Functional Determinants of Metastatic Dormancy

转移休眠的功能决定因素

• 批准号: 10428636
• 负责人: Julio A. Aguirre-Ghiso
• 金额: $ 61.06万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10428636
• 关键词: Adopted; Affect; Aftercare; Aging; Alveolar Macrophages; Automobile Driving; BMP7 gene; Bone Marrow; Breast; CSPG4 gene; Cancer Model; Cancer Patient; Carcinoma; Cell Survival; Clinical Trials; Cues; Data; Epigenetic Process; Evolution; Genes; Genetic Transcription; Goals; Hematopoietic stem cells; Homeostasis; Hypoxia; Impairment; Inflammatory; Link; Lung; Malignant Neoplasms; Mediating; Mesenchymal; Mesenchymal Stem Cells; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Lung; Methods; Monitor; Mus; Neoplasm Metastasis; Organ; Primary Lesion; Primary Neoplasm; Proteins; Publishing; Relapse; Residual Cancers; Signal Transduction; Site; Systemic disease; TGFB2 gene; Testing; Therapeutic; Tissues; Tretinoin; Up-Regulation; WNT5A gene; age effect; aged; cancer cell; cancer therapy; cue reactivity; imprint; macrophage; malignant breast neoplasm; nestin protein; novel; pluripotency; prevent; programs; rational design; response; stem cell function; stem cell niche; therapy development; tumor hypoxia

SUMMARY. The majority of cancer patients die of metastases originating from disseminated cancer cells (DCCs), years and decades after treatment. This has been linked to the ability of DCCs to survive in a dormant state and evade therapies. Our long-term goal is to understand dormancy of DCCs as a systemic disease mechanism to target them and prevent relapse. Our overarching hypothesis is that complementary mechanism between gene programs in primary lesions and target organs niche signals, converge to instruct DCCs in target organs to enter dormancy via quiescence, pluripotency and survival programs. We further hypothesize that such signals can be manipulated to suppress metastasis. Using epithelial cancer models we have discovered that early dissemination spawns mesenchymal-like (M-Like) dormant breast cancer (BC) DCCs. We also discovered that hypoxia in advanced primary tumors can prime DCC precursors to activate quiescence programs and enter dormancy in target organs. Importantly, M-like early DCC precursors also display a strong hypoxia response. Both early and late DCCs were found to respond to retinoic acid, WNT5A, BMP7 and TGF2 signals derived from stromal target organ niches. These activate transcriptional programs integrated by ZFP281 (a novel early DCC dormancy regulator) and NR2F1 to induce dormancy. Our new aims build on these findings and explore three significant new discoveries: 1) Hypoxia signals in early and late primary lesions turn on quiescence programs that epigenetically imprint DCC precursors to enter dormancy when they arrive to target organs, 2) early or late DCCs that arrive to the bone marrow (BM) enter dormancy in response to TGF2 and BMP7 produced by Nestin+/NG2+ mesenchymal stem cells (N+MSCs), which control hematopoietic stem cells (HSCs) dormancy; loss of N+MSCs or TGF2 expression in these MSCs led to bone metastasis and 3), in lungs, early and late DCCs reside in pro-dormancy niches orchestrated by alveolar macrophages (AMs), which when depleted awaken dormant DCCs. We propose to study how signals from primary lesion hypoxia along with BM and lung homeostatic niches are integrated to keep DCCs dormant. The specific aims are: AIM 1. Determine how hypoxia primes DCCs for dormancy. AIM 2. Determine how NG2+/Nestin+ MSCs orchestrate dormancy niches and how aging affects these mechanisms. AIM 3. Determine how tissue resident lung alveolar macrophages (AMs) dictate DCC fate and how aging impacts the function of these niches. Our proposal will integrate how primary lesions (early or late) may pre-program DCCs for dormancy in defined target organ niches which further reinforce dormancy via specific cues, which may be affected by aging. This approach will aid the design of rational methods to predict dormancy onset, monitor residual cancer and develop therapies to induce and maintain dormancy or eradicate minimal residual cancer.

总结。大多数癌症患者死于源自播散性癌细胞的转移