Cancer’s Wild Card

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Challenging Carcinomas

The Battle Against Epithelial Cancers

Explore the Battle

A Sinister Hand

Pathogenic
Plasticity

Reveal Plasticity

The wild card

LGR5,
The Moving Target

Decipher LGR5

Challenging Carcinomas:

The Battle Against Epithelial Cancers

Epithelial cancers (carcinomas) are common. They are associated with poor outcomes and their biology is complex.

The stakes are high because epithelial cancers combine high rates of recurrence with high risks.¹

Head and neck cancer (H&N or HNSCC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC) are examples of epithelial cancers and share risk factors (eg, smoking, alcohol).^1–4

Head and Neck^1,2

Colorectal^1,3

Lung^1,4

They are among the most prevalent epithelial cancers. In the US alone, they account for roughly 200,000 deaths and 450,000 new cases annually.^5,6 Metastasis is common and approximately half of patients experience recurrence.^1,3,4,7

A clear therapeutic target has been identified (EGFR)…but in spite of this, outcomes remain poor.^5,8,9

Why are these carcinomas so challenging? Because epithelial cancers can gain unique advantages that allow them to adapt, resist, move, and multiply.

The possibilities and limitations of EGFR as a target.

EGFR (epidermal growth factor receptor) has long been a go-to target in the battle against epithelial cancers. EGFR is an attractive target because it is commonly overexpressed in epithelial tumors (ranging from 40% to 90%^10–12), and because it is linked to growth, invasion, and resistance.^8,13,14

As a result, current standard therapies include EGFR-targeted therapies such as monoclonal antibodies and receptor tyrosine kinase inhibitors (RTKi).^8,13,14

Figure is hypothetical and does not reflect data from a specific clinical study.

After an initial response, epithelial cancers often develop resistance.⁹ Plasticity, in the form of epithelial-mesenchymal transition (EMT), is a known mechanism of resistance, whereby cancer cells use stem-cell–like capabilities to circumvent EGFR-targeted therapy.^8,15,16

Plasticity is the master manipulator.

A newly appreciated mechanism of cancer progression, pathogenic plasticity, is emerging as a super hallmark that dictates traditional cancer behavior (eg, proliferation and metastasis).^16–20

Normal cell

Cancer cell

Cancer cell with plasticity
(stem-cell–like capabilities)

Tumor expansion 
(heterogeneous cell mass)

Plasticity gives cancer cells the ability to fluctuate between proliferative/dormant states, as well as differentiate into different cell types.^{16,18,21–25} These dynamics support tumor growth and resistance, allowing epithelial cancer cells to hide, move, and grow.^22–24

Epithelial-mesenchymal transition: When an epithelial cell becomes unrecognizable.

Cell Transition 
Transition to another cell lineage (epithelial to mesenchymal)

Plasticity, in the form of epithelial-mesenchymal transition (EMT),^15,26,27 allows epithelial cancer cells to lose many of their key epithelial traits (such as cell-to-cell adhesion) to gain mesenchymal abilities (such as motility).¹⁶

The cancer cells become unrecognizable as epithelial cells. This allows them to resist EGFR-targeted therapy and metastasize to other parts of the body.^15,27

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A Sinister Hand:

Pathogenic Plasticity

Cancer exploits natural plasticity by flipping LGR5.

Plasticity is an effective mechanism for epithelial cancers to exploit because it is constantly active in epithelial tissue.^28–30

^aAdult stem cells expressing LGR5 are also found in the mouth and lungs where they support tissue homeostasis.²⁹ LGR5, leucine-rich-repeat-containing G-protein-coupled receptor-5 (also known as GPR49).

Throughout the body, adult stem cells use plasticity to replace epithelial cells that die or are sloughed off.^31,32 In the intestinal epithelium, for example, adult stem cells in the basal crypt are responsible for replenishing epithelial cells lost to shedding.³⁰

Adult stem cells in epithelial tissue can be identified by a protein called LGR5. LGR5 is an epithelial stem cell receptor that binds to R-Spondins (RSPOs), which are stem cell growth factors and potent signal enhancers.^28–30

LGR5-positive cells support tissue homeostasis across epithelial tissues such as the intestines, mouth, and lungs.^34–39

LGR5-positive cells are long-lived (>6 months) and self-renewing
Expression of LGR5 is typically restricted to a small subpopulation of cells

In epithelial cancers, LGR5 expression can become dysregulated and that changes everything. Cancer cells acquire this “wild card” protein and become capable of pathogenic plasticity, which integrates cell proliferation and differentiation to drive cancer progression.^28,40

Cancer can boost LGR5 expression 10x.

During the tumorigenesis process, LGR5 expression increases dramatically (10-fold), priming cancer cells for tumor initiation.⁴⁰

^aAdenomas and well/moderately differentiated adenocarcinomas.⁴⁰

This overexpression is found across epithelial cancers, and has been correlated with poor outcomes.

