首页 > 最新文献

Cancer research最新文献

英文 中文
Editor's Note: Low-Dose Paclitaxel Reduces S100A4 Nuclear Import to Inhibit Invasion and Hematogenous Metastasis of Cholangiocarcinoma. 编者按:小剂量紫杉醇可减少 S100A4 核输入,从而抑制胆管癌的侵袭和血行转移。
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-15 DOI: 10.1158/0008-5472.CAN-24-3017
Massimiliano Cadamuro, Gaia Spagnuolo, Luisa Sambado, Stefano Indraccolo, Giorgia Nardo, Antonio Rosato, Simone Brivio, Chiara Caslini, Tommaso Stecca, Marco Massani, Nicolò Bassi, Eugenio Novelli, Carlo Spirli, Luca Fabris, Mario Strazzabosco
{"title":"Editor's Note: Low-Dose Paclitaxel Reduces S100A4 Nuclear Import to Inhibit Invasion and Hematogenous Metastasis of Cholangiocarcinoma.","authors":"Massimiliano Cadamuro, Gaia Spagnuolo, Luisa Sambado, Stefano Indraccolo, Giorgia Nardo, Antonio Rosato, Simone Brivio, Chiara Caslini, Tommaso Stecca, Marco Massani, Nicolò Bassi, Eugenio Novelli, Carlo Spirli, Luca Fabris, Mario Strazzabosco","doi":"10.1158/0008-5472.CAN-24-3017","DOIUrl":"10.1158/0008-5472.CAN-24-3017","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 22","pages":"3909"},"PeriodicalIF":12.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inflammasome-Activating Nanovaccine for Cancer Immunotherapy. 用于癌症免疫疗法的炎症体激活纳米疫苗
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-15 DOI: 10.1158/0008-5472.CAN-24-2905
Wenyao Zhen, Xiaoyuan Chen

A range of advanced nanovaccines (NV) combined with immunotherapies has recently emerged for treating malignant tumors and has demonstrated promising tumor-suppressive effects. Nevertheless, their effectiveness is often limited by immunosuppression within the tumor microenvironment. To overcome this challenge, new approaches for NV development are required to improve antigen cross-presentation and to remodel the tumor microenvironment. In this issue of Cancer Research, Zhou and colleagues have developed a photo-enhanceable inflammasome-activating nanovaccine (PIN) designed for precise, in situ delivery of a tumor antigen and a hydrophobic small molecule that activates the NLRP3 inflammasome pathway. Near infrared light exposure enables the accumulation of PINs at tumor sites by inducing a photo-triggered charge reversal in the BODIPY-modified PAMAM nanocarrier. Systemic administration of PINs resulted in effective intratumoral activation of the NLRP3 inflammasome and antigen cross-presentation in antigen-presenting cells upon light exposure, leading to enhanced immune responses through increased proinflammatory cytokine production without significant systemic toxicity. Importantly, PINs also enhanced the efficacy of immune checkpoint blockade and promoted the development of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Overall, inflammasome-activating NVs represent a cancer immunotherapy strategy by harnessing the innate immune system to achieve robust responses against tumors. Ongoing research and development are crucial to addressing current limitations and advancing this innovative technology toward clinical application. See related article by Zhou et al., p. 3834.

最近出现了一系列与免疫疗法相结合的先进纳米疫苗(NV),用于治疗恶性肿瘤,并显示出良好的肿瘤抑制效果。然而,它们的有效性往往受到肿瘤微环境中免疫抑制的限制。为了克服这一挑战,需要开发新的 NV 方法来改善抗原交叉呈递和重塑肿瘤微环境。在本期《癌症研究》(Cancer Research)杂志上,Zhou及其同事开发了一种光增强炎性体激活纳米疫苗(PIN),用于原位精确递送肿瘤抗原和疏水性小分子,从而激活NLRP3炎性体通路。近红外线照射可诱导 BODIPY 修饰的 PAMAM 纳米载体发生光触发电荷反转,从而使 PINs 在肿瘤部位聚集。全身给药 PINs 可有效激活肿瘤内的 NLRP3 炎症小体,并在光照射时在抗原递呈细胞中进行抗原交叉递呈,从而通过增加促炎细胞因子的产生来增强免疫反应,而不会产生明显的全身毒性。重要的是,PINs 还能增强免疫检查点阻断的疗效,并促进黑色素瘤和肝细胞癌小鼠模型中长期免疫记忆的发展。总之,炎症体激活 NV 代表了一种癌症免疫疗法策略,它利用先天性免疫系统对肿瘤产生强有力的反应。要解决目前的局限性并推动这项创新技术走向临床应用,持续的研究和开发至关重要。见 Zhou 等人的相关文章,第 3834 页。
{"title":"Inflammasome-Activating Nanovaccine for Cancer Immunotherapy.","authors":"Wenyao Zhen, Xiaoyuan Chen","doi":"10.1158/0008-5472.CAN-24-2905","DOIUrl":"10.1158/0008-5472.CAN-24-2905","url":null,"abstract":"<p><p>A range of advanced nanovaccines (NV) combined with immunotherapies has recently emerged for treating malignant tumors and has demonstrated promising tumor-suppressive effects. Nevertheless, their effectiveness is often limited by immunosuppression within the tumor microenvironment. To overcome this challenge, new approaches for NV development are required to improve antigen cross-presentation and to remodel the tumor microenvironment. In this issue of Cancer Research, Zhou and colleagues have developed a photo-enhanceable inflammasome-activating nanovaccine (PIN) designed for precise, in situ delivery of a tumor antigen and a hydrophobic small molecule that activates the NLRP3 inflammasome pathway. Near infrared light exposure enables the accumulation of PINs at tumor sites by inducing a photo-triggered charge reversal in the BODIPY-modified PAMAM nanocarrier. Systemic administration of PINs resulted in effective intratumoral activation of the NLRP3 inflammasome and antigen cross-presentation in antigen-presenting cells upon light exposure, leading to enhanced immune responses through increased proinflammatory cytokine production without significant systemic toxicity. Importantly, PINs also enhanced the efficacy of immune checkpoint blockade and promoted the development of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Overall, inflammasome-activating NVs represent a cancer immunotherapy strategy by harnessing the innate immune system to achieve robust responses against tumors. Ongoing research and development are crucial to addressing current limitations and advancing this innovative technology toward clinical application. See related article by Zhou et al., p. 3834.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 22","pages":"3709-3711"},"PeriodicalIF":12.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling. 肿瘤相关巨噬细胞中的清道夫受体 CD36 通过抑制 I 型干扰素信号促进癌症进展
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-15 DOI: 10.1158/0008-5472.CAN-23-4027
Ziyan Xu, Alexandra Kuhlmann-Hogan, Shihao Xu, Hubert Tseng, Dan Chen, Shirong Tan, Ming Sun, Victoria Tripple, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M Kaech

