Abbott Keene L, Subudhi Sonu, Ferreira Raphael, Gültekin Yetiş, Steinbuch Sophie C, Munim Muhammad Bin, Honeder Sophie E, Kumar Ashwin S, Ramesh Diya L, Wu Michelle, Hansen Jacob A, Sivanand Sharanya, Riedmayr Lisa M, Duquette Mark, Ali Ahmed, Henning Nicole, Shevzov-Zebrun Anna, Gourgue Florian, Barbeau Anna M, Waite Millenia, Kunchok Tenzin, Ferraro Gino B, Do Brian T, Spanoudaki Virginia, Sánchez-Rivera Francisco J, Jin Xin, Church George M, Jain Rakesh K, Vander Heiden Matthew G
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
bioRxiv. 2024 Oct 25:2024.10.24.616714. doi: 10.1101/2024.10.24.616714.
Cancer metastasis is a major contributor to patient morbidity and mortality, yet the factors that determine the organs where cancers can metastasize are incompletely understood. In this study, we quantify the absolute levels of over 100 nutrients available across multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different organs. We then asked how tumor growth in different tissues relates to nutrient availability and tumor biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. Additionally, we identify purine synthesis as a requirement for tumor growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumor de novo nucleotide synthesis activity. These data suggest that a complex interplay of multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.
癌症转移是导致患者发病和死亡的主要原因，然而，对于决定癌症能够转移至哪些器官的因素，我们尚未完全了解。在本研究中，我们量化了小鼠多种组织中超过100种可用营养素的绝对水平，并研究了这与乳腺癌细胞在不同器官中生长能力的关系。我们构建了具有广泛转移潜能的乳腺癌细胞，使其对特定营养素具有营养缺陷型，并评估它们在不同器官中定植的能力。然后，我们探究了不同组织中的肿瘤生长与营养素可用性和肿瘤生物合成活性之间的关系。我们发现，单一营养素本身并不能决定乳腺癌细胞能够作为转移灶生长的部位。此外，我们确定嘌呤合成是许多组织中肿瘤生长和转移的必要条件，并发现这种表型与组织核苷酸可用性或肿瘤从头核苷酸合成活性无关。这些数据表明，微环境中多种营养素之间的复杂相互作用决定了转移性癌症生长的潜在部位，并突出了外在环境因素与内在细胞特性之间的相互依存关系，这种相互依存关系影响着乳腺癌细胞能够作为转移灶生长的部位。
