Our continued inability to develop selective therapies that prevent the emergence of disseminated breast tumor cells into lethal metastases necessitates new approaches. We have shown that disseminated tumor cells (DTCs) occupy the perivascular niche (PVN), that this niche promotes chemotherapeutic resistance, and that targeting interactions between DTCs and the PVN sensitizes DTCs to chemotherapy. Translating this approach to pre-clinical models of breast cancer prevented metastases in over 60% of at-risk mice. Questioning the mechanism(s) of resistance in the remainder of mice led us to consider the dynamic response of the vascular niche to chemotherapy. Our preliminary data indicate that genotoxic agents trigger the secretion of pro-survival factors into the PVN, and that the major trigger of this chemotherapy-associated vascular secretome is the DNA damage response (DDR). Therefore, here our goal is to target the cause (i.e., the DDR) and the consequence (i.e., the chemotherapy-associated vascular secretome) of vascular evolution, which we suspect promotes therapeutic resistance of DTCs. We will pursue this goal through 2 specific aims:
Specific Aim 1. To determine whether individual extracellular factors elicited from vascular endothelium by chemotherapy protect DTCs. We have defined a global vascular response to DNA damaging agents. Netrin-1 is a prominent component of this secretome with documented pro-survival functions. Our data show that endo- thelial-derived Netrin-1 protects DTCs from chemotherapy. Using organotypic, transgenic and preclinical mod- els, we will determine: i) whether endothelial cells are the relevant source of chemotherapy-elicited Netrin-1 in vivo; ii) whether targeting Netrin-1 as an adjuvant sensitizes DTCs to chemotherapy; iii) whether this syner- gizes with targeting pre-existing protective factors in the PVN; and iv) the safety of these approaches.
Specific Aim 2. To identify DNA damage driven signaling pathways in vascular endothelium that induce the chemotherapy-associated vascular secretome. Our preliminary data demonstrate that genotoxic therapy elicits a stereotypic DDR from quiescent endothelium, and that targeting a nucleator of this response mutes the ma- jority of the chemotherapy-associated vascular secretome. This approach may be a more robust alternative to targeting a single pro-survival factor such as Netrin-1. Here, we will identify and target the signaling pathway that connects DDR to the vascular secretome, and measure the efficacy and toxicity of this approach. The significance and innovation of this work lie in the discovery of origins and outputs of chemoprotective factors in the DTC niche. Targeting both will result in the first approach to specifically target DTCs, impacting breast cancer survival in a positive and lasting fashion.
We have proposed that it is necessary to eradicate disseminated tumor cells (DTCs) in distant tissues like bone marrow in order to prevent breast cancer metastasis. We have shown that DTCs are resistant to chemotherapy because of the niche that they occupy, and found that chemotherapy triggers robust changes within this niche that, paradoxically, actually protect DTCs from therapy. We propose to identify and target this response in order to deprive DTCs of pro-survival signals, thus preventing their ability to cause lethal complications in the future.
