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Tumor Metastasis Research

Lung cancer cells invade surrounding tissues and start to spread (metastasis).

Credit: National Cancer Institute

Research in tumor metastasis seeks to define the mechanisms that allow tumor cells to leave the primary tumor, survive and travel through the circulation or lymph and ultimately enter distant tissues and expand. This research encompasses investigation of basic molecular mechanisms by which metastatic cell behavior originates including phenotypic changes, mechanisms of invasion, metastatic dissemination, homing to and colonization of distal organs or dormancy. Identification of specific molecular targets can facilitate the development of therapeutic interventions for treatment of metastatic disease.  Metastasis research examines both cell intrinsic events including epigenetic regulation of metastases promoting genes and programs as well as cell extrinsic programs that impact metastatic niches and microenvironments. Research that employs or develops novel model organisms to study all aspects of metastasis is also supported.

Research in this area is supported and directed by the Tumor Metastasis Branch.

Early Metastatic Dissemination

One of the earliest steps in metastasis is tumor cells leaving the primary tumor site and entering the circulation.  Funded research focuses on identification and behavior of circulating/disseminated tumor cells.

Key research areas include:

  • Identification of circulating tumor cells including the application of technological advances such as single cell sequencing and intravital microscopy to identify and track circulating tumor cells
  • Non-invasive mechanisms that facilitate tumor cell dissemination and survival and resistance to apoptosis in the circulation
  • Models to study early metastatic dissemination
  • Cancer stem cells

Recent studies have demonstrated that generation of metastasis-competent circulating tumor cells may occur in the very early stages of tumor development, often before palpable primary tumors are detected. Moreover, the earliest disseminated cancer cells can have distinct gene expression profiles and enhanced metastatic potential compared to disseminated cells derived from later stage tumors. Further research using these and other innovative approaches will not only improve early detection but also identify unique interventional strategies for potentially more aggressive metastasis.

Cellular Invasion and Migration

A fundamental trait of metastatic tumor cells is the ability to migrate and invade into adjacent tissue. Research investigating basic mechanisms (genetic, epigenetic, metabolic) that enhance metastatic capability including cell motility, invasion, or phenotypic changes and the impact of the tumor microenvironment on acquisition of metastatic properties are supported.

Key research areas include:

  • Basic cellular mechanisms including changes in molecular motors and cytoskeleton which contribute to enhanced cell motility
  • Changes in gene expression, phenotypic plasticity, and polarity, facilitating invasion and migration
  • Regulation of epithelial and mesenchymal phenotypes; epithelial mesenchymal transition
  • miRNA, lncRNA and non–coding RNA that promote invasion and migration
  • Proteases and remodeling of extracellular matrix; loss of adherens junction; cytoskeletal
  • Impact of hypoxia, metabolic changes
  • Tumor, stromal and immune cell generated factors and enhanced motility

Recent studies are also investigating mechanisms which contribute to collective versus individual cell movement with respect to metastatic spread.

Extravasation and Intravasation

Metastatic cells leaving the primary tumor enter blood or lymphatic vessels (intravasate) and subsequently extravasate from the vasculature when they arrive at distal metastasis supporting sites or organs.

Key research areas include:

  • Cell and vascular adhesion molecules
  • Vascular permeability
  • Angiogenesis and vasculogenesis
  • Immune cell assisted intravasation
  • Novel mechanisms of extravasation

Recent studies have revealed that clusters of tumor cells entering the circulation exhibit a significantly greater ability to survive and colonize distal organs compared to single disseminated tumor cells. Relatively little is known regarding the mechanism(s) employed by metastatic clusters. Metastatic cancer cells may also employ novel mechanisms such as necroptosis of the endothelial barrier to either enter or exit the circulation.

The Metastatic Niche and Colonization

The tissue or organ to which disseminated tumor cells ultimately home (tropism) is determined by a number of factors. Recent studies have shown that remarkably, the sites for future metastatic colonization are often pre-conditioned by distant tumor cells. Research investigating the nature of these pre-conditioning factors as well as the contribution of the metastatic niche microenvironment in promoting colonization by disseminated tumor cells at distal sites is also supported.

Key research areas include:

  • Chemokines, cytokines, and metastatic niche conditioning
  • Metastatic exosome biogenesis, cargo and trafficking
  • Bone marrow derived cells and metastatic priming
  • Immune cell profiling and function in metastatic niche
  • Proteases, adhesion receptors and remodeling of extracellular matrix in metastatic sites
  • Colonization and proliferation within the metastatic niche

Emerging evidence also suggests that communication between primary tumor cells and the metastatic niche is a bi-directional event whereby the primed metastatic niches release soluble factors which in turn enhance the metastatic capacity of cancer cells still residing in the primary tumor. Thus, additional research into the metastatic microenvironment and the reciprocal interactions between cells could refine the use of current immunotherapies to directly target metastases.

Metastatic Dormancy

Disseminated tumors cells arriving at primed metastatic sites often persist in a dormant state for unspecified periods of time (months to decades). Understanding how the dormant state is maintained and preventing the emergence of macrometastatic lesions are critical areas of research.

Key research areas include:

  • Cell intrinsic dormancy programs and dormancy signatures
  • Influence of the metastatic microenvironment including stromal and immune cells on dormancy
  • Angiogenic dormancy
  • Emergence from dormancy; both cell intrinsic and microenvironmental influences

In addition, the development of suitable experimental models of dormancy will greatly facilitate research in this area and identify points for therapeutic intervention to prevent re-emergence from metastatic dormancy.

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