Cancer tissue of origin constrains the growth and metabolism of metastases

Metastases arise from a subset of cancer cells that disseminate from the primary tumor; however, the factors that contribute to proliferation of cancer cells in a secondary site are incompletely understood. The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize. Specific cancer types metastasize to consistent subsets of tissues, suggesting that factors within the primary tumor influence the tissue environments where cancers can grow. Using pancreatic cancer as a model, we find that primary and metastatic tumors are metabolically similar to each other and that the tumor initiating capacity and proliferation of both primary- and metastasis-derived cells is favored in the primary site relative to the metastatic site. Moreover, propagating lung or liver metastatic cells in vivo to enrich for tumor cells adapted to grow in the lung or the liver does not enhance their relative ability to form large tumors in those sites, change their preference to grow in the primary site, nor stably alter their metabolism relative to primary tumors. To assess whether this preference for the primary site is specific to pancreatic cancer, we analyzed liver and lung cancer cells and find that these cells also best form tumors in the tissue that corresponds to their primary site. Together, these data suggest that the cancer tissue-of-origin influences the metabolism of both primary and metastatic tumors and may impact whether cancer cells can thrive in a metastatic site. One-Sentence Summary Tissue-of-origin is a major determinant of metastatic tumor metabolism and accessing the right metabolic environment may contribute to why cancers metastasize to specific tissues. ### Competing Interest Statement M.G.V.H. is a scientific advisor for Agios Pharmaceuticals, iTeos Therapeutics, Faeth Therapeutics, Sage Therapeutics, and Auron Therapeutics. A.N.L.:Present address: Pfizer Inc., 1 Portland St., Cambridge, MA, 02139, USA. All other authors declare no competing interests.