NCOA1

30多年前，美国德克萨斯州贝勒医学院的研究人员发现了一类名为类固醇受体共激活因子（steroid receptor coactivator，SRC）的蛋白质。SRC家族中的三个主要成员SRC-1、SRC-2和SRC3通过与核受体（nuclear receptor）结合，与转录因子和转录启动复合物相互作用，能够调节基因转录的启动和增强过程。最初，共激活因子被认为仅仅充当核受体和转录因子组装的一个“桥梁”，但随着研究的深入，科学家们渐渐发现，共激活因子不仅是转录的动力助推器，甚至参与了基因表达的所有子步骤，因而也就对多种生理过程具有调节作用。已经证明，SRC在转录起始、延伸、RNA剪接乃至mRNA翻译中都有发挥作用。5月30日，贝勒医学院的Bert W. O'Malley团队在PNAS上发文“Steroid receptor coactivator 3 is a key modulator of regulatory T cell–mediated tumor evasion”，表明在调节性T细胞（Tregs）中敲除SRC-3的基因，可根除小鼠身上的肿瘤并提供长期的抗癌保护。图1 研究成果（图源：[2]）多年来，O'Malley团队一直对SRC-3及其在癌症中的作用特别感兴趣。SRC-3不仅在所有人类癌症中都高度表达并对癌症的多个方面都有促进作用，在抑制身体免疫反应的Tregs中也高度表达。O'Malley团队因此怀疑Tregs中丰富的SRC-3在控制癌症进展中发挥作用，并试图研究敲除Tregs中的SRC-3基因会对癌症生长有何影响。 敲除了SRC-3的Tregs面对肿瘤无往不利 研究人员首先通过交叉繁殖转基因小鼠，得到了特定在Tregs中敲除SRC-3基因的小鼠。Tregs 通过多种不同机制限制效应免疫细胞增殖和功能发挥作用，Tregs功能的丧失会导致病理性慢性自身免疫性疾病，然而，这些基因工程小鼠的体重、生殖能力、血液细胞因子/趋化因子的水平等，都并未表现出在Tregs功能完全消除或使用检查点抑制剂的小鼠身上观察到的病理特征。研究人员随后将一种侵袭性乳腺癌细胞系注射到小鼠的乳腺脂肪垫中。结果观察到乳腺肿瘤在对照组小鼠中急剧生长，而在实验组小鼠身上，乳腺肿瘤在细胞注射后的第五天被观察到，但在20天后已检测不到。在排除了小鼠的背景遗传因素和他莫昔芬治疗对乳腺肿瘤生长的潜在影响后，研究人员证实Tregs中SRC-3基因的敲除导致了肿瘤的根除。图2小鼠在注射乳腺癌细胞系后肿瘤生长对比（图源：[2]）此外，不论是预防肿瘤发生，还是驱动先前存在的肿瘤消退，都可以靠在Tregs中敲除SRC-3基因实现。甚至在停止治疗后肿瘤复发的问题上，实验组小鼠也表现良好，细胞注射218天后都未检测到肿瘤复发。鉴于此，研究人员进一步测试了Tregs中SRC-3基因敲除是否对之后的新肿瘤形成具有长期抵抗，结果显示乳腺癌细胞系在肿瘤根除小鼠身上的“再注射”也无法建立新的乳腺肿瘤。研究人员使用免疫组织化学分析方法，在较早时间节点观察了尚未被完全根除的肿瘤发现，敲除了SRC-3基因的Tregs渗入了肿瘤内部。对小鼠前列腺癌模型的试验则给出了和乳腺癌模型相似的结果，即敲除了SRC-3基因的Tregs也可以根除前列腺肿瘤。敲除SRC-3如何使Tregs对肿瘤重拳出击研究人员发现，在细胞水平上，Tregs中SRC-3基因敲除的小鼠的肿瘤（消失前），相比于对照组小鼠的肿瘤，表现出广泛的细胞减少，浸润性CD4+ T细胞、CD8+ T细胞和CD49b+ NK细胞数量显著升高，肿瘤中的Foxp3+Tregs更少，表明这建立起了抗肿瘤微环境。对肿瘤进行细胞因子/趋化因子分析发现，肿瘤中Ifng和Cxcl9水平显著增加。Ifng是一种中枢促炎细胞因子，可以抑制肿瘤进展并激活CD8+ T细胞和NK细胞；Cxcl9是一种趋化因子，可招募激活CD8+和NK细胞。这表明，敲除了SRC-3基因的Tregs通过增强肿瘤中的Ifng/Cxcl9，募集CD8+和NK细胞支持抗肿瘤免疫微环境的建立。Tregs RNA分析显示，敲除SRC-3使得Tregs中的共抑制分子Tigit、Klrb1c和Klrk1的下调，这些分子能够选择性地抑制促炎性T细胞反应。有意思的是，不同于肿瘤中的Tregs，敲除SRC-3使得脾脏中的Tregs中的抗炎细胞因子如Tgf-β、Il-10和Il-35表达升高。这表明敲除SRC-3后，Tregs在脾脏和肿瘤中的分子表型非常不同，而T细胞受体的激活可能是肿瘤中诱导Ifng的关键。研究人员还发现，Ifng能够增加肿瘤细胞中的某些Tregs趋化配体，而敲除SRC-3使得Tregs中相应受体水平显著升高。这说明Ifng能够以这样一条通路发出募集Tregs到肿瘤的信号。Ifng还增加了肿瘤细胞中Cxcl9 mRNA 的表达水平。此外，相比于未改造的Tregs会抑制常规T细胞的增殖，敲除SRC-3后的Tregs不仅不再对常规T细胞“过多约束”，甚至还反过来限制未改造Tregs对常规T细胞的抑制作用。这些都说明敲除SRC-3的Tregs在根除肿瘤的过程中担任了“挑大梁”的角色。图3 模型概念（图源：[2]）新疗法是否指日可待Tregs的过继性细胞转移（Adoptive Cell Transfer，ACT）疗法常用于治疗各种慢性自身免疫性疾病，但并不适用于治疗实体癌。在这里，由于敲除了SRC-3的Tregs表现出根除肿瘤的能力以及对未改造Tregs的抑制作用，研究人员试图评估单次注射改造后的Tregs能否根除野生型小鼠身上已存在的肿瘤。结果显示，注射成功地抑制了小鼠身上的乳腺肿瘤生长，且在ACT后超过215天都未观察到肿瘤复发。对ACT治疗后尚未完全根除的肿瘤进行分析，研究人员发现，注射Tregs在肿瘤中的分布、肿瘤中其他免疫细胞的数量、Ifng/Cxcl9的水平以及小鼠肿瘤复发及对新生肿瘤的抵抗情况，均与在基因工程敲除Tregs中SRC的小鼠身上观察到的结果类似。不过，经测试，ACT治疗想要实现理想的肿瘤清除效果，对剂量有所要求。该研究的第一作者、贝勒生殖医学中心分子和细胞生物学副教授 Sang Jun Han博士表示：“当前其他疗法或多或少可以在一段时间内减轻肿瘤负担或使肿瘤消失，但通常癌症仍会复发。我们这次在动物模型上的发现则表明，敲除了SRC-3的Tregs不仅可以根除已有的肿瘤，甚至极有希望提供长久的保护防止肿瘤的复发。未来，这将可能成为癌症治疗的一个有效靶点，而且，还不会造成类似于免疫检查点抑制剂造成的自身免疫副作用。”