B. , van der Gulden Hanneke , de Bruijn Roebi , Lattanzio Maria Valeria , van der Burg Eline , Drenth Anne Paulien , Verkaik Nicole S. , Hahn Kerstin , Klarenbeek Sjoerd , de Korte-Grimmerink Renske , van de Ven Marieke , Pritchard Colin E.J. , Huijbers Ivo J. , Xia Bing , van Gent Dik C. , Essers Jeroen , van Attikum Haico , Ray Chaudhuri Arnab , Bouwman Peter , Jonkers Jos
Published: March 2023

Abstract
The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer.
Significance:
These findings reveal the importance of a patient-derived BRCA1 coiled-coil domain sequence variant in embryonic development, mammary tumor suppression, and therapy response.

See related commentary by Mishra et al., p. 6080
Data from Targeting the IRE1α/XBP1 Endoplasmic Reticulum Stress Response Pathway in ARID1A-Mutant Ovarian Cancers
Authors: Zundell Joseph A. , Fukumoto Takeshi , Lin Jianhuang , Fatkhudinov Nail , Nacarelli Timothy , Kossenkov Andrew V. , Liu Qin , Cassel Joel , Hu Chih-Chi Andrew , Wu Shuai , Zhang Rugang
Published: March 2023

Abstract
The SWI/SNF chromatin-remodeling complex is frequently altered in human cancers. For example, the SWI/SNF component ARID1A is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), for which effective treatments are lacking. Here, we report that ARID1A transcriptionally represses the IRE1α–XBP1 axis of the endoplasmic reticulum (ER) stress response, which confers sensitivity to inhibition of the IRE1α–XBP1 pathway in ARID1A-mutant OCCC. ARID1A mutational status correlated with response to inhibition of the IRE1α–XBP1 pathway. In a conditional Arid1aflox/flox/Pik3caH1047R genetic mouse model, Xbp1 knockout significantly improved survival of mice bearing OCCCs. Furthermore, the IRE1α inhibitor B-I09 suppressed the growth of ARID1A-inactivated OCCCs in vivo in orthotopic xenograft, patient-derived xenograft, and the genetic mouse models. Finally, B-I09 synergized with inhibition of HDAC6, a known regulator of the ER stress response, in suppressing the growth of ARID1A-inactivated OCCCs. These studies define the IRE1α−XBP1 axis of the ER stress response as a targetable vulnerability for ARID1A-mutant OCCCs, revealing a promising therapeutic approach for treating ARID1A-mutant ovarian cancers.
Significance:
These findings indicate that pharmacological inhibition of the IRE1α–XBP1 pathway alone or in combination with HDAC6 inhibition represents an urgently needed therapeutic strategy for ARID1A-mutant ovarian cancers.
Data from Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity
Authors: Grisaru-Tal Sharon , Dulberg Shai , Beck Lir , Zhang Chunyan , Itan Michal , Hediyeh-zadeh Soroor , Caldwell Julie , Rozenberg Perri , Dolitzky Avishay , Avlas Shmuel , Hazut Inbal , Gordon Yaara , Shani Ophir , Tsuriel Shlomo , Gerlic Motti , Erez Neta , Jacquelot Nicolas , Belz Gabrielle T. , Rothenberg Marc E. , Davis Melissa J. , Yu Hua , Geiger Tamar , Madi Asaf , Munitz Ariel
Published: March 2023

Abstract
The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastases are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein–coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated antitumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing antitumorigenic eosinophil activities. Specifically, TNFα/IFNγ–activated eosinophils facilitated CD4+ and CD8+ T-cell infiltration and promoted antitumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt antitumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics.
Significance:
These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer.
Data from Network Analysis Identifies Regulators of Basal-Like Breast Cancer Reprogramming and Endocrine Therapy Vulnerability
Authors: Choi Sea R. , Hwang Chae Young , Lee Jonghoon , Cho Kwang-Hyun
Published: March 2023

Abstract
Basal-like breast cancer is the most aggressive breast cancer subtype with the worst prognosis. Despite its high recurrence rate, chemotherapy is the only treatment for basal-like breast cancer, which lacks expression of hormone receptors. In contrast, luminal A tumors express ERα and can undergo endocrine therapy for treatment. Previous studies have tried to develop effective treatments for basal-like patients using various therapeutics but failed due to the complex and dynamic nature of the disease. In this study, we performed a transcriptomic analysis of patients with breast cancer to construct a simplified but essential molecular regulatory network model. Network control analysis identified potential targets and elucidated the underlying mechanisms of reprogramming basal-like cancer cells into luminal A cells. Inhibition of BCL11A and HDAC1/2 effectively drove basal-like cells to transition to luminal A cells and increased ERα expression, leading to increased tamoxifen sensitivity. High expression of BCL11A and HDAC1/2 correlated with poor prognosis in patients with breast cancer. These findings identify mechanisms regulating breast cancer phenotypes and suggest the potential to reprogram basal-like breast cancer cells to enhance their targetability.
Significance:
A network model enables investigation of mechanisms regulating the basal-to-luminal transition in breast cancer, identifying BCL11A and HDAC1/2 as optimal targets that can induce basal-like breast cancer reprogramming and endocrine therapy sensitivity.
Data from ASO-Based PKM Splice-Switching Therapy Inhibits Hepatocellular Carcinoma Growth
Authors: Ma Wai Kit , Voss Dillon M. , Scharner Juergen , Costa Ana S.H. , Lin Kuan-Ting , Jeon Hyun Yong , Wilkinson John E. , Jackson Michaela , Rigo Frank , Bennett C. Frank , Krainer Adrian R.
Published: March 2023

