A brain-enriched lncRNA shields cancer cells from immune-mediated killing for metastatic colonization in the brain.
A brain-enriched lncRNA shields cancer cells from immune-mediated killing for metastatic colonization in the brain.
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富含大脑的lncRNA可保护癌细胞免受免疫介导的杀伤，从而在大脑中进行转移定植
DOI：
10.1073/pnas.2200230119
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发表时间：
2022-05-31
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
脑转移是晚期癌症患者常见的并发症，目前治疗选择有限，乳腺-脑转移（B2BM）是主要类型之一。在这项工作中，我们报告说，脑转移瘤致癌长非编码RNA（BMOR）是一个关键的脑富集长非编码RNA的发展B2BM。我们证明，BMOR允许B2BM细胞通过逃避脑微环境中的免疫介导的杀伤来定殖脑组织。在分子水平上，BMOR结合并灭活B2BM细胞中的IRF 3。最后，BMOR沉默子可以有效地抑制体内脑转移瘤的发展。因此，我们的研究结果揭示了一种癌细胞逃避脑微环境中免疫介导的杀伤以促进脑转移发展的方法，并建立了针对B2BM的潜在靶向策略的治疗靶点。脑转移，包括普遍的乳腺-脑转移（B2BM），由于缺乏有效的治疗，代表了癌症护理中迫切的未满足的医疗需求。免疫逃避是癌细胞转移到脑组织以进行脑转移所必需的。然而，使癌细胞能够避免大脑微环境中免疫介导的杀伤的内在遗传电路仍然知之甚少。在这里，我们报告了在B2BM细胞中表达的脑富集的长非编码RNA（BMOR）是脑转移发展所必需的，并且对于驱动癌细胞在脑组织中定植是必要的和足够的。从机制上讲，BMOR使癌细胞能够通过结合和灭活IRF 3来逃避脑微环境中的免疫介导的杀伤，从而发展脑转移。在临床前脑转移小鼠模型中，锁定核酸-BMOR（一种设计的靶向BMOR的沉默物）有效抑制脑转移癌细胞在脑中的转移性定殖。总之，我们的研究揭示了脑转移癌细胞转移性脑组织定植期间B2BM免疫逃避的机制，其中B2BM细胞通过获得脑富集的长非编码RNA遗传特征来逃避脑微环境中的免疫介导的杀伤。
Brain metastasis with current limited treatment options is a common complication in advanced cancer patients, and breast-to-brain metastasis (B2BM) is one of the major types. In this work, we report that brain metastasis oncogenic long noncoding RNA (BMOR) is a key brain-enriched long noncoding RNA for the development of B2BM. We demonstrate that BMOR allows B2BM cells to colonize the brain tissue by evading immune-mediated killing in the brain microenvironment. At the molecular level, BMOR binds and inactivates IRF3 in B2BM cells. Finally, BMOR silencer can effectively suppress the development of brain metastasis in vivo. Therefore, our findings reveal a way in which cancer cells evade immune-mediated killing in the brain microenvironment for brain metastasis development and establish therapeutic targets with potential targeted strategies against B2BM. Brain metastases, including prevalent breast-to-brain metastasis (B2BM), represent an urgent unmet medical need in the care of cancer due to a lack of effective therapies. Immune evasion is essential for cancer cells to metastasize to the brain tissue for brain metastasis. However, the intrinsic genetic circuits that enable cancer cells to avoid immune-mediated killing in the brain microenvironment remain poorly understood. Here, we report that a brain-enriched long noncoding RNA (BMOR) expressed in B2BM cells is required for brain metastasis development and is both necessary and sufficient to drive cancer cells to colonize the brain tissue. Mechanistically, BMOR enables cancer cells to evade immune-mediated killing in the brain microenvironment for the development of brain metastasis by binding and inactivating IRF3. In preclinical brain metastasis murine models, locked nucleic acid-BMOR, a designed silencer targeting BMOR, is effective in suppressing the metastatic colonization of cancer cells in the brain for brain metastasis. Taken together, our study reveals a mechanism underlying B2BM immune evasion during cancer cell metastatic colonization of brain tissue for brain metastasis, where B2BM cells evade immune-mediated killing in the brain microenvironment by acquiring a brain-enriched long noncoding RNA genetic feature.
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影响因子：
5.2
作者：
Arico, Eleonora;Castiello, Luciano;Belardelli, Filippo
通讯作者：
Belardelli, Filippo
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF
影响因子：
16.6
作者：
Chang KC;Diermeier SD;Yu AT;Brine LD;Russo S;Bhatia S;Alsudani H;Kostroff K;Bhuiya T;Brogi E;Pappin DJ;Bennett CF;Rigo F;Spector DL
通讯作者：
Spector DL
影响因子：
64.5
作者：
Klemm F;Maas RR;Bowman RL;Kornete M;Soukup K;Nassiri S;Brouland JP;Iacobuzio-Donahue CA;Brennan C;Tabar V;Gutin PH;Daniel RT;Hegi ME;Joyce JA
通讯作者：
Joyce JA
影响因子：
11.4
作者：
Chattopadhyay, Saurabh;Marques, Joao T.;Sen, Ganes C.
通讯作者：
Sen, Ganes C.