Han表示：“我们对结果感到非常兴奋。接下来我们将继续钻研，以将这些发现转化为一种新颖、更有效、更持久的癌症疗法。”O'Malley还是生物制药公司CoRegen 的首席科学官。目前，贝勒医学院已将该研究的发现以及相关的所有专利和知识产权授权给CoRegen，希望能以此开发出一种革命性的、无副作用的癌症疗法并使之商业化。责编|风立宵校对|风立宵End参考资料：[1]York B, O'Malley BW. Steroid receptor coactivator (SRC) family: masters of systems biology. J Biol Chem. 2010 Dec 10;285(50):38743-50. doi: 10.1074/jbc.R110.193367.[2]Han, S.J., Jain, P., Gilad, Y., et al. Steroid receptor coactivator 3 is a key modulator of regulatory T cell–mediated tumor evasion. Proceedings of the National Academy of Sciences. 2023; 120(23): e2221707120. https://doi-org.libproxy1.nus.edu.sg/10.1073/pnas.2221707120[3]https://www.genengnews.com/topics/cancer/gene-elimination-in-tregs-triggers-lifelong-anticancer-response-in-mice/ [4]https://www.eurekalert.org/news-releases/990392 本文系生物探索原创，欢迎个人转发分享。其他任何媒体、网站如需转载，须在正文前注明来源生物探索。   往期精选 围观 ‍把病毒困在“陷阱”里！海德堡大学探明病毒渗透最后一步，或将带来预防新手段！ 热文基因振荡器：在两种衰老模式间来回切换，细胞寿命延长了82%！ 热文用超声波突破皮肤屏障！MIT科学家为皮肤给药提供可穿戴解决方案 热文新发现：加速癌症发展的染色体外DNA，甚至出现在癌症之前，推动组织癌变！ 热文 在基因组中“跳来跳去”的转座子，有望成为免疫疗法抗击肿瘤的新靶点！点击“阅读原文”，了解更多~

HOUSTON, June 01, 2023 (GLOBE NEWSWIRE) -- CoRegen, a biopharmaceutical company pursuing novel treatments for patients impacted by some of the most aggressive forms of cancer and chronic diseases, announced today the publication of research, titled, “Steroid receptor coactivator 3 is a key modulator of regulatory T cell-mediated tumor evasion,” in the peer-reviewed journal Proceedings of the National Academy of Sciences (PNAS). This work showcases the discovery of steroid receptor coactivator 3 (SRC-3) as a crucial regulator of the anti-cancer immune response. SRC-3 is a pleiotropic coactivator suspected of playing a critical role in the function of regulatory T cells (Tregs), which are essential in restraining immune responses for immune homeostasis. When SRC-3 expression was disrupted in Tregs, it was shown to result in complete tumor eradication in aggressive syngeneic breast cancer mouse models without recurrence or side effects. This approach has been tested with triple negative breast cancer, glioblastoma, advanced prostate cancer and pancreatic cancer and consistently achieved tumor eradication without recurrence or side effects in preclinical studies. CoRegen is capitalizing on nearly 50 years of research by Bert O’Malley M.D., a renowned molecular endocrinologist who currently serves as the Chancellor of Baylor College of Medicine and the Inventor, Principal Scientist and Board Member of CoRegen. He has won more than 65 awards, received the National Medal of Science from President Bush. Dr. O’Malley and his team discovered a protein called steroid receptor coactivator (SRC-1) that is required for the effective regulation of gene activity