Abstract
The M2 pyruvate kinase (PKM2) isoform is upregulated in most cancers and plays a crucial role in regulation of the Warburg effect, which is characterized by the preference for aerobic glycolysis over oxidative phosphorylation for energy metabolism. PKM2 is an alternative-splice isoform of the PKM gene and is a potential therapeutic target. Antisense oligonucleotides (ASO) that switch PKM splicing from the cancer-associated PKM2 to the PKM1 isoform have been shown to induce apoptosis in cultured glioblastoma cells when delivered by lipofection. Here, we explore the potential of ASO-based PKM splice switching as a targeted therapy for liver cancer. A more potent lead constrained-ethyl (cEt)/DNA ASO induced PKM splice switching and inhibited the growth of cultured hepatocellular carcinoma (HCC) cells. This PKM isoform switch increased pyruvate-kinase activity and altered glucose metabolism. In an orthotopic HCC xenograft mouse model, the lead ASO and a second ASO targeting a nonoverlapping site inhibited tumor growth. Finally, in a genetic HCC mouse model, a surrogate mouse-specific ASO induced Pkm splice switching and inhibited tumorigenesis, without observable toxicity. These results lay the groundwork for a potential ASO-based splicing therapy for HCC.
Significance:
Antisense oligonucleotides are used to induce a change in PKM isoform usage in hepatocellular carcinoma, reversing the Warburg effect and inhibiting tumorigenesis.
Data from Targeting Cellular Iron Homeostasis with Ironomycin in Diffuse Large B-cell Lymphoma
Authors: Devin Julie , Cañeque Tatiana , Lin Yea-Lih , Mondoulet Lucie , Veyrune Jean-Luc , Abouladze Matthieu , Garcia De Paco Elvira , Karmous Gadacha Ouissem , Cartron Guillaume , Pasero Philippe , Bret Caroline , Rodriguez Raphaël , Moreaux Jerome
Published: March 2023

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common hematological malignancy. Although more than half of patients with DLBCL achieve long-term remission, the majority of remaining patients succumb to the disease. As abnormal iron homeostasis is implicated in carcinogenesis and the progression of many tumors, we searched for alterations in iron metabolism in DLBCL that could be exploited to develop novel therapeutic strategies. Analysis of the iron metabolism gene expression profile of large cohorts of patients with DLBCL established the iron score (IS), a gene expression–based risk score enabling identification of patients with DLBCL with a poor outcome who might benefit from a suitable targeted therapy. In a panel of 16 DLBCL cell lines, ironomycin, a promising lysosomal iron-targeting small molecule, inhibited DLBCL cell proliferation at nanomolar concentrations compared with typical iron chelators. Ironomycin also induced significant cell growth inhibition, ferroptosis, and autophagy. Ironomycin treatment resulted in accumulation of DNA double-strand breaks, delayed progression of replication forks, and increased RPA2 phosphorylation, a marker of replication stress. Ironomycin significantly reduced the median number of viable primary DLBCL cells of patients without major toxicity for nontumor cells from the microenvironment and presented low toxicity in hematopoietic progenitors compared with conventional treatments. Significant synergistic effects were also observed by combining ironomycin with doxorubicin, BH3 mimetics, BTK inhibitors, or Syk inhibitors. Altogether, these data demonstrate that a subgroup of high-risk patients with DLBCL can be identified with the IS that can potentially benefit from targeting iron homeostasis.
Significance:
Iron homeostasis represents a potential therapeutic target for high-risk patients with DLBCL that can be targeted with ironomycin to induce cell death and to sensitize tumor cells to conventional treatments.
Data from A Fusion Transcription Factor–Driven Cancer Progresses to a Fusion-Independent Relapse via Constitutive Activation of a Downstream Transcriptional Target
Authors: Boudjadi Salah , Pandey Puspa Raj , Chatterjee Bishwanath , Nguyen Thanh Hung , Sun Wenyue , Barr Frederic G.
Published: March 2023

