Cancer tissue of origin constrains the growth and metabolism of metastases

Abstract

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.

Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism

“…The finding that FA metabolism is already altered in a p53-dependent manner in primary BCs is biologically important. It is in full agreement with a recent study that demonstrated that the metabolic programs of primary tumors were very similar to those of their metastases, arguing that cancer cells retain many aspects of a metabolic program that is defined by the tissue-of-origin even when exposed to a new metastatic niche ( 82 ). That study concluded that despite much evidence for specific metabolic adaptations within metastatic niches, the metabolic program of the primary tumors may constrain cancer metastasis ( 82 ).…”

“…It is in full agreement with a recent study that demonstrated that the metabolic programs of primary tumors were very similar to those of their metastases, arguing that cancer cells retain many aspects of a metabolic program that is defined by the tissue-of-origin even when exposed to a new metastatic niche ( 82 ). That study concluded that despite much evidence for specific metabolic adaptations within metastatic niches, the metabolic program of the primary tumors may constrain cancer metastasis ( 82 ). This is in line with older gene expression analyses showing that the metastatic potential of human tumors is encoded in the bulk of the primary tumor ( 83 ).…”

Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation

“…Mechanisms that determine a cancer cell's metastatic fate toward one organ site over another are poorly understood and are not sufficiently accounted for by a model of serial, divergent acquisition of somatic mutations 33,34 . The fact that cancer types with different oncogenic dependencies and distinct lineages exhibit a shared preponderance for metastasis to a specific organ (for example, LM in both melanoma and colorectal cancer) suggests that target-organ-specific adaptations occur and may be determined by the required metabolic requirements and phenotypic plasticity 35 .…”

“…Filled graphs in (b,c) indicate viral concentration/dilution used for the large-scale CRISPR screen. d, Pearson correlation coefficient of the normalized sgRNA read counts from Brie plasmid pool, transduced cells in vitro edited over time (10,14,21,28,35,42,49,56 days after spin infection), from primary tumors (n = 8), from liver (n = 14), lung (n = 3), and lymph node (n = 8) metastases. For each biological sample type, biological replicates (R1, R2, R3… R8), for technical replicates (R3.1, R3.2) are shown.…”