In head and neck cancer, LGR5 overexpression was associated with lower overall survival⁴¹
In colorectal cancer, LGR5 overexpression was associated with a 30% reduction in disease-free survival (1 year) and 3x increased risk of liver metastasis and recurrence (5 years)^42,43
In non-small cell lung cancer (NSCLC), LGR5 was shown to be overexpressed in tumor cells compared with normal adjacent tissue⁴⁴

Signaling, plasticity, and disease progression.

How is LGR5 a wild card?

LGR5 accelerates Wnt/beta-catenin signaling, a key driver of tumorigenesis, resistance, and metastasis.^29,45–48 Increasing levels of beta-catenin can drive metastasis by triggering epithelial-mesenchymal transition.

During epithelial-mesenchymal transition, cancer cells shed their epithelial features (cell-to-cell adhesion) and take on a mesenchymal identity; in the process, they gain traits that make them more mobile and invasive.^43,49,50

Once these mesenchymal-like cancer cells reach a new site, they undergo a complementary mesenchymal-epithelial transition (MET) and generate metastatic tumors.

With cell-to-cell adhesion and other epithelial traits restored, these cells are capable of tumor initiation and proliferation.^24,51

The battle against epithelial cancer is fluid and ever-changing. Wnt-signaling and EMT are normal stem-cell capabilities, but if epithelial cancer cells acquire LGR5, it can be used like a wild card to flip these mechanisms of plasticity into treatment resistance and metastasis.

As a receptor for RSPOs, the presence of LGR5 helps cancer cells re-purpose normal stem-cell capabilities, increasing resistance and metastatic growth.^30,38,47,52

But LGR5 is not just an accelerator of Wnt-signaling. It is also a moving target that helps epithelial cancers adapt.

Research the Science

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The Wild Card:

LGR5, The Moving Target

Is there a deadly dynamic between LGR5 and resistance to EGFR‑targeted therapy?

Preclinical studies have shown that tumor cells treated with EGFR-targeted agents (RTKi or monoclonal antibody) increase expression of LGR5.^23,35,53,54

Reprinted from Basak O et al. Induced quiescence of Lgr5+ stem cells in intestinal organoids enables differentiation of hormone-producing enteroendocrine cells. Cell Stem Cell. 2017;20(2):177-190.e4, Copyright 2017, with permission from Elsevier.

RTK, receptor tyrosine kinase.
^aEpidermal growth factor, Noggin, and R‑spondin-1 (ENR).

EGFR-targeted therapy is an established option of epithelial cancer treatment, but resistance is common. After an initial response, epithelial cancers often develop resistance, and epithelial-mesenchymal transition (EMT) is a known mechanism.^8,15

LGR5 is overexpressed in epithelial cancers, but as an epithelial protein, it is silenced when cells transition to a mesenchymal state.^47,55–62

As such, the effects of EGFR-directed therapy on LGR5 expression could be attenuated during the metastatic process.^28,60–63

LGR5 is a dynamic regulator of cancer cell plasticity.

LGR5 is a dynamic protein that is constantly internalized and replaced at the cell surface. This allows cancer cells to adapt to changes in the tumor environment.^47,55–57

In response to stress (eg, cancer treatment, nutrient deprivation), cancer cells silence expression of LGR5.^55,56,58

Silencing LGR5 expression flips cancer cells into a dormant state enabling resistance to therapies targeting rapidly dividing cells, or a mesenchymal phenotype that allows for mobility and metastasis.^60,61,63

Flipping between LGR5-positive and LGR5-negative states allows cancer cells to adapt to stress, resist treatment, and metastasize.^28,60,62

LGR5-positive cells are epithelial and proliferative^{28,60,61,64,65}
LGR5-negative cells are mesenchymal and dormant^{28,60,61,64,65}

LGR5, a wild card target that is moving.

LGR5 is a moving target that many epithelial cancers use as a wild card during tumorigenesis.

In early cancer, LGR5-positive cells are highly proliferative and can be the cell of origin for primary epithelial tumors.^40,61,63

But in response to treatment or stress, cancer cells with plasticity silence LGR5 and change type (mesenchymal), allowing for motility and invasion.^61,63

Epithelial cancer cells with plasticity are dynamic, thanks to LGR5. For that reason, treatment strategies need to be just as dynamic.

EGFR is a viable marker for epithelial cancers, but resistance to EGFR-targeted therapies is common.^8,9,15 LGR5 is a compelling target, but its expression fluctuates during disease pathogenesis.^61,63

Targeting LGR5 in isolation may not result in long-term tumor control. Developing an effective therapeutic strategy around LGR5 may require the integration of other targets or pathways.^23,49,66,67

Pathogenic plasticity is the hand many epithelial cancers are playing, and LGR5 can be their wild card.

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