Abstract
Targeted monotherapies usually fail due to development of resistance by a subgroup of cells that evolve into recurrent tumors. Alveolar rhabdomyosarcoma is an aggressive myogenic soft-tissue cancer that is associated with a characteristic PAX3-FOXO1 gene fusion encoding a novel fusion transcription factor. In our myoblast model of PAX3-FOXO1–induced rhabdomyosarcoma, deinduction of PAX3-FOXO1 simulates a targeted therapy that antagonizes the fusion oncoprotein. This simulated therapy results initially in regression of the primary tumors, but PAX3-FOXO1–independent recurrent tumors eventually form after a delay. We report here that upregulation of FGF8, a direct transcriptional target of PAX3-FOXO1, is a mechanism responsible for PAX3-FOXO1–independent tumor recurrence. As a transcriptional target of PAX3-FOXO1, FGF8 promoted oncogenic activity in PAX3-FOXO1–expressing primary tumors that developed in the myoblast system. In the recurrent tumors forming after PAX3-FOXO1 deinduction, FGF8 expression was necessary and sufficient to induce PAX3-FOXO1–independent tumor growth through an autocrine mechanism. FGF8 was also expressed in human PAX3-FOXO1–expressing rhabdomyosarcoma cell lines and contributed to proliferation and transformation. In a human rhabdomyosarcoma cell line with reduced PAX3-FOXO1 expression, FGF8 upregulation rescued oncogenicity and simulated recurrence after PAX3-FOXO1–targeted therapy. We propose that deregulated expression of a PAX3-FOXO1 transcriptional target can generate resistance to therapy directed against this oncogenic transcription factor and postulate that this resistance mechanism may ultimately be countered by therapeutic approaches that antagonize the corresponding downstream pathways.
Significance:
In a model of cancer initiated by a fusion transcription factor, constitutive activation of a downstream transcriptional target leads to fusion oncoprotein-independent recurrences, thereby highlighting a novel progression mechanism and therapeutic target.
Data from Association of Genetic Ancestry and Molecular Signatures with Cancer Survival Disparities: A Pan-Cancer Analysis
Authors: Lee Kara Keun , Rishishwar Lavanya , Ban Dongjo , Nagar Shashwat Deepali , Mariño-Ramírez Leonardo , McDonald John F. , Jordan I. King
Published: March 2023

Abstract
While overall cancer mortality has steadily decreased in recent decades, cancer health disparities among racial and ethnic population groups persist. Here we studied the relationship between cancer survival disparities (CSD), genetic ancestry (GA), and tumor molecular signatures across 33 cancers in a cohort of 9,818 patients. GA correlated with race and ethnicity but showed observable differences in effects on CSD, with significant associations identified in four cancer types: breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSCC), kidney renal clear cell carcinoma (KIRC), and skin cutaneous carcinoma (SKCM). Differential gene expression and methylation between ancestry groups associated cancer-related genes with CSD, of which, seven protein-coding genes [progestin and adipoQ receptor family member 6 (PAQR6), Lck-interacting transmembrane adaptor 1 (LIME1), Sin3A-associated protein 25 (SAP25), MAX dimerization protein 3 (MXD3), coiled-coil glutamate rich protein 2 (CCER2), refilin A (RFLNA), and cathepsin W (CTSW)] significantly interacted with GA and exacerbated observed survival disparities. These findings indicated that regulatory changes mediated by epigenetic mechanisms have a greater contribution to CSD than population-specific mutations. Overall, we uncovered various molecular mechanisms through which GA might impact CSD, revealing potential population-specific therapeutic targets for groups disproportionately burdened by cancer.
Significance:
This large-cohort, multicancer study identifies four cancer types with cancer survival disparities and seven cancer-related genes that interact with genetic ancestry and contribute to disparities.
Data from Combinatorial Inactivation of Tumor Suppressors Efficiently Initiates Lung Adenocarcinoma with Therapeutic Vulnerabilities
Authors: Yousefi Maryam , Boross Gábor , Weiss Carly , Murray Christopher W. , Hebert Jess D. , Cai Hongchen , Ashkin Emily L. , Karmakar Saswati , Andrejka Laura , Chen Leo , Wang Minwei , Tsai Min K. , Lin Wen-Yang , Li Chuan , Yakhchalian Pegah , Colón Caterina I. , Chew Su-Kit , Chu Pauline , Swanton Charles , Kunder Christian A. , Petrov Dmitri A. , Winslow Monte M.
Published: March 2023

Abstract
Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most common subtype. Many oncogenes and tumor suppressor genes are altered in this cancer type, and the discovery of oncogene mutations has led to the development of targeted therapies that have improved clinical outcomes. However, a large fraction of lung adenocarcinomas lacks mutations in known oncogenes, and the genesis and treatment of these oncogene-negative tumors remain enigmatic. Here, we perform iterative in vivo functional screens using quantitative autochthonous mouse model systems to uncover the genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Generation of hundreds of diverse combinations of tumor suppressor alterations demonstrates that inactivation of suppressors of the RAS and PI3K pathways drives the development of oncogene-negative lung adenocarcinoma. Human genomic data and histology identified RAS/MAPK and PI3K pathway activation as a common feature of an event in oncogene-negative human lung adenocarcinomas. These Onc-negativeRAS/PI3K tumors and related cell lines are vulnerable to pharmacologic inhibition of these signaling axes. These results transform our understanding of this prevalent yet understudied subtype of lung adenocarcinoma.
Significance:
To address the large fraction of lung adenocarcinomas lacking mutations in proto-oncogenes for which targeted therapies are unavailable, this work uncovers driver pathways of oncogene-negative lung adenocarcinomas and demonstrates their therapeutic vulnerabilities.