Atypical Angiogenic Mimicry During Collective Lung Cancer Invasion

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Abstract Collective invasion is a major mode of metastasis observed in patients across most solid tumor types. How the collective invasion pack operates, communicates, and navigates as a single cohesive unit remains unclear. To address this, we published on an image-guided genomics platform to isolate any living cell(s) within a collective invasion pack, and expand the population for genomic and molecular analysis, a technique we termed Spatiotemporal Cellular & Genomic Analysis (SaGA). We used SaGA to deconstruct the collective invasion pack and dissect the molecular profiles of leader and follower cells invading as a hierarchical cohesive unit. To generate the collective invasion pack, leader and follower cells undergo a VEGF/Notch-based angiogenic mimicry program that promotes cell:cell cooperation and invasion that is similar, but not identical to angiogenesis. VEGF secreted by invasive leaders recruits proliferative followers into the collective pack; once the pack is formed, leader and follower cells undergo a Notch1-Dll4 cell patterning program that includes the Dll4 antagonist, Jagged-1 (Jag1). Based upon our published and preliminary data, we hypothesize that cooperative signaling among contiguous cells via Notch1 and its ligands are required to form the spatially dependent signaling events within the invasion pack. We propose that this fosters cell:cell cooperation and leads to increased metastatic efficiency. To test this, in Aim 1 we will define how atypical angiogenic mimicry via Notch1/Jag1/Dll4 signaling operates to spatially regulate cooperation and invasion. This would be a significant step forward in understanding how this pathway operates to maintain the collective invasion pack, drive metastasis, and facilitate ECM remodeling. In Aim 2, we use Jag1 as a lung cancer leader cell biomarker to isolate the first patient leader cells and probe atypical angiogenic mimicry. This allows us to define the metastatic potential and translational impact of this rare yet invasive population in lung cancer patients. Throughout, we leverage unique resources developed here including SaGA-derived cell lines, the first set of early and late-stage invading lung patient-derived organoids, ex vivo imaging, and a rare set of lung primary tumors with paired metastatic brain tissue. We speculate that these data will provide mechanistic insight into the atypical angiogenic mimicry program and translational value towards understanding lung cancer patient leader cell biology.