Science - 27.03.2020

SCIENCE

GRAPHIC: KELLIE HOLOSKI/

SCIENCE

By Ning Ma and Stefanie S. Jeffrey

C

ancer is associated with consider-

able morbidity and mortality, and

despite therapeutic advances, it still

represents the second leading cause

of death worldwide ( 1 ). As cancers

grow, evolve, and spread, they shed

circulating tumor cells (CTCs), as well as

other tumor-associated cells and products,

into the bloodstream. Capturing and ana-

lyzing CTCs or other tumor-associated cells

and products from a patient’s blood sample

can provide insight into a particular can-

cer’s biology, response to treatment, and/

or potential therapeutic targets ( 2 ). CTCs

are heterogeneous; a pressing question con-

cerns which CTCs represent those directly

involved in metastasis, the major cause of

cancer-related death. On page 1468 of this

issue, Ebright et al. ( 3 ) identify genes in

patient-derived CTCs encoding ribosomal

proteins (RPs) that were associated with

metastatic progression in mouse models,

poor outcome in patients, and alterations

in global translation. These findings could

point to potential biomarkers or targets for

future metastatic cancer therapies.

Tumors and their metastases are spatially

and temporally heterogeneous, highly influ-

enced by the context of the microenviron-

ment in which they grow and their expo-

sure to immune cells, stromal cells, and cell

products ( 4 ). As tumors evolve according to

their intrinsic biology, their environment,

and drug selection pressures, genetic, epi-

genetic, and transcriptional alterations can

diverge ( 5 ). Moreover, biomarker and thera-

peutic target discordance may occur be-

tween the primary tumor and metastases,

and even between different metastases, in

the same patient. This makes optimal treat-

ment selection a challenge throughout the

course of disease.

Because metastases are commonly mul-

tifocal, it is impractical, invasive, and po-

tentially dangerous to biopsy each one to

identify changing biomarkers that may in-

fluence subsequent drug selection. Instead,

sampling blood or other bodily fluids such

as urine, saliva, or tears—known as “liquid

biopsy”—facilitates the analyses of cells or

tumor-associated products that may offer

a more comprehensive snapshot of tumor

burden and its molecular diversity through-

out the body at any given time. Liquid bi-

opsy components under investigation in-

clude CTCs, either separate or aggregated

with immune cells; circulating endothelial,

stem, and stromal cells; cell-free compo-

nents such as DNA and RNAs; and nu-

merous other factors, such as extracellular

vesicles (see the figure). Currently approved

clinical use of liquid biopsy is limited but

expanding, with a few approved tests for

cancer screening or for identification of

specific actionable mutations that guide

cancer drug treatment, especially when tis-

sue biopsy is not possible. Multiple studies

are under way for early diagnosis, monitor-

ing of tumor recurrence, evaluation of treat-

ment response, and identification of emerg-

ing targets or resistance indicators during

disease progression ( 6 , 7 ).

CTCs are heterogeneous live cells in blood;

some retain the capability of seeding or re-

seeding metastases and thereby contribute

to increased metastatic growth. Ebright et

al. provide a singular approach to determin-

ing metastatic CTC subsets: They captured

CTCs from patients with hormone receptor–

positive (HR+) metastatic breast cancer, the

most common subtype. They cultured the

CTCs and transduced them with a library

of single guide RNAs to allow genome-wide

transcriptional activation (CRISPRa) ( 8 ).

The cells were then injected in mice, and the

highly expressed genes that were associated

with lung metastases were identified. They

found expected genes, such as oncogenes or

those involved in transcriptional and trans-

lational regulation, cell motility, and cell cy-

cle progression. But they also unexpectedly

found that metastatic CTCs expressed genes

encoding multiple RPs, which were associ-

ated with increased global translation.

Human cells show plasticity. Epithelial-

to-mesenchymal transition in cancer is a

state whereby epithelial cells lose cell po-

larity and cell adhesion proteins, becoming

more invasive and migratory—an important

step in metastasis. Mesenchymal-like cells

may revert by mesenchymal-to-epithelial

transition, gaining epithelial properties as

they integrate and grow in distant organs.

CTCs and CTC clusters are heterogeneous

even in the same blood sample ( 9 ) and may

show epithelial, mesenchymal, and hybrid

phenotypes ( 10 , 11 ). Ebright et al. found

that high RP–expressing CTCs captured

from the blood of patients with HR+ breast

cancer showed increased expression of epi-

thelial markers and decreased expression

of mesenchymal markers, and that these

patients had worse overall survival. Their

work implies that epithelial cell fate may be

associated with higher ribosomal content

and a greater propensity for metastasis.

When CTC cell lines were transduced to

overexpress specific RPs and then injected

into the tail veins of mice, metastases devel-

CANCER

Deciphering cancer clues from blood

Circulating tumor cells are accessible indicators of real-time cancer biology

Primary tumor

with cellular

heterogeneity

Metastatic

tumor cells

seed additional

metastases

CTCs seed

metastases

into distant

organs

Tumor cell

clones

Cell-free

nucleic

acids

Extracellular

vesicles

CTC cluster

Blood

sample

containing

CTCs

Department of Surgery, Stanford University School of

Medicine, Stanford, CA, USA. Email: [email protected]

INSIGHTS | PERSPECTIVES

1424 27 MARCH 2020 • VOL 367 ISSUE 6485

A snapshot of metastatic cancer biology

Tumor-associated cells and products intravasate into the bloodstream, circulate, extravasate into tissues,

and enable metastatic tumor growth in distant organs. Circulating tumor cells (CTCs) captured from a blood

sample reflect the diversity of cells from a primay tumor and different metastases.