Brain metastases arise later than metastases at other sites. Once they do, they are rapidly debilitating and lethal. The time it takes for brain metastases to emerge suggests that a dormancy phase is involved. This notion is supported by clinical and experimental data. Indeed, our own preliminary data show that breast cancer cells become dormant upon entering the brain, and that emerging from this state is the rate-limiting step of metastasis. These data indicate that targeting dormant disseminated tumor cells (DTCs) is a logical approach to brain metastasis prevention. However, despite a growing understanding of dormancy mechanisms in common metastatic sites like lung and bone marrow, a parallel understanding of how DTCs are driven into a dormant state in brain has not developed. The overarching goal of this proposal is to address this issue. We will formulate a basic framework for how the brain microenvironment drives DTCs into a dormant state, with support from clinical specimens, so that we can leverage this understanding for therapies that keep DTCs dormant indefinitely. Our recent investigations have revealed that dormant DTCs occupy the brain?s vascular niche, where perivascular astrocytes suppress their outgrowth. We suspect that astrocytic contributions to the parenchymal basement membrane are responsible for DTC suppression, and that these contributions converge on a common receptor: dystroglycan. Therefore, our hypotheses are that: (i) astrocytic basement membrane is a key driver of DTC dormancy, and (ii) dystroglycan function must remain intact for DTCs to interpret these signals. We will test these hypotheses through two specific aims:
Aim 1. Determine whether astrocytic basement membrane promotes and sustains DTC dormancy.
Aim 2. Elucidate the dystroglycan-mediated signaling axis that effects DTC quiescence in brain. We have brought every relevant resource to bear in order to address these aims. These resources span: (i) long-term intravital imaging to determine the fate of DTCs following ablation of DTC-associated astrocytes; (ii) transgenic mice to measure the outcome of ablating astrocyte derived basement membrane molecules on DTC fate; (iii) rare clinical specimens to establish whether astrocytes and astrocytic basement membrane are asso- ciated with dormant DTCs in humans; and (iv) a host of mutant, over- and under- expression constructs to solve how dystroglycan functions from the outside-in to drive DTC quiescence. The significance and innovation of this work lie in the identification of the first dormancy drivers in brain, ultimately to unravel dystroglycan-driven signaling that effects disseminated breast tumor cell quiescence. This work will set the stage for agonists of dystroglycan function that serve as prophylactics for brain metastasis prevention.
Brain metastases are a growing problem across cancers. They can take many years to manifest, but are lethal once they do. Here, we propose to investigate breast tumor cells upon their arrival to the brain in order to define the cues that make them dormant, and to unravel the consequent signaling. We believe that solving these mysteries will inspire approaches to prevent brain metastasis by leveraging our discoveries for prophylactic therapies.