and have extensively characterized a family of SRCs (SRC-1, SRC-2 and SR-3) that regulate a variety of cellular functions. Of these, SRC-3 has been shown to be highly expressed in almost all human cancers and appears to also play a key role in cancer growth. Additionally, it was determined that when SRC-3 was removed from the Treg cell, a number of other genes, typically individually targeted in other cancer therapies, were down regulated while other genes were upregulated. These changes to the Treg were only observed inside the tumor but are believed to be one of the key drivers of the successful outcome of the studies. The team also discovered that Tregs lacking SRC-3 mediated long-lasting tumor eradication by effectively modifying the environment surrounding the tumor into one that favored its elimination. A subsequent injection of additional cancer cells in treated mice did not give rise to new tumors, showing that there was no need to introduce additional SRC-3 knock-out Tregs to sustain tumor resistance. Importantly, transferring these cells to animals carrying pre-established breast tumors also resulted in cancer eradication. “We are highly encouraged by these findings,” said Dr. O’Malley. “By identifying SRC-3 and its critical role in the function of Tregs, it is our hope we may introduce entirely new methods for addressing the needs of patients with some of the most aggressive forms of cancer.” “As a partner and significant shareholder, Baylor College of Medicine has tremendous confidence in the CoRegen management team and is looking forward to working with CoRegen to commercialize the groundbreaking discoveries originating from the O’Malley Laboratory. Baylor College of Medicine has and will continue to dedicate significant resources and infrastructure to assist CoRegen in its efforts to bring life-saving therapies to the world,” said Michael Dilling, Executive Director, Baylor College of Medicine Licensing Group. Steve Gorlin, chief executive officer of CoRegen, added, “I have had the great fortune of having founded and led multiple companies reaching billion-dollar valuations, with some having resulted in the sale to large pharma. In my entire career, I have never seen an opportunity similar to that of CoRegen and view these data as stepping-stones towards potentially creating truly transformative therapeutics for patients in need. I look forward to continuing the advances generated from Dr. O’Malley’s lab in the years to come.” CoRegen has partnered with Baylor College of Medicine to further develop and commercialize several of the groundbreaking discoveries originating from the O’Malley Laboratory with a team of more than 30 scientists and several meaningful