Spatiotemporal resolution of niche and genomic co-evolution in brain-metastatic organotropism

Columbia University Health Sciences, New York NY

Investigators

Abstract

PROJECT SUMMARY Brain metastasis (BM) is a feared complication that occurs in patient with multiple advanced cancer types including melanoma and non-small cell lung cancer and is associated with high treatment resistance, morbidity and mortality. Extensive genomic profiling of patient tumors has not identified a specific divergent somatic mutation that determines brain-metastatic organotropism, but in prior studies of patient biopsies, we found that BMs have a higher degree of chromosomal instability (CIN) compared to extra-cranial metastases across a variety of cancer types. Using multi-modal single-cell and spatial genomics across multiple cancer lineages, we have also found a consistent association of CIN and a pro-tumorigenic tumor microenvironment (TME) with BM. Defining the causal relationship between CIN and BM has previously been challenging due to lack of pre-clinical models that faithfully recapitulate human disease. Here, we have overcome these barriers, and through development and implementation of several experimental and technical innovations, are able to model the co- evolution of cancer cell states and the TME during brain-metastatic progression. Furthermore, we have assembled unique patient cohorts in which we collected primary tumors and matched BMs from the same individual, thus, enabling a more accurate evaluation of salient BM biology during metastatic progression in patients. Building on these, we now propose in Aim 1 to perform spatio-temporal analyses of the entire brain- metastatic arc, beginning with a single-cell interacting with the blood-brain-barrier, all the way to fully developed macro-BM. This will be enhanced by using a novel niche-labeling method coupled with spatial transcriptomics, which will allow for deconvolution of cell-to-cell interactions over time and in space; furthermore, using novel molecular tools, we will modulate the rate of CIN and test the causal relationship of this genomic feature with the evolution of an immunosuppressive TME and the rate of BM development. In Aim 2, we will test these concepts in large NSCLC and melanoma patient cohorts with matched PT and BM, and will employ a series of analytical innovations to quantify tumor remodel during metastatic progression to the brain. Together, this work will provide insights into the brain-metastatic cascade through an unprecedented lens, functionally define the role of CIN as a hallmark of brain metastasis, and enable the dissection of these concepts in unique patient samples. Given the increasing interest in targeting CIN and enhanced consideration of metastatic disease site in treatment decisions, this work has important translational implications. With access to world-class mentorship in bioinformatic analysis and cancer biology at the Columbia University Irving Medical Center, this project will provide me with a solid foundation for a career as a future physician-scientist in cancer biology.