Prevention and treatment of metastatic disease is one of the most difficult challenges facing cancer treatment. While our knowledge of metastatic disease has grown significantly, precise therapies to intervene early and stop metastasis are not available. The discovery that disseminated cancer cells (DCCs) or even recurrent clones in hematological malignancies can originate very early in cancer evolution and that early or late evolved systemically disseminated clones can enter years- to decades-long periods of dormancy, reshaped our notion of metastasis targeting. For the first time we gained insight into an unexpected biology, that is that cancer pauses its progression, revealing a window of opportunity for early intervention.
To advance this strategy, we must, however, overcome the hurdles of refining our understanding of the basic mechanisms of cancer dormancy and relapse and predicting during remission whom and when will relapse. Given that recurrence is, in general, stochastic in nature, we reasoned that changes in the host might hold the answers to what controls dormancy and reactivation.
The Cancer Dormancy and Tumor Microenvironment Institute (CDTMI) is the first Institute ever created to integrate an orthogonal approach to address the question of how residual cancer dormancy, aging, lifestyle-related perturbations of target organ niches, epigenetics, genetics, and treatments influence relapse across all cancers.
The CDTMI combines the themes of cancer dormancy and metastasis, evolutionary biology, age-related tissue pathologies like clonal hematopoiesis, adaptive and innate immunity, and adult stem cell quiescence in tissue microenvironments across solid cancer and hematological malignancies.
The CDTMI also collaborates with other Institutes and Centers of Excellence at Montefiore Einstein to leverage technological advancements and knowledge across disciplines not immediately obvious to the problem of cancer dormancy and relapse to foster a multidisciplinary and innovative Institute with a transformative impact.
Our vision supports the hypothesis that residual dormant cancer cells persist after therapy and/or populated target organs long before clinical relapse due to early spread. We posit that residual cancer cells are kept dormant by the same homeostatic signals and cell types that instruct adult stem and differentiated cells to maintain orderly repair and restricted growth patterns. We envision that as we age and/or perturb those homeostatic programs in ways that mimic aging-related damage, heterogeneous dormant residual cancer cell sub-populations may become reactivated and form metastases in solid cancer or systemic recurrence in hematological malignancies. The timing of these microenvironment-driven transitions may be further influenced by the transcriptional and/or epi/genetic “maturity” of DCCs. The programs at the CDTMI aim to solve this puzzle by identifying the host- and residual cancer cell-specific mechanisms that induce and maintain dormancy but, when disrupted, can fuel reactivation.
The CDTMI takes advantage of remarkable technological advances in genome editing, transgenic animal models, proteomics, metabolomics, engineering, intravital and whole-body imaging, single-cell profiling and spatial transcriptomics that allow biological systems to be probed and manipulated with unprecedented resolution. Combining expertise in medical oncology, epidemiology, cell biology, evolutionary biology, aging, immunology, hematopoiesis, engineering, optical subcellular and whole-body imaging, and computational biology along with the patient advocates, optimally positions our multidisciplinary Institute to address this big vision and deliver new biomarkers and therapeutic strategies.
Our Mission Objectives
- To identify the intrinsic and TME mechanisms that control cancer dormancy
- To determine how changes in the host contribute to awakening of dormant cancer cells.
- Study the effect of aging on cancer dormancy and its relationship with the immune system
- Identify dormancy biomarkers and therapeutics to kill dormant cells or maintain dormancy
Description of the research themes and areas of focus to address the problem of cancer dormancy
We hypothesize that dormancy states of early or late evolved disseminated cancer cells (DCCs) in solid cancers (B) or residual cancer cells in hematological malignancies (C) are affected by common but also distinct alterations of target organs niches (A & D) caused by aging, senescence and, among others, inflammatory processes that may create dysfunctional adult stem cell niches and loss of tissue homeostasis (A). Alone or in addition to these changes, bone marrow (BM)-originating alterations such as fibrosis, now coupled with genetic alterations in the cancer cells and/or lifestyle-led changes in target organs that alter the crosstalk between distinct niches and dormant cancer cells could cause their reactivation (A). Our focus is on cancers and sites where we have documented early and late dissemination and dormancy of these early and late evolved DCCs in genetically engineered mouse models and/or patients (B) and in hematological malignancies where minimal residual disease and relapse are a major problem (B). Our focus is also on target organs where recurrences can emerge across these cancers such as the brain, lung, liver, lymph nodes and bone marrow. The CDTMI membership, which is being expanded by an active recruitment effort (see recruitment tab) brings together complementary expertise in the host variables (colored circles from A) and cancer models (B & C) described here. The Institute’s translational focus is also supported by our ability to access relevant human samples via a close collaboration with NYPOG to ask questions about dormancy and metastasis in fresh bone marrow aspirates and lymph node samples, among others, to isolate DCCs and host cells for profiling, FFPE primary and metastatic tissues to validate markers and complement DCC analysis as well as normal host tissue to interrogate the effect of the variables in panel A on the target organ niches that induce dormancy of cancer cells. Importantly the CDTMI will participate in the MECC programs of community outreach and engagement (COE) to create a space of communication and education with patient advocates and the community to fine-tune our science with a patient-centered perspective. Our vision pursues a model of integrated and collaborative science. This complementation enables an unsurpassed level of integration, co-experimentation, cross-fertilization of ideas and communication to address and solve the problem of cancer dormancy and relapse.