Lecture 16: Tumor Heterogeneity and Plasticity

These flashcards cover key vocabulary terms and concepts related to tumor heterogeneity and tumor growth as discussed in the lecture.

Tumor Heterogeneity

Differences in genotype, phenotype, or molecular characteristics between patients as well as within a single tumor.

Tumorigenesis

The evolutionary process where tumors develop through variation, selection, and expansion.

Natural Selection

The process that determines which cells survive and expand within a tumor due to environmental pressures.

Tumor Microenvironment

The surrounding environment and conditions that influence tumor growth and behavior.

Apoptosis

The process of programmed cell death that eliminates damaged cells.

what is the clinical importance of tumor heterogeneity

It overall Makes it harder to treat cancer

1. Biopsy may not detect the whole tumor, stops us from seeing unique parts of tumor cells

2. Different cells respond differently + resistant populations → hard to treat brain tumor and skin tumor the same way

3. What might prevent tumor in one patient will not prevent tumor in another patient

Why do mutated cells not become cancer cells

because they have to bypass apoptosis, senescence, cell cycle check points, and immune survellience.

Rate of evolution of tumor cells

Some cells have a context dependent growth rate which can make some cancers easier or harder to detect

How does context matter for acquiring cancer/ mutations that drive cancer

Mutations are context dependent on

1. Cell type

2. Tissue enviroemtn

3. External environment

4. Host genetics

Reason why a mutation in a lung can cause lung cancer but the same mutation in skin does not cause skin cancer

Explain the melanoma BRAF and NRAS mutations

These mutations are necessary but not sufficient for melanoma development

Explain Gain of function mutations in epithelial environment vs mesenchymal environment

Mutations in GNAQ GNA11 and PLCB4 survive and proliferate in mesenchymal environment like the eye and die in an epithelial environment like the skin

Selection

Influences whether a cell persists or is eliminated or can expands

1. Dynamic

2. Cannot predict the outcome of selection

3. Context dependent

Overall shapes which cells can contribute to the population over time

What are the two models of tumorigenesis

Monoclonal - tumor arises from one cell

Polyclonal - tumor arises from multiple cells

X chromosome Inactivation in support of monoclonal tumor

• In females one x chromosome can be inactivated

• If maternal/paternal x chromsome inactive all following daughter cells show the same X inactivation

Phylogenetic analysis of tumors in support of monoclonal tumor

Next generation sequencing allowed scientists to to see multiple tumor types that showed shared mutations that derive from a “parent mutation”

What is expansion of cells

“Survival of the fittest”

1. Cells within a tissue can have many different mutations

2. The cells that obtain mutations can override the barriers to tumor formation, lead to tumor development

3. The most fit tumors evolve even more overtime

Explain the example of expansion for colorectal cancer

1. Need an adenoma tumor as a precursor to carcinoma

2. The adenoma tumor obtains multiple driver mutations but additionally many barriers need to be overcome to make carcinoma

New model vs Old model for tumor formation

Old model → 1 mutation outcompetes all cells

New model → many mutations in different cells lead to tumor formation

Driver mutation

Mutation that makes cells more fit can stem from cells with competitive or non-competitive advantages

Passenger mutation

Neutral mutations do not directly contribute to cancer progression

How can tumors be monoclonal in origin yet genetically heterogenous

• A single cell can acquire a driver mutations which provides a fitness advantage

• As the cells divides, sub populations within the tumor acquire additional distinct genetic alterations

Ex: adenoma cells branch out and gain other mutations to become metastatic