Metastasis is the deadliest feature of cancer, accounting for greater than 90% of cancer-related mortality. The clinical manifestation of metastatic lesions is the end result of a treacherous journey that few tumor cells are capable of completing, including local invasion and intravasation, survival in the circulation, homing and extravasation into the parenchyma of distant organs, and finally, adaptation to the new environment and outgrowth of secondary lesions. Development of successful therapeutic strategies to specifically target metastasis depends on understanding tumor-intrinsic and extrinsic mechanisms that dictate metastatic behaviors, the metastatic niches for the seeding and outgrowth of metastases in different organ sites and the molecular features that render metastatic cancer resistant to current therapies.
The Ludwig Princeton Branch plays a leading role in the study of cancer metastasis, including signaling networks that regulate cellular plasticity during metastasis, stromal niches that regulate organ-tropic metastasis, metabolic adaptation of metastatic cancer cells, as well as the development of novel anti-metastasis therapeutic agents.
Related Publications
Han Y, Kang Y. J Bone Oncol. 2024 Mar 1;45:100592. doi: 10.1016/j.jbo.2024.100592. PMID: 38450202; PMCID: PMC10912615.
Metastasis is a major contributor to cancer patient mortality. Tumour cells often develop phenotypic plasticity to successfully metastasize to different target organs. Recent progress in the study of bone metastasis has provided novel insight into the biological processes that drive the spread and growth of cancer cells in the bone. In this review, we provide a summary of how the bone marrow microenvironment promotes phenotypic plasticity of metastatic tumour cells and alters therapeutic responses. We highlight pivotal transformations in cellular status driven by plasticity, including mesenchymal-epithelial transition, acquisition of stem-like traits, and awakening from dormancy. Additionally, we describe the phenomenon of host-organ mimicry and metabolic rewiring that collectively serve as key attributes of disseminated tumour cells, enabling their successful colonization and growth within the bone marrow microenvironment.
Celià -Terrassa T, Kang Y. PLoS Biol. 2024 Feb 7;22(2):e3002487. doi: 10.1371/journal.pbio.3002487. PMID: 38324529; PMCID: PMC10849258.
Epithelial-to-mesenchymal transition (EMT), a biological phenomenon of cellular plasticity initially reported in embryonic development, has been increasingly recognized for its importance in cancer progression and metastasis. Despite tremendous progress being made in the past 2 decades in our understanding of the molecular mechanism and functional importance of EMT in cancer, there are several mysteries around EMT that remain unresolved. In this Unsolved Mystery, we focus on the variety of EMT types in metastasis, cooperative and collective EMT behaviors, spatiotemporal characterization of EMT, and strategies of therapeutically targeting EMT. We also highlight new technical advances that will facilitate the efforts to elucidate the unsolved mysteries of EMT in metastasis.
Nolan E, Kang Y, Malanchi I. Cold Spring Harb Perspect Med. 2023 Mar 27:a041326. doi: 10.1101/cshperspect.a041326. Online ahead of print. PMID: 36987584
Cancer metastasis, or the development of secondary tumors in distant tissues, accounts for the vast majority of fatalities in patients with breast cancer. Breast cancer cells show a striking proclivity to metastasize to distinct organs, specifically the lung, liver, bone, and brain, where they face unique environmental pressures and a wide variety of tissue-resident cells that together create a strong barrier for tumor survival and growth. As a consequence, successful metastatic colonization is critically dependent on reciprocal cross talk between cancer cells and host cells within the target organ, a relationship that shapes the formation of a tumor-supportive microenvironment. Here, we discuss the mechanisms governing organ-specific metastasis in breast cancer, focusing on the intricate interactions between metastatic cells and specific niche cells within a secondary organ, and the remarkable adaptations of both compartments that cooperatively support cancer growth. More broadly, we aim to provide a framework for the microenvironmental prerequisites within each distinct metastatic site for successful breast cancer metastatic seeding and outgrowth.