Understanding Tumor Metastasis: How Cancer Spreads

Cancer cells can break away from the primary tumor, invade surrounding tissues, and spread to distant organs—a process known as metastasis. This hallmark of advanced cancer poses the greatest threat to patient survival. At the heart of this challenge is a complex biological journey involving cellular migration, immune evasion, and colonization of new tissues.

Research supported by the Tumor Metastasis Branch aims to unravel the intricate mechanisms that allow tumor cells to leave their original site, navigate through the body, and establish new tumors elsewhere. This work spans from genetic alterations at the cellular level to the systemic effects seen throughout the body.

Key Areas of Metastasis Research

???? Cellular Invasion and Migration

Metastatic cancer cells are highly mobile and capable of invading surrounding tissues. Researchers are exploring both internal (intrinsic) factors—like gene expression changes—and external (extrinsic) influences—such as the tumor microenvironment—that drive this behavior.

Current research focuses on:

Single-cell and collective movement of tumor cells

Changes in gene expression, cell polarity, and cell shape (e.g., EMT and MET)

Dysregulated molecules like miRNAs, lncRNAs, and post-translational protein modifications

Altered adhesion and extracellular matrix remodeling

Perineural invasion (migration along nerves)

The role of immune and stromal cells in supporting invasion

Understanding how tumor cells move helps reveal how they survive and spread during metastasis.

???? Intravasation and Extravasation

Once invasive, tumor cells enter the bloodstream or lymphatic system (intravasation), travel through the body, and exit into new tissues (extravasation).

Research focuses on:

Interactions with blood and lymphatic vessels

The role of immune cells and blood components like platelets

Effects of vascular permeability and mechanical stress

The enhanced survival of tumor cell clusters in circulation compared to individual cells

These steps are critical for successful metastatic seeding.

????️ Early Metastatic Dissemination

Some cancer cells gain metastatic potential early in tumor development—sometimes before the primary tumor is detectable. These early disseminators often have unique molecular and metabolic traits.

Areas of study include:

Identifying circulating tumor cells (CTCs) using advanced technologies like barcoding and single-cell sequencing

Investigating phenotypic plasticity of CTCs

Understanding cancer stem-like cells and their role in early spread

Using novel models like microfluidic platforms to study early dissemination

Uncovering early metastatic behaviors may lead to better diagnostic and therapeutic approaches.

???? The Metastatic Niche and Colonization

Colonization—the growth of tumor cells in distant organs—is often the bottleneck in metastasis. Tumor cells need supportive environments, or “niches,” to thrive.

Current research investigates:

How the primary tumor conditions future metastatic sites

Roles of exosomes, cytokines, and host responses

Interactions between cancer cells and stromal, neural, or immune cells

Mechanisms of immune evasion and therapy resistance

Interestingly, certain tissues like skeletal muscle naturally resist metastasis, offering clues for potential therapies.

⏳ Metastatic Dormancy

Disseminated cancer cells can remain dormant for years before forming detectable tumors. Understanding what keeps them in this silent state—and what wakes them up—is a key challenge.

Focus areas include:

Dormancy programs inside tumor cells

Signals from the microenvironment (e.g., immune or nerve cells)

Angiogenic dormancy (lack of blood vessel growth)

Models to study dormancy and its reversal

Targeting dormant cells may prevent future metastatic flare-ups.

???? Systems Biology & Whole-Body Impact

Metastasis is more than just a localized event—it’s a whole-body process. Even organs without detectable tumor cells can be affected, as seen in cancer cachexia, a syndrome of severe weight and muscle loss.

Key research themes:

Using computational models to understand and predict metastasis

Mapping large-scale biological data across systems (immune, neural, vascular, etc.)

Investigating systemic effects that contribute to disease progression

Exploring how cancer perturbs normal physiological networks

This systems approach is uncovering how cancers orchestrate complex changes throughout the body to support their growth and spread.

The Big Picture

Metastasis is not a single event but a multistep, dynamic process involving cellular reprogramming, environmental manipulation, and systemic disruption. By investigating each stage—from local invasion to distant colonization—researchers hope to develop new ways to detect, prevent, and ultimately treat metastatic cancer.

Stay tuned as we dive deeper into emerging discoveries from the Tumor Metastasis Branch and beyond.

Kim Lockheimer, DFM, PhD