New Study Implicates an Inherited Risk Factor of Alzheimer’s Disease in Cancer Metastasis

By Lavanyaa Manjunatha, Ph.D.

Cancer metastasis is an advanced stage of the disease that is difficult to cure. A new study conducted on the mouse model of melanoma reveals that a single germline gene, APOE is involved in metastasis and cancer progression.

Background

Apolipoproteins are amphipathic molecules that interact with the aqueous environment of plasma and the water-insoluble lipids. They are encoded by the APOE gene, which exists as three different variants APOE2, APOE3, and APOE4. Their protein products differ in one or two amino acids and have varied functions owing to their differential binding to APOE receptors. APOE mediates several functions, namely the transport of lipids, cholesterol, fat-soluble vitamins, and immