Lecture 17: Tumor Heterogeneity and Plasticity Part 2

Non- genetic tumor heterogeneity

Cells can have different epigenetic or diff traits that do not exactly have to do with DNA

Cell state

The internal condition of a cell given time defined by

1. Gene expression

2. Signaling activity

3. Molecular programs

4. Enviornmental inputs

Overall anything besides DNA

Phenotype

Measurable or visible characteristics of a cell

1. Morphology (shape)

2. Behavior

3. Growth rate

4. Invasiveness

5. Response to treatment

Quiescent + DNA damage. How do they show the same phenotype

They both show the phenotype of non-dividing cells

• One comes from low signal activity and the other comes from DNA damage signaling

Plasticity

Ability for cell to change cell state and therefore phenotype

What is the advantage of plasticity

Cells can adapt without changing their phenotype

• When in combination with genetic changes we have tumor heterogeneity and tumor adaptation

Cancer stem cell model of tumor organization

Tumor cells are like stem cells they differentiate into phenotypically defined cells

What are the requirements for the stem cell model

• Only a certain subset of cells can self renew, differentiate and generate diverse cell types

What is evidence that supports the stem cell like model

1. When normal bulk cells were taken out of from a mouse and put into other mice, many of the cells did not grow tumors

2. however when Isolated CSC were taken out of the original tumor, the mice obtained tumors that grew very similar to the original tumor

What is evidence that challenges the CSC model?

1. Plasticity allows cells to adopt stem-cell like behaviors, we know this because cells can become metastatic and go throw the EMT pathway

2. Lineage tracing shows that differentiated cells can contribute to tumor growth

3. In tumor specific cancers, frequency of TIC were increased dramatically

CSC stemness may be a cell state

Cells can gain or loose stem- like properties

• “stemness” may be dynamic and context dependent

How can we identify cell states and phenotypes

We can use single cell approaches

1. Single cell RNA seq: measures the single frequency of gene expression in one cell, can identify different cell states in a tumor, will also reveal whether a gene is being transcribed, is it accessible

2. We can also track phenotypes over time, identify distinct cell states within a tumor,

how does Sc-RNA seq work

Single cells captured inside of its own droplet, along with a unique barcode for the cell, once mRNA is exposed can directly capture the unique cDNA from each droplet

Explain Retina mapping

Different cells that show similar cell states are clustered together allows you to map unique regions within tumors/ tissues

What are spatial transcriptomes

Allows you to map gene expression back to tissue location

• maps the unique expression patterns within a tissue or tumor

• Shows the microenvironment of the cell

How can you track cell fate?

Use lineage tracing → track descendants or each individual cell

• allows us to see where cells go overtime and what cells expand from original cells → allows us to see how cell states changes overtime