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  2. 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

  • Proc Natl Acad Sci U S A. 2022 May 31;119(22):e2200230119. doi: 10.1073/pnas.2200230119.
Weiguang Liu 1 Peng Sun 2 Lingling Xia 1 Xilin He 1 Zhengmiao Xia 1 Yehong Huang 1 Wenzhuo Liu 1 Lulu Li 1 Liming Chen 1 3
Affiliations

Affiliations

  • 1 Department of Biochemistry, School of Life Sciences, Nanjing Normal University, 210023 Nanjing, China.
  • 2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Pathology, Sun Yat-sen University Cancer Center, 528404 Guangzhou, China.
  • 3 Cancer Institute, School of Life Sciences, Nanjing Normal University, 210023 Nanjing, China.
Abstract

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.

Keywords

BMOR; IRF3; brain metastasis; immune evasion; lncRNA.

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