partnerships. About CoRegen CoRegen is a biopharmaceutical company leveraging its unique and patented master gene regulatory platform for the treatment of cancers and other malignant and high intensity chronic illnesses. Although the CoRegen platform has a wide range of potential therapies it will initially focus on select cancers. As of today, in preclinical mouse studies, the CoRegen cancer therapy has been shown to completely eradicate established tumors, prevent the growth of new tumors and prevent recurrence with no signs of toxicity, inflammation or off target effects. The therapy has been tested on glioblastoma, pancreatic, triple negative breast and advanced prostate cancer. CoRegen’s patent estate also contains small molecule agents that inhibit and enhance the family of steroid receptor coactivators. The inhibitor drugs show activity against cancers by themselves but are also likely to be synergistic with other therapeutic modalities. The enhancer drugs show a wide range of activity including dramatically reversing damage and improving function after both myocardial infarction and stroke in rodent models. Company Contact: Matthew Rosen, Executive Vice Chairman mrosen@coregeninc.com Media Contact: Andrew Mielach LifeSci Communications amielach@lifescicomms.com

FRIDAY, May 26, 2023 -- Young patients with a history of multiple concussions report greater cognitive, sleep, and neuropsychiatric symptoms than those with one prior head injury, according to a study published online May 9 in the Journal of Neurosurgery: Pediatrics . Addison Quinones, from the Icahn School of Medicine at Mount Sinai in New York City, and colleagues investigated the effects of prior recurrent head injury on the symptom profiles of student-athletes after another suspected concussion. The analysis included student athletes (aged 12 to 22 years) reporting a single prior sports-related concussion (SRC1; 2,253 students) and athletes reporting two or more prior concussions (SRC2+; 976 students) at baseline. The researchers found that at postinjury test 1 (PI1), the SRC2+ group had lower severity of headaches but increased nervousness, irritability, sadness, visual problems, and neuropsychiatric symptoms versus SRC1. In a multivariate analysis, decreased headache severity was associated with increased prior concussion (β = −0.27). At postinjury test 2, the SRC2+ cohort had increased cognitive (β = 1.22), sleep (β = 0.63), and neuropsychiatric (β = 0.67) symptoms versus the SRC1 cohort. "Careful assessment of specific symptoms should be considered in patients with a history of recurrent head injury prior to return to play," the authors write. Abstract/Full Text (subscription or payment may be required) Posted May 2023