Tumor-associated macrophages (TAMs) are a heterogenous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment (TME). In this study, we unveiled a mechanism by which scavenger receptor CD36 suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I interferon (IFN-I) production, mirroring the inverse correlation between CD36 and IFN-I response observed in cancer patients. IFN-I, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFN-I signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacological inhibition of CD36 to rejuvenate anti-tumor immunity.

肿瘤相关巨噬细胞(TAMs)是髓系细胞的一个异质群体,它决定着肿瘤微环境(TME)的炎症基调。本研究揭示了清道夫受体 CD36 抑制 TAM 炎症状态的机制。CD36在TAMs中上调并与免疫抑制特征相关,髓系特异性删除CD36可显著降低肿瘤生长。此外,CD36缺失的TAM获得了炎症特征,包括I型干扰素(IFN-I)分泌升高,这反映了在癌症患者中观察到的CD36与IFN-I反应之间的反相关性。CD36缺陷TAMs产生的IFN-I,尤其是IFNβ,直接诱导肿瘤细胞静止并延缓肿瘤生长。从机理上讲,CD36 通过氧化脂质信号下游的 p38 激活,对巨噬细胞中的 IFN-I 信号起到天然抑制作用。这些发现确定了 CD36 是 TAM 功能和肿瘤炎症微环境的关键调节因子,为药物抑制 CD36 以恢复抗肿瘤免疫力提供了更多的依据。
{"title":"Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling.","authors":"Ziyan Xu, Alexandra Kuhlmann-Hogan, Shihao Xu, Hubert Tseng, Dan Chen, Shirong Tan, Ming Sun, Victoria Tripple, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M Kaech","doi":"10.1158/0008-5472.CAN-23-4027","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-4027","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) are a heterogenous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment (TME). In this study, we unveiled a mechanism by which scavenger receptor CD36 suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I interferon (IFN-I) production, mirroring the inverse correlation between CD36 and IFN-I response observed in cancer patients. IFN-I, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFN-I signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacological inhibition of CD36 to rejuvenate anti-tumor immunity.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tumor heterogeneity and cooperating cancer hallmarks driven by divergent EMT programs. 由不同 EMT 程序驱动的肿瘤异质性和合作性癌症标志。
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-15 DOI: 10.1158/0008-5472.CAN-24-4309
Phoebe Carter, Yibin Kang

Epithelial-to-mesenchymal transition (EMT) is known to play roles in orchestrating cellular plasticity across many physiological and pathological contexts. Partial EMT, wherein cells maintain both epithelial and mesenchymal features, is gaining recognition for its functional importance in cancer in recent years. There are many factors regulating both partial and full EMT, and the precise mechanisms underlying these processes vary depending on the biological context. Furthermore, how different EMT states cooperate to create a heterogeneous tumor population and promote different pro-malignant features remains largely undefined. In a recent study published in Nature Cancer, Youssef and colleagues described how two disparate EMT programs, active in either organ fibrosis or embryonic development, are utilized within different cells within the same murine mammary tumor model. This work provides mechanistic insight into the development of intratumoral heterogeneity, providing evidence for the cooperation between the two EMT trajectories.

众所周知,上皮细胞向间充质细胞的转化(EMT)在许多生理和病理情况下都起着协调细胞可塑性的作用。近年来,部分 EMT(即细胞同时保持上皮和间质特征)在癌症中的功能重要性日益得到认可。调节部分和完全 EMT 的因素有很多,这些过程的确切机制因生物环境而异。此外,不同的 EMT 状态如何相互配合以形成异质性肿瘤群体并促进不同的促恶性特征在很大程度上仍未确定。在最近发表于《自然-癌症》(Nature Cancer)上的一项研究中,Youssef 及其同事描述了在同一鼠乳腺肿瘤模型中,两种不同的 EMT 程序是如何在不同细胞内被利用的,这两种 EMT 程序活跃于器官纤维化或胚胎发育过程中。这项工作从机理上揭示了瘤内异质性的发展,为两种EMT轨迹之间的合作提供了证据。
{"title":"Tumor heterogeneity and cooperating cancer hallmarks driven by divergent EMT programs.","authors":"Phoebe Carter, Yibin Kang","doi":"10.1158/0008-5472.CAN-24-4309","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-4309","url":null,"abstract":"<p><p>Epithelial-to-mesenchymal transition (EMT) is known to play roles in orchestrating cellular plasticity across many physiological and pathological contexts. Partial EMT, wherein cells maintain both epithelial and mesenchymal features, is gaining recognition for its functional importance in cancer in recent years. There are many factors regulating both partial and full EMT, and the precise mechanisms underlying these processes vary depending on the biological context. Furthermore, how different EMT states cooperate to create a heterogeneous tumor population and promote different pro-malignant features remains largely undefined. In a recent study published in Nature Cancer, Youssef and colleagues described how two disparate EMT programs, active in either organ fibrosis or embryonic development, are utilized within different cells within the same murine mammary tumor model. This work provides mechanistic insight into the development of intratumoral heterogeneity, providing evidence for the cooperation between the two EMT trajectories.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Hypoxic Bone Marrow Stromal Cells Secrete miR-140-5p and miR-28-3p That Target SPRED1 to Confer Drug Resistance in Multiple Myeloma. 缺氧骨髓基质细胞分泌miR-140-5p和miR-28-3p靶向SPRED1,赋予多发性骨髓瘤耐药性。
IF 11.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-01-02 DOI: 10.1158/0008-5472.CAN-23-0189
Hui Zhang, Zhimin Du, Chenggong Tu, Xinyan Zhou, Eline Menu, Jinheng Wang

Bone marrow stromal cell (BMSC)-derived small extracellular vesicles (sEV) promote drug resistance to bortezomib in multiple myeloma cells. Elucidating the components of BMSC sEV that induce drug resistance in multiple myeloma cells could help identify strategies to overcome resistance. Considering the hypoxic nature of the myeloma microenvironment, we explored the role of hypoxia in regulating BMSC sEV cargo and investigated whether hypoxia-driven sEV miRNAs contribute to the drug resistance in multiple myeloma cells. Hypoxia increased the release of sEVs from BMSCs, and these sEVs more strongly attenuated bortezomib sensitivity in multiple myeloma cells than sEVs from BMSCs under normoxic conditions. RNA sequencing revealed that significantly elevated levels of miR-140-5p and miR-28-3p were enclosed in hypoxic BMSC-derived sEVs. Both miR-140-5p and miR-28-3p conferred bortezomib resistance in multiple myeloma cells by synergistically targeting SPRED1, a member of the Sprouty protein family that regulates MAPK activation. SPRED1 inhibition reduced sensitivity to bortezomib in multiple myeloma cells through activating MAPK-related pathways and significantly promoted multiple myeloma bortezomib resistance and tumor growth in a mouse model. These findings shed light on the role of hypoxia-induced miRNAs shuttled in BMSC-derived sEVs to multiple myeloma cells in inducing drug resistance and identify the miR-140-5p/miR-28-3p/SPRED1/MAPK pathway as a potential targetable axis for treating multiple myeloma.

Significance: Hypoxia induces stromal cells to secrete extracellular vesicles with increased miR-140-5p and miR-28-3p that are transferred to multiple myeloma cells and drive drug resistance by increasing the MAPK signaling.

骨髓基质细胞(BMSC)衍生的细胞外小泡(sEV)促进多发性骨髓瘤(MM)细胞对硼替佐米的耐药性。阐明BMSC sEV诱导MM细胞耐药性的成分有助于确定克服耐药性的策略。考虑到骨髓瘤微环境的缺氧性质,我们探索了缺氧在调节BMSC sEV货物中的作用,并研究了缺氧驱动的sEV miRNA是否有助于MM细胞的耐药性。低氧增加了骨髓间充质干细胞sEV的释放,并且在常氧条件下,这些sEV比骨髓间充细胞sEV更强烈地减弱了MM细胞中硼替佐米的敏感性。RNA测序显示,miR-140-5p和miR-28-3p水平显著升高,被封闭在缺氧BMSC衍生的sEV中。miR-140-5p和miR-28-3p通过协同靶向SPRED1(调节MAPK激活的Sprouty蛋白家族成员),在MM细胞中赋予硼替佐米抗性。SPRED1抑制通过激活MAPK相关途径降低了MM细胞对硼替佐米的敏感性,并在小鼠模型中显著促进了MM对硼替佐米的耐药性和肿瘤生长。这些发现阐明了缺氧诱导的miRNA在BMSC衍生的sEV到MM细胞中穿梭在诱导耐药性中的作用,并确定miR-140-5p/miR-28-3p/SPRED1/MAPK通路是治疗MM的潜在靶向轴。
{"title":"Hypoxic Bone Marrow Stromal Cells Secrete miR-140-5p and miR-28-3p That Target SPRED1 to Confer Drug Resistance in Multiple Myeloma.","authors":"Hui Zhang, Zhimin Du, Chenggong Tu, Xinyan Zhou, Eline Menu, Jinheng Wang","doi":"10.1158/0008-5472.CAN-23-0189","DOIUrl":"10.1158/0008-5472.CAN-23-0189","url":null,"abstract":"<p><p>Bone marrow stromal cell (BMSC)-derived small extracellular vesicles (sEV) promote drug resistance to bortezomib in multiple myeloma cells. Elucidating the components of BMSC sEV that induce drug resistance in multiple myeloma cells could help identify strategies to overcome resistance. Considering the hypoxic nature of the myeloma microenvironment, we explored the role of hypoxia in regulating BMSC sEV cargo and investigated whether hypoxia-driven sEV miRNAs contribute to the drug resistance in multiple myeloma cells. Hypoxia increased the release of sEVs from BMSCs, and these sEVs more strongly attenuated bortezomib sensitivity in multiple myeloma cells than sEVs from BMSCs under normoxic conditions. RNA sequencing revealed that significantly elevated levels of miR-140-5p and miR-28-3p were enclosed in hypoxic BMSC-derived sEVs. Both miR-140-5p and miR-28-3p conferred bortezomib resistance in multiple myeloma cells by synergistically targeting SPRED1, a member of the Sprouty protein family that regulates MAPK activation. SPRED1 inhibition reduced sensitivity to bortezomib in multiple myeloma cells through activating MAPK-related pathways and significantly promoted multiple myeloma bortezomib resistance and tumor growth in a mouse model. These findings shed light on the role of hypoxia-induced miRNAs shuttled in BMSC-derived sEVs to multiple myeloma cells in inducing drug resistance and identify the miR-140-5p/miR-28-3p/SPRED1/MAPK pathway as a potential targetable axis for treating multiple myeloma.</p><p><strong>Significance: </strong>Hypoxia induces stromal cells to secrete extracellular vesicles with increased miR-140-5p and miR-28-3p that are transferred to multiple myeloma cells and drive drug resistance by increasing the MAPK signaling.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"39-55"},"PeriodicalIF":11.2,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41100779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
XPO1 Enables Adaptive Regulation of mRNA Export Required for Genotoxic Stress Tolerance in Cancer Cells. XPO1能够适应性调节癌症细胞基因毒性应激耐受所需的mRNA输出。
IF 11.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-01-02 DOI: 10.1158/0008-5472.CAN-23-1992
Rossella Marullo, Sarah C Rutherford, Maria V Revuelta, Nahuel Zamponi, Biljana Culjkovic-Kraljacic, Nikita Kotlov, Nicolás Di Siervi, Juan Lara-Garcia, John N Allan, Jia Ruan, Richard R Furman, Zhengming Chen, Tsiporah B Shore, Adrienne A Phillips, Sebastian Mayer, Jingmei Hsu, Koen van Besien, John P Leonard, Katherine L B Borden, Giorgio Inghirami, Peter Martin, Leandro Cerchietti

