A study published in *Nature* (2005) identifies a set of genes that mediate breast cancer metastasis to the lungs. These genes are associated with the ability of cancer cells to spread to the lungs and are distinct from those involved in bone metastasis. The research used in vivo selection, transcriptomic analysis, functional verification, and clinical validation to identify these genes. The study found that some genes provide growth advantages in both the primary tumor and the lung microenvironment, while others contribute to aggressive growth specifically in the lung. Many of these genes encode extracellular proteins and were previously unknown to be relevant to cancer metastasis. The study highlights that metastasis is a critical step in the progression of solid tumors, involving multiple steps such as intravasation, survival in circulation, extravasation, angiogenesis, and uninhibited growth. The molecular requirements for these steps may vary by tissue. The research also shows that the identity and timing of genetic changes that enable metastatic functions are not well understood, but genomic instability may lead to cellular heterogeneity, allowing rare variants with enhanced metastatic abilities to evolve through natural selection. The study used a breast cancer cell line, MDA-MB-231, derived from a patient with widespread metastasis, to identify genes that mediate lung metastasis. By testing different sublines and selecting for those with increased lung metastatic activity, the researchers identified a gene expression signature associated with aggressive lung metastasis. This signature included 95 genes, with 48 overexpressed and 47 underexpressed in the most metastatic populations. These genes were largely distinct from those associated with bone metastasis. The study also found that certain genes, such as EREG, GRO1, MMP1, MMP2, SPARC, IL13Rα2, and VCAM1, may play roles in the tumor microenvironment and are involved in lung metastasis. Functional validation showed that overexpression of these genes increased metastatic activity, while knockdown reduced it. The study also identified a subset of genes that are specifically involved in lung metastatic virulence. The research further showed that the lung metastasis signature is clinically relevant, as it is associated with poor prognosis in patients with breast cancer. The signature was found in a subset of primary tumors that had a higher risk of lung metastasis. The study also demonstrated that these genes may have dual roles, contributing to both breast tumorigenicity and lung metastasis. The findings suggest that metastasis is a complex process involving multiple genes and that understanding these genes could lead to new therapeutic strategies for cancer treatment. The study provides insights into the molecular mechanisms underlying breast cancer metastasis and highlights the importance of identifying genes that mediate metastasis to specific organs.A study published in *Nature* (2005) identifies a set of genes that mediate breast cancer metastasis to the lungs. These genes are associated with the ability of cancer cells to spread to the lungs and are distinct from those involved in bone metastasis. The research used in vivo selection, transcriptomic analysis, functional verification, and clinical validation to identify these genes. The study found that some genes provide growth advantages in both the primary tumor and the lung microenvironment, while others contribute to aggressive growth specifically in the lung. Many of these genes encode extracellular proteins and were previously unknown to be relevant to cancer metastasis. The study highlights that metastasis is a critical step in the progression of solid tumors, involving multiple steps such as intravasation, survival in circulation, extravasation, angiogenesis, and uninhibited growth. The molecular requirements for these steps may vary by tissue. The research also shows that the identity and timing of genetic changes that enable metastatic functions are not well understood, but genomic instability may lead to cellular heterogeneity, allowing rare variants with enhanced metastatic abilities to evolve through natural selection. The study used a breast cancer cell line, MDA-MB-231, derived from a patient with widespread metastasis, to identify genes that mediate lung metastasis. By testing different sublines and selecting for those with increased lung metastatic activity, the researchers identified a gene expression signature associated with aggressive lung metastasis. This signature included 95 genes, with 48 overexpressed and 47 underexpressed in the most metastatic populations. These genes were largely distinct from those associated with bone metastasis. The study also found that certain genes, such as EREG, GRO1, MMP1, MMP2, SPARC, IL13Rα2, and VCAM1, may play roles in the tumor microenvironment and are involved in lung metastasis. Functional validation showed that overexpression of these genes increased metastatic activity, while knockdown reduced it. The study also identified a subset of genes that are specifically involved in lung metastatic virulence. The research further showed that the lung metastasis signature is clinically relevant, as it is associated with poor prognosis in patients with breast cancer. The signature was found in a subset of primary tumors that had a higher risk of lung metastasis. The study also demonstrated that these genes may have dual roles, contributing to both breast tumorigenicity and lung metastasis. The findings suggest that metastasis is a complex process involving multiple genes and that understanding these genes could lead to new therapeutic strategies for cancer treatment. The study provides insights into the molecular mechanisms underlying breast cancer metastasis and highlights the importance of identifying genes that mediate metastasis to specific organs.