Project Funding Details

More than 90% of cancer-associated deaths are due to metastasis, and yet, the molecular mechanism governing this process is not well understood. Metastatic organotropism, i.e., the property of cancer cells to preferentially colonize specific niches, has no association with their genetic alterations. Thus, the preferential selection of specific organs for their growth and survival must be mediated by the intrinsic properties of metastatic cells and their perfect match with features of the secondary microenvironment. Building on preliminary results on brain breast cancer (BC) metastases, here we envision that metastatic cells are selected for survival and proliferation in specific secondary sites by the exploitation of local trophic signals and the capacity of cancer cells to use them as they express enough quantities of the matched receptor. Focusing on brain BC metastasis, local enrichment of natural ERBB ligands (neuregulins) in the brain microenvironment selects ERBB-expressing metastatic cells released from the mammary primary site. We plan to systematically map the growth factor signals governing metastatic organotropism using a comprehensive multi-omics approach. We will characterize transcriptional profiles of metastatic cells in diverse anatomical sites and perform an innovative screening study to determine essential growth factor signals in human cancer cells. Lastly, we will challenge the limits of our model and verify whether we can manipulate the organotropism of metastatic cells to the extent of changing the roads of metastatic dissemination. To obtain metastases in distinct organs, pan-metastatic human BC cell lines engineered to express GFP-luc will be intracardially injected in NSG mice. We will compare the transcriptional profiles of masses growing in different organs to identify unique organ-specific signatures. Furthermore, we plan to perform a novel CRISPR/Cas9 depletion screening to knockout several growth factor receptors in tumor cells to determine the essential growth factor signal that cancer cells exploit to colonize each secondary organ. Finally, we will verify whether overexpression of brain metastasis-permissive signals in liver-specific metastatic cells can endow them with the capacity to colonize the brain and vice-versa. We expect to find recurrent transcriptional modules in different metastatic cells colonizing a specific organ, pointing at the use of a recognizable set of receptors to exploit the local trophic signals that characterize each secondary site. For example, gene expression signatures related to ERBB receptor activation should distinguish brain-metastatic cells; the sgRNA screening should confirm that the knockout of ERBB family members impairs the growth of metastatic cells in the brain. Eventually, overexpression of ERBB receptors in liver-specific metastatic cells should allow the development of masses in the brain. In parallel, the artificial expression of NRGs in the liver would permit the colonization of brain-specific metastatic cells. We believe that if our hypothesis holds true, the robustness of such mechanism will help to prospectively consider the use of already actionable targets of normal signal transduction mechanism for interrupting the metastatic process of cancer cells irrespectively of their genetic alterations, paving the way for the development of more attractive and broadly use anti-oncogenic drugs.