Exportin-1 (XPO1), the main soluble nuclear export receptor in eukaryotic cells, is frequently overexpressed in diffuse large B-cell lymphoma (DLBCL). A selective XPO1 inhibitor, selinexor, received approval as single agent for relapsed or refractory (R/R) DLBCL. Elucidating the mechanisms by which XPO1 overexpression supports cancer cells could facilitate further clinical development of XPO1 inhibitors. We uncovered here that XPO1 overexpression increases tolerance to genotoxic stress, leading to a poor response to chemoimmunotherapy. Upon DNA damage induced by MYC expression or exogenous compounds, XPO1 bound and exported EIF4E and THOC4 carrying DNA damage repair mRNAs, thereby increasing synthesis of DNA damage repair proteins under conditions of increased turnover. Consequently, XPO1 inhibition decreased the capacity of lymphoma cells to repair DNA damage and ultimately resulted in increased cytotoxicity. In a phase I clinical trial conducted in R/R DLBCL, the combination of selinexor with second-line chemoimmunotherapy was tolerated with early indication of efficacy. Overall, this study reveals that XPO1 overexpression plays a critical role in the increased tolerance of cancer cells to DNA damage while providing new insights to optimize the clinical development of XPO1 inhibitors.

Significance: XPO1 regulates the dynamic ribonucleoprotein nuclear export in response to genotoxic stress to support tolerance and can be targeted to enhance the sensitivity of cancer cells to endogenous and exogenous DNA damage. See related commentary by Knittel and Reinhardt, p. 3.

Exportin-1(XPO1)是真核细胞中主要的可溶性核输出受体,在弥漫性大B细胞淋巴瘤(DLBCL)中经常过表达。选择性XPO1抑制剂selinexor作为复发性或难治性(R/R)DLBCL的单一药物获得批准。阐明XPO1过表达支持癌症细胞的机制可以促进XPO1抑制剂的进一步临床开发。我们在这里发现,XPO1过表达增加了对基因毒性应激的耐受性,导致对化学免疫疗法的反应不佳。在MYC表达或外源性化合物诱导DNA损伤时,XPO1结合并输出携带DNA损伤修复mRNA的EIF4E和THOC4,从而在周转增加的条件下增加DNA损伤修复蛋白的合成。因此,XPO1抑制降低了淋巴瘤细胞修复DNA损伤的能力,并最终导致细胞毒性增加。在R/R-DLBCL中进行的一项I期临床试验中,selinexor与二线化学免疫疗法的组合具有耐受性,并具有早期疗效指征。总体而言,这项研究表明,XPO1过表达在增加癌症细胞对DNA损伤的耐受性中起着关键作用,同时为优化XPO1抑制剂的临床开发提供了新的见解。
{"title":"XPO1 Enables Adaptive Regulation of mRNA Export Required for Genotoxic Stress Tolerance in Cancer Cells.","authors":"Rossella Marullo, Sarah C Rutherford, Maria V Revuelta, Nahuel Zamponi, Biljana Culjkovic-Kraljacic, Nikita Kotlov, Nicolás Di Siervi, Juan Lara-Garcia, John N Allan, Jia Ruan, Richard R Furman, Zhengming Chen, Tsiporah B Shore, Adrienne A Phillips, Sebastian Mayer, Jingmei Hsu, Koen van Besien, John P Leonard, Katherine L B Borden, Giorgio Inghirami, Peter Martin, Leandro Cerchietti","doi":"10.1158/0008-5472.CAN-23-1992","DOIUrl":"10.1158/0008-5472.CAN-23-1992","url":null,"abstract":"<p><p>Exportin-1 (XPO1), the main soluble nuclear export receptor in eukaryotic cells, is frequently overexpressed in diffuse large B-cell lymphoma (DLBCL). A selective XPO1 inhibitor, selinexor, received approval as single agent for relapsed or refractory (R/R) DLBCL. Elucidating the mechanisms by which XPO1 overexpression supports cancer cells could facilitate further clinical development of XPO1 inhibitors. We uncovered here that XPO1 overexpression increases tolerance to genotoxic stress, leading to a poor response to chemoimmunotherapy. Upon DNA damage induced by MYC expression or exogenous compounds, XPO1 bound and exported EIF4E and THOC4 carrying DNA damage repair mRNAs, thereby increasing synthesis of DNA damage repair proteins under conditions of increased turnover. Consequently, XPO1 inhibition decreased the capacity of lymphoma cells to repair DNA damage and ultimately resulted in increased cytotoxicity. In a phase I clinical trial conducted in R/R DLBCL, the combination of selinexor with second-line chemoimmunotherapy was tolerated with early indication of efficacy. Overall, this study reveals that XPO1 overexpression plays a critical role in the increased tolerance of cancer cells to DNA damage while providing new insights to optimize the clinical development of XPO1 inhibitors.</p><p><strong>Significance: </strong>XPO1 regulates the dynamic ribonucleoprotein nuclear export in response to genotoxic stress to support tolerance and can be targeted to enhance the sensitivity of cancer cells to endogenous and exogenous DNA damage. See related commentary by Knittel and Reinhardt, p. 3.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"101-117"},"PeriodicalIF":11.2,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10758694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41108499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Autotaxin Secretion Is a Stromal Mechanism of Adaptive Resistance to TGFβ Inhibition in Pancreatic Ductal Adenocarcinoma. 自分泌轴蛋白是胰腺导管腺癌对TGFβ抑制的适应性抵抗的基质机制。
IF 11.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-01-02 DOI: 10.1158/0008-5472.CAN-23-0104
Silvia Pietrobono, Fabio Sabbadini, Monica Bertolini, Domenico Mangiameli, Veronica De Vita, Federica Fazzini, Giulia Lunardi, Simona Casalino, Enza Scarlato, Valeria Merz, Camilla Zecchetto, Alberto Quinzii, Giusy Di Conza, Michael Lahn, Davide Melisi

The TGFβ receptor inhibitor galunisertib demonstrated efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the randomized phase II H9H-MC-JBAJ study, which compared galunisertib plus the chemotherapeutic agent gemcitabine with gemcitabine alone. However, additional stromal paracrine signals might confer adaptive resistance that limits the efficacy of this therapeutic strategy. Here, we found that autotaxin, a secreted enzyme that promotes inflammation and fibrosis by generating lysophosphatidic acid (LPA), mediates adaptive resistance to TGFβ receptor inhibition. Blocking TGFβ signaling prompted the skewing of cancer-associated fibroblasts (CAF) toward an inflammatory (iCAF) phenotype. iCAFs were responsible for a significant secretion of autotaxin. Paracrine autotaxin increased LPA-NFκB signaling in tumor cells that triggered treatment resistance. The autotaxin inhibitor IOA-289 suppressed NFκB activation in PDAC cells and overcame resistance to galunisertib and gemcitabine. In immunocompetent orthotopic murine models, IOA-289 synergized with galunisertib in restoring sensitivity to gemcitabine. Most importantly, treatment with galunisertib significantly increased plasma levels of autotaxin in patients enrolled in the H9H-MC-JBAJ study, and median progression-free survival was significantly longer in patients without an increase of autotaxin upon treatment with galunisertib compared with those with increased autotaxin. These results establish that autotaxin secretion by CAFs is increased by TGFβ inhibition and that circulating autotaxin levels predict response to the combination treatment approach of gemcitabine plus galunisertib.

Significance: TGFβ inhibition skews cancer-associated fibroblasts toward an inflammatory phenotype that secretes autotaxin to drive adaptive resistance in PDAC, revealing autotaxin as a therapeutic target and biomarker of galunisertib response.

在随机2期H9H-MC-JBAJ研究中,TGFβ受体抑制剂加洛尼西替对胰腺导管腺癌(PDAC)患者显示出疗效,该研究将加洛尼西替加化疗剂吉西他滨与单独吉西他宾进行了比较。然而,额外的基质旁分泌信号可能会产生适应性耐药性,从而限制这种治疗策略的疗效。在这里,我们发现自轴蛋白,一种通过产生溶血磷脂酸(LPA)来促进炎症和纤维化的分泌酶,介导对TGFβ受体抑制的适应性抵抗。阻断TGFβ信号传导促使癌症相关成纤维细胞(CAFs)向炎症(iCAF)表型倾斜。iCAFs是自打蛋白大量分泌的原因。旁分泌自分泌蛋白增加了肿瘤细胞中LPA-NF-κB信号传导,从而引发治疗耐药性。自打蛋白抑制剂IOA-289抑制PDAC细胞中NF-κB的激活,并克服对格鲁西替和吉西他滨的耐药性。在具有免疫活性的原位小鼠模型中,IOA-289与galunisertib协同恢复对吉西他滨的敏感性。最重要的是,在H9H-MC-JBAJ研究中加入的患者中,用galuniserib治疗显著提高了血浆中的自打蛋白水平,并且与自打蛋白增加的患者相比,用galUniserib治疗后没有增加自打蛋白的患者的中位无进展生存期显著更长。这些结果表明,TGFβ抑制增加了CAFs的自打蛋白分泌,并且循环自打蛋白水平预测了对吉西他滨加格劳西替的联合治疗方法的反应。
{"title":"Autotaxin Secretion Is a Stromal Mechanism of Adaptive Resistance to TGFβ Inhibition in Pancreatic Ductal Adenocarcinoma.","authors":"Silvia Pietrobono, Fabio Sabbadini, Monica Bertolini, Domenico Mangiameli, Veronica De Vita, Federica Fazzini, Giulia Lunardi, Simona Casalino, Enza Scarlato, Valeria Merz, Camilla Zecchetto, Alberto Quinzii, Giusy Di Conza, Michael Lahn, Davide Melisi","doi":"10.1158/0008-5472.CAN-23-0104","DOIUrl":"10.1158/0008-5472.CAN-23-0104","url":null,"abstract":"<p><p>The TGFβ receptor inhibitor galunisertib demonstrated efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the randomized phase II H9H-MC-JBAJ study, which compared galunisertib plus the chemotherapeutic agent gemcitabine with gemcitabine alone. However, additional stromal paracrine signals might confer adaptive resistance that limits the efficacy of this therapeutic strategy. Here, we found that autotaxin, a secreted enzyme that promotes inflammation and fibrosis by generating lysophosphatidic acid (LPA), mediates adaptive resistance to TGFβ receptor inhibition. Blocking TGFβ signaling prompted the skewing of cancer-associated fibroblasts (CAF) toward an inflammatory (iCAF) phenotype. iCAFs were responsible for a significant secretion of autotaxin. Paracrine autotaxin increased LPA-NFκB signaling in tumor cells that triggered treatment resistance. The autotaxin inhibitor IOA-289 suppressed NFκB activation in PDAC cells and overcame resistance to galunisertib and gemcitabine. In immunocompetent orthotopic murine models, IOA-289 synergized with galunisertib in restoring sensitivity to gemcitabine. Most importantly, treatment with galunisertib significantly increased plasma levels of autotaxin in patients enrolled in the H9H-MC-JBAJ study, and median progression-free survival was significantly longer in patients without an increase of autotaxin upon treatment with galunisertib compared with those with increased autotaxin. These results establish that autotaxin secretion by CAFs is increased by TGFβ inhibition and that circulating autotaxin levels predict response to the combination treatment approach of gemcitabine plus galunisertib.</p><p><strong>Significance: </strong>TGFβ inhibition skews cancer-associated fibroblasts toward an inflammatory phenotype that secretes autotaxin to drive adaptive resistance in PDAC, revealing autotaxin as a therapeutic target and biomarker of galunisertib response.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"118-132"},"PeriodicalIF":11.2,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10758691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41178115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Hypoxia-Responsive CAR-T Cells Exhibit Reduced Exhaustion and Enhanced Efficacy in Solid Tumors. 低氧反应性CAR-T细胞在实体瘤中表现出减少衰竭和增强疗效。
IF 11.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-01-02 DOI: 10.1158/0008-5472.CAN-23-1038
Xiuxiu Zhu, Jun Chen, Wuling Li, Yanmin Xu, Juanjuan Shan, Juan Hong, Yongchun Zhao, Huailong Xu, Jiabin Ma, Junjie Shen, Cheng Qian

Expanding the utility of chimeric antigen receptor (CAR)-T cells in solid tumors requires improving their efficacy and safety. Hypoxia is a feature of most solid tumors that could be used to help CAR-T cells discriminate tumors from normal tissues. In this study, we developed hypoxia-responsive CAR-T cells by engineering the CAR to be under regulation of hypoxia-responsive elements and selected the optimal structure (5H1P-CEA CAR), which can be activated in the tumor hypoxic microenvironment to induce CAR-T cells with high polyfunctionality. Hypoxia-responsive CAR T cells were in a "resting" state with low CAR expression under normoxic conditions. Compared with conventional CAR-T cells, hypoxia-responsive CAR-T cells maintained lower differentiation and displayed enhanced oxidative metabolism and proliferation during cultivation, and they sowed a capacity to alleviate the negative effects of hypoxia on T-cell proliferation and metabolism. Furthermore, 5H1P-CEA CAR-T cells exhibited decreased T-cell exhaustion and improved T-cell phenotype in vivo. In patient-derived xenograft models, hypoxia-responsive CAR-T cells induced more durable antitumor activity than their conventional counterparts. Overall, this study provides an approach to limit CAR expression to the hypoxic tumor microenvironment that could help to enhance CAR T-cell efficacy and safety in solid tumors.

Significance: Engineering CAR-T cells to upregulate CAR expression under hypoxic conditions induces metabolic reprogramming, reduces differentiation, and increases proliferation to enhance their antitumor activity, providing a strategy to improve efficacy and safety.

扩大嵌合抗原受体(CAR)-T细胞在实体瘤中的应用需要提高其疗效和安全性。缺氧是大多数实体瘤的一个特征,可用于帮助CAR-T细胞区分肿瘤和正常组织。在本研究中,我们通过将CAR工程化为受缺氧反应元件调控的缺氧反应性CAR-T细胞,并选择了最佳结构(5H1P-CEA-CAR),该结构可以在肿瘤缺氧微环境中被激活,以诱导具有高多功能性的CAR-T细胞。低氧反应性CAR-T细胞在常氧条件下处于低CAR表达的“静息”状态。与传统的CAR-T细胞相比,缺氧反应性CAR-T细胞在培养过程中保持较低的分化,并表现出增强的氧化代谢和增殖,它们具有减轻缺氧对T细胞增殖和代谢的负面影响的能力。此外,5H1P-CEA CAR-T细胞在体内表现出T细胞耗竭减少和T细胞表型改善。在患者来源的异种移植物模型中,缺氧反应性CAR-T细胞比传统细胞诱导了更持久的抗肿瘤活性。总之,这项研究提供了一种将CAR表达限制在缺氧肿瘤微环境中的方法,有助于提高CAR-T细胞在实体瘤中的疗效和安全性。
{"title":"Hypoxia-Responsive CAR-T Cells Exhibit Reduced Exhaustion and Enhanced Efficacy in Solid Tumors.","authors":"Xiuxiu Zhu, Jun Chen, Wuling Li, Yanmin Xu, Juanjuan Shan, Juan Hong, Yongchun Zhao, Huailong Xu, Jiabin Ma, Junjie Shen, Cheng Qian","doi":"10.1158/0008-5472.CAN-23-1038","DOIUrl":"10.1158/0008-5472.CAN-23-1038","url":null,"abstract":"<p><p>Expanding the utility of chimeric antigen receptor (CAR)-T cells in solid tumors requires improving their efficacy and safety. Hypoxia is a feature of most solid tumors that could be used to help CAR-T cells discriminate tumors from normal tissues. In this study, we developed hypoxia-responsive CAR-T cells by engineering the CAR to be under regulation of hypoxia-responsive elements and selected the optimal structure (5H1P-CEA CAR), which can be activated in the tumor hypoxic microenvironment to induce CAR-T cells with high polyfunctionality. Hypoxia-responsive CAR T cells were in a \"resting\" state with low CAR expression under normoxic conditions. Compared with conventional CAR-T cells, hypoxia-responsive CAR-T cells maintained lower differentiation and displayed enhanced oxidative metabolism and proliferation during cultivation, and they sowed a capacity to alleviate the negative effects of hypoxia on T-cell proliferation and metabolism. Furthermore, 5H1P-CEA CAR-T cells exhibited decreased T-cell exhaustion and improved T-cell phenotype in vivo. In patient-derived xenograft models, hypoxia-responsive CAR-T cells induced more durable antitumor activity than their conventional counterparts. Overall, this study provides an approach to limit CAR expression to the hypoxic tumor microenvironment that could help to enhance CAR T-cell efficacy and safety in solid tumors.</p><p><strong>Significance: </strong>Engineering CAR-T cells to upregulate CAR expression under hypoxic conditions induces metabolic reprogramming, reduces differentiation, and increases proliferation to enhance their antitumor activity, providing a strategy to improve efficacy and safety.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"84-100"},"PeriodicalIF":11.2,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49688822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Progressively Enhancing Stemness of Adoptively Transferred T Cells with PI3Kδ Blockade Improves Metabolism and Antitumor Immunity. 用PI3Kδ阻断剂逐渐增强过继转移的T细胞的干性可改善代谢和抗肿瘤免疫。
IF 11.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-01-02 DOI: 10.1158/0008-5472.CAN-23-0801
Guillermo O Rangel Rivera, Connor J Dwyer, Hannah M Knochelmann, Aubrey S Smith, Bülent Arman Aksoy, Anna C Cole, Megan M Wyatt, Soundharya Kumaresan, Jessica E Thaxton, Gregory B Lesinski, Chrystal M Paulos

Generating stem-like memory T cells (TSCM) is a potential strategy to improve adoptive immunotherapy. Elucidating optimal ways to modulate signaling pathways that enrich TSCM properties could identify approaches to achieve this goal. We discovered herein that blocking the PI3Kδ pathway pharmaceutically to varying degrees can generate T cells with increasingly heightened stemness properties, based on the progressive enrichment of the transcription factors Tcf1 and Lef1. T cells with enhanced stemness features exhibited metabolic plasticity, marked by improved mitochondrial function and glucose uptake after tumor recognition. Conversely, T cells with low or medium stemness were less metabolically dynamic, vulnerable to antigen-induced cell death, and expressed more inhibitory checkpoint receptors. Only T-cell receptor-specific or chimeric antigen receptor (CAR)-specific T cells with high stemness persisted in vivo and mounted protective immunity to tumors. Likewise, the strongest level of PI3Kδ blockade in vitro generated human tumor-infiltrating lymphocytes and CAR T cells with elevated stemness properties, in turn bolstering their capacity to regress human solid tumors. The stemness level of T cells in vitro was important, ultimately impacting their efficacy in mice bearing three distinct solid tumors. Lef1 and Tcf1 sustained antitumor protection by donor high CD8+ TSCM or CD4+ Th17SCM, as deletion of either one compromised the therapeutic efficacy. Collectively, these findings highlight the importance of strategic modulation of PI3Kδ signaling in T cells to induce stemness and lasting protective responses to solid tumors.

Significance: Elevating T-cell stemness by progressively blocking PI3Kδ signaling during ex vivo manufacturing of adoptive cell therapies alters metabolic and functional properties to enhance antitumor immunity dependent on Tcf1 and Lef1.

产生干细胞样记忆T细胞(TSCM)是改善过继免疫疗法的一种潜在策略。阐明调节富含TSCM特性的信号通路的最佳方法可以确定实现这一目标的方法。我们在本文中发现,基于转录因子Tcf-1和Lef-1的逐渐富集,在药物上不同程度地阻断PI3Kδ途径可以产生具有越来越高的干性特性的T细胞。具有增强的干性特征的T细胞表现出代谢可塑性,其特征是肿瘤识别后线粒体功能和葡萄糖摄取的改善。相反,具有低或中等干性的T细胞代谢动力学较差,易受抗原诱导的细胞死亡的影响,并表达更具抑制性的检查点受体。只有具有高度干性的TCR或CAR特异性T细胞在体内持续存在,并对肿瘤产生保护性免疫。同样,体外最强水平的PI3Kδ阻断产生了具有高干性特性的人类肿瘤浸润淋巴细胞(TIL)和CAR T细胞,从而增强了它们消退人类实体瘤的能力。体外T细胞的干性水平很重要,最终影响了它们在携带三种不同实体瘤的小鼠中的疗效。Lef-1和Tcf-1通过供体高CD8+TSCM或CD4+Th17SCM维持抗肿瘤保护,因为其中任一种的缺失损害了治疗效果。总之,这些发现强调了T细胞中PI3Kδ信号的战略性调节对诱导干性和对实体瘤的持久保护反应的重要性。
{"title":"Progressively Enhancing Stemness of Adoptively Transferred T Cells with PI3Kδ Blockade Improves Metabolism and Antitumor Immunity.","authors":"Guillermo O Rangel Rivera, Connor J Dwyer, Hannah M Knochelmann, Aubrey S Smith, Bülent Arman Aksoy, Anna C Cole, Megan M Wyatt, Soundharya Kumaresan, Jessica E Thaxton, Gregory B Lesinski, Chrystal M Paulos","doi":"10.1158/0008-5472.CAN-23-0801","DOIUrl":"10.1158/0008-5472.CAN-23-0801","url":null,"abstract":"<p><p>Generating stem-like memory T cells (TSCM) is a potential strategy to improve adoptive immunotherapy. Elucidating optimal ways to modulate signaling pathways that enrich TSCM properties could identify approaches to achieve this goal. We discovered herein that blocking the PI3Kδ pathway pharmaceutically to varying degrees can generate T cells with increasingly heightened stemness properties, based on the progressive enrichment of the transcription factors Tcf1 and Lef1. T cells with enhanced stemness features exhibited metabolic plasticity, marked by improved mitochondrial function and glucose uptake after tumor recognition. Conversely, T cells with low or medium stemness were less metabolically dynamic, vulnerable to antigen-induced cell death, and expressed more inhibitory checkpoint receptors. Only T-cell receptor-specific or chimeric antigen receptor (CAR)-specific T cells with high stemness persisted in vivo and mounted protective immunity to tumors. Likewise, the strongest level of PI3Kδ blockade in vitro generated human tumor-infiltrating lymphocytes and CAR T cells with elevated stemness properties, in turn bolstering their capacity to regress human solid tumors. The stemness level of T cells in vitro was important, ultimately impacting their efficacy in mice bearing three distinct solid tumors. Lef1 and Tcf1 sustained antitumor protection by donor high CD8+ TSCM or CD4+ Th17SCM, as deletion of either one compromised the therapeutic efficacy. Collectively, these findings highlight the importance of strategic modulation of PI3Kδ signaling in T cells to induce stemness and lasting protective responses to solid tumors.</p><p><strong>Significance: </strong>Elevating T-cell stemness by progressively blocking PI3Kδ signaling during ex vivo manufacturing of adoptive cell therapies alters metabolic and functional properties to enhance antitumor immunity dependent on Tcf1 and Lef1.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"69-83"},"PeriodicalIF":11.2,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41100240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Leveraging Tissue-Specific Enhancer-Target Gene Regulatory Networks Identifies Enhancer Somatic Mutations That Functionally Impact Lung Cancer. 利用组织特异性增强子靶基因调控网络识别功能性影响癌症的增强子体细胞突变。
IF 11.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-01-02 DOI: 10.1158/0008-5472.CAN-23-1129
Judith Mary Hariprakash, Elisa Salviato, Federica La Mastra, Endre Sebestyén, Ilario Tagliaferri, Raquel Sofia Silva, Federica Lucini, Lorenzo Farina, Mario Cinquanta, Ilaria Rancati, Mirko Riboni, Simone Paolo Minardi, Luca Roz, Francesca Gorini, Chiara Lanzuolo, Stefano Casola, Francesco Ferrari

