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Single Cell Analysis Unveils the Role of the Tumor Immune Microenvironment and Notch Signaling in Dormant Minimal Residual Disease

ABSTRACT: Understanding the complex ecosystem that promotes dormant cell survival and elucidating those factors that eventually overcome growth constraints and result in proliferation may provide new insights and help identify novel strategies to prolong dormancy and prevent recurrence. To dissect the molecular pathways and the microenvironments involved in regulation of tumor dormancy, we utilized a novel immunocompetent transgenic model to study residual disease, dormancy, and relapse. We discovered a significant reorganization of cancer cell structures, stroma, and immune cells with cancer cells showing dormant cell signatures. Single-cell RNA sequencing uncovered remodeling of myeloid and lymphoid compartments. Additionally, the Jagged-1/Notch signaling pathway was shown to regulate many aspects of tumorigenesis including stem cell development, epithelial-mesenchymal transition, and immune cell homeostasis during dormancy. An anti-Jagged-1 inhibitory antibody prolonged dormancy and delayed tumor recurrence due to the pleotropic effects of inhibiting the Jagged-1/Notch signaling pathway both in the tumor cells and the microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE171464 | GEO | 2021/12/18

REPOSITORIES: GEO

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Reawakening of Dormant Tumor Cells by Modified Lipids derived from Stress Activated Neutrophils

Project description:Tumor recurrence years after seemingly successful treatment of primary tumors is one of the major causes of mortality in cancer patients. Reactivation of dormant tumor cells is largely responsible for this phenomenon. Using models of lung and ovarian cancer, we found a specific mechanism that may govern this process mediated by stress and neutrophils. Stress hormones cause rapid release of S100A8/A9 proteins by neutrophils. S100A8/A9 induce activation of myeloperoxidase resulting in accumulation of oxidized lipids. These lipids up-regulate fibroblast growth factor pathway in tumor cells causing tumor cell exit from the dormancy and formation of tumor lesions. Higher serum levels of S100A8/A9 were associated with shorter time to recurrence in patients with lung cancer after complete tumor resection. Targeting of S100A8/A9 or β2 adrenergic receptors abrogated stress induced reactivation of dormant tumor cells. These observations demonstrate a mechanism linking stress, and specific neutrophils activation with early recurrence in cancer.

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Project description:The goal of this project is to characterize the ECM composition of actively proliferative and dormant head and neck squamous cell carcinoma xenografts and identify components of the ECM niche instructing tumor cell dormancy.

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B3GALT6 Promotes Dormant Breast Cancer Cell Survival and Recurrence by Enabling Heparan Sulfate-Mediated FGF Signaling

Project description:Breast cancer mortality results from incurable recurrent tumors, putatively seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling RTC survival is therefore essential for improving patient outcomes. We derived a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant chemotherapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identified the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness. B3GALT6 is required for the linkage of glycosaminoglycans (GAGs) to proteins to generate proteoglycans and its germline loss-of-function causes skeletal dysplasias. We determined that B3GALT6-mediated biosynthesis of heparan sulfate GAGs predicts poor patient outcomes, promotes tumor recurrence by enhancing dormant RTC survival in multiple contexts, and does so via a B3GALT6-heparan sulfate/HS6ST1-heparan 6-O-sulfation/FGF1-FGFR2 signaling axis. These findings implicate B3GALT6 in cancer and suggest targeting of FGFR2 signaling as a novel approach to eradicate dormant RTCs, thereby preventing recurrence.

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Dormant SOX9-positive cells facilitate MYC-driven recurrence of medulloblastoma

Project description:Tumor recurrence is a slow biological process involving therapy resistance, immune escape and metastasis and is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. By studying paired primary-recurrent patient samples and patient-derived xenografts we identified significant accumulation of SOX9-positive cells in relapses and metastases. They exist as rare, quiescent cells in Group 3 and Group 4 patients that constitute two thirds of medulloblastoma. To follow relapse at the single cell level we developed an inducible dual Tet Off animal model of MYC-driven MB, where MYC can be directed from treatment-sensitive bulk cells to resistant, dormant SOX9-positive cells. SOX9 promoted immune escape, DNA repair suppression and was essential for recurrence. Tumor cell dormancy was non-hierarchical, migratory and depended on MYC suppression by SOX9 to promote relapse. By using computational modeling and treatment we further showed how doxorubicin and MGMT inhibitors are specifically targeting relapsing cells.

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Osteoclasts Control Re-activation of Dormant Myeloma Cells by Remodeling the Endosteal Niche

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Density Gradients Separate Dormant and Treatment-Resistant Human Glioblastoma Cells

Project description:Glioblastoma (GBM) is among the most aggressive cancers. Despite aggressive radiotherapy and treatment with the alkylating agent temozolomide (TMZ), patients ultimately succumb to the disease. Although much interest has focused on highly tumorigenic GBM stem cells (GSCs), adaption of a concept from microbial research proposes that a minor population of dormant âpersisterâ cells in cancer evade current therapies. To separate dormant and treatment-resistant tumor cells in human GBM tumorspheres, we have refined density gradient protocols previously used for separation of neurosphere-forming neural stem cells (NSCs). We find that a minor cell population in human GBM tumorsphere cultures and patient-derived tumor biopsies display increased cell density. These high-density GBM cells (HDGCs) display dormancy, variable expression of proposed GSC markers, and 10-100 fold higher levels of reprogramming gene expression compared to low-density GBM cells (LDGCs). Transcriptional profiling data confirmed the slow-cycling state of HDGCs. As a result, HDGCs show decreased tumorsphere formation capacity in vitro and reduced tumorigenicity in vivo. Using tumorspheres and xenografts, we demonstrated that HDGCs show increased treatment-resistance to ionizing radiation (IR) and temozolomide treatment compared to LDGCs. Similar to the NSC lineage, our data suggest that dormant HDGCs become increasingly sensitive to anti-proliferative therapies as they become activated and further differentiate. In conclusion, density gradients represents a marker-independent approach to separate dormant and treatment-resistant tumor cells in human GBMs and other solid cancers. 12 samples, no replicates, derived from 5 individual patients

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