The goal of the Laboratory for the Study of Metastatic Microenvironments (LSM2) is to understand how microenvironments within distant tissues regulate the four “hallmarks” of disseminated tumor cells (DTCs): long-term survival, reversible growth arrest, immune evasion and therapeutic resistance. Solving these puzzles is key to extending metastasis-free survival of cancer patients; with the ultimate goal of preventing metastasis altogether.
Four major research directions are underway in our laboratory:
Breast cancer stereotypically yields metastases in the brain, lung, liver, bones and lymph nodes. But in a substantial fraction of patients, metastases may not emerge for five, 10, or even 20 years after treatment. How are DTCs kept at bay in the interim?
In 2013, we established that dormant breast cancer cells localize to the outer surface of microvessels- a microenvironment called the perivascular niche. There, endothelial-derived factors effect quiescence. Specifically, we reported that endothelial derived thrombospondin-1 suppresses DTC outgrowth in lung and in bone marrow. Interestingly, although DTCs are found on microvessels within the brain as well, brain endothelium does not express thrombospondin-1. This is but one minor reflection of how vascular and perivascular environments vary by tissue. Our hypothesis is that these unique perivascular environments effect dormancy in unique ways. To elucidate the tissue-specificity of the perivascular niche and of dormancy, we engineer mimetics of microvascular beds of a number of different tissues, including those where disseminated breast tumor cells commonly emerge (e.g., brain, lung, bone marrow and liver) as well as those where they rarely do.
Ghajar et al., Nature Cell Biology 2013
Dai et al. [in revision]
Lim et al. [in revision]
To address this question, we have adopted a high-content/high-throughput approach leveraging organotypic vascular niches, reporters of quiescence and apoptosis, and a 5,500 compound library. Our findings have revealed— unsurprisingly— that the drugs that target quiescent vs. proliferative tumor cells are completely different. By combining sequencing with therapeutic pressures, we have begun to unravel the pathways targeted by these compounds, with the hopes that this will inform us about the unique molecular and metabolic requirements of dormant DTCs. The goal is to define safe and specific therapies we can apply to eradicate dormant DTCs.
Pisarsky et al. [in progress]
It is assumed commonly that quiescent DTCs do not respond to genotoxic therapy because such therapies only target rapidly dividing cells. We challenged this notion, showing that chemotherapeutic regimens employed in the treatment of invasive breast cancer select for perivascular tumor cells in the bone marrow. Using organotypic vascular niches, we discovered that endothelium protects DTCs from chemotherapy, and that the mechanisms are cell cycle-independent, relying instead on interactions between integrins and molecules present within the vascular niche. Targeting integrins sensitized the vast majority of DTCs to chemotherapy, yielding drastic enhancements to metastasis-free survival in pre-clinical models.
This finding has motivated us to measure how chemotherapy impacts other non-dividing cells; especially endothelium. We hypothesized that chemotherapy causes DNA damage within the endothelium, and that this damage is linked to a vascular secretome that paradoxically protects DTCs from chemotherapy. We are now working to thoroughly define this secretome, and the signaling that links it to DNA damage. Targeting what we have called the chemotherapy-associated vascular secretome at its root or at its stem may yield efficacious therapies that can be applied with or without integrin inhibitors to eradicate DTCs.
We have used model antigens and immune-competent models to establish that dormant DTCs evade immunity, and uncover intrinsic and extrinsic mechanisms that allow them to do so. These findings have motivated us— in collaboration with Stan Riddell’s Lab— to explore engineered T cell receptor (TCR)- and chimeric antigen receptor (CAR)-based approaches to target dormant DTCs. Our goals are to: (i) identify the formant of immunotherapy best suited to eradicate dormant DTCs, (ii) re-engineer these cells so that they are optimized to traffic to and eradicate rare cell populations, and (iii) profile human DTCs so that we can identify realistic (neo)antigens that we can target with engineered T cells.
Goddard et al., Nature Cell Biology 2018
Grzelak et al. [under revision]
Goddard et al. [in preparation]