Enhancers are noncoding regulatory DNA regions that modulate the transcription of target genes, often over large distances along with the genomic sequence. Enhancer alterations have been associated with various pathological conditions, including cancer. However, the identification and characterization of somatic mutations in noncoding regulatory regions with a functional effect on tumorigenesis and prognosis remain a major challenge. Here, we present a strategy for detecting and characterizing enhancer mutations in a genome-wide analysis of patient cohorts, across three lung cancer subtypes. Lung tissue-specific enhancers were defined by integrating experimental data and public epigenomic profiles, and the genome-wide enhancer-target gene regulatory network of lung cells was constructed by integrating chromatin three-dimensional architecture data. Lung cancers possessed a similar mutation burden at tissue-specific enhancers and exons but with differences in their mutation signatures. Functionally relevant alterations were prioritized on the basis of the pathway-level integration of the effect of a mutation and the frequency of mutations on individual enhancers. The genes enriched for mutated enhancers converged on the regulation of key biological processes and pathways relevant to tumor biology. Recurrent mutations in individual enhancers also affected the expression of target genes, with potential relevance for patient prognosis. Together, these findings show that noncoding regulatory mutations have a potential relevance for cancer pathogenesis and can be exploited for patient classification.

Significance: Mapping enhancer-target gene regulatory interactions and analyzing enhancer mutations at the level of their target genes and pathways reveal convergence of recurrent enhancer mutations on biological processes involved in tumorigenesis and prognosis.

增强子是调节靶基因转录的非编码调控DNA区域,通常沿着基因组序列长距离调控。增强子的改变与包括癌症在内的各种病理状况有关。然而,识别和表征对肿瘤发生和预后具有功能影响的非编码调控区的体细胞突变仍然是一个重大挑战。在这里,我们提出了一种策略,用于在三种癌症亚型的患者群的全基因组分析中检测和表征增强子突变。通过整合实验数据和公开的表观基因组图谱来定义肺组织特异性增强子,并通过整合染色质3D结构数据来构建肺细胞的全基因组增强子靶基因调控网络。肺癌在组织特异性增强子和外显子上具有相似的突变负荷,但在突变特征上存在差异。根据突变效应的通路水平整合和突变对单个增强子的频率,优先考虑功能相关的改变。富含突变增强子的基因集中在与肿瘤生物学相关的关键生物过程和途径的调控上。个体增强子的复发突变也影响靶基因的表达,与患者预后有潜在相关性。总之,这些发现表明,非编码调节突变与癌症发病机制具有潜在相关性,可用于患者分类。
{"title":"Leveraging Tissue-Specific Enhancer-Target Gene Regulatory Networks Identifies Enhancer Somatic Mutations That Functionally Impact Lung Cancer.","authors":"Judith Mary Hariprakash, Elisa Salviato, Federica La Mastra, Endre Sebestyén, Ilario Tagliaferri, Raquel Sofia Silva, Federica Lucini, Lorenzo Farina, Mario Cinquanta, Ilaria Rancati, Mirko Riboni, Simone Paolo Minardi, Luca Roz, Francesca Gorini, Chiara Lanzuolo, Stefano Casola, Francesco Ferrari","doi":"10.1158/0008-5472.CAN-23-1129","DOIUrl":"10.1158/0008-5472.CAN-23-1129","url":null,"abstract":"<p><p>Enhancers are noncoding regulatory DNA regions that modulate the transcription of target genes, often over large distances along with the genomic sequence. Enhancer alterations have been associated with various pathological conditions, including cancer. However, the identification and characterization of somatic mutations in noncoding regulatory regions with a functional effect on tumorigenesis and prognosis remain a major challenge. Here, we present a strategy for detecting and characterizing enhancer mutations in a genome-wide analysis of patient cohorts, across three lung cancer subtypes. Lung tissue-specific enhancers were defined by integrating experimental data and public epigenomic profiles, and the genome-wide enhancer-target gene regulatory network of lung cells was constructed by integrating chromatin three-dimensional architecture data. Lung cancers possessed a similar mutation burden at tissue-specific enhancers and exons but with differences in their mutation signatures. Functionally relevant alterations were prioritized on the basis of the pathway-level integration of the effect of a mutation and the frequency of mutations on individual enhancers. The genes enriched for mutated enhancers converged on the regulation of key biological processes and pathways relevant to tumor biology. Recurrent mutations in individual enhancers also affected the expression of target genes, with potential relevance for patient prognosis. Together, these findings show that noncoding regulatory mutations have a potential relevance for cancer pathogenesis and can be exploited for patient classification.</p><p><strong>Significance: </strong>Mapping enhancer-target gene regulatory interactions and analyzing enhancer mutations at the level of their target genes and pathways reveal convergence of recurrent enhancer mutations on biological processes involved in tumorigenesis and prognosis.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"133-153"},"PeriodicalIF":11.2,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10758689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49674593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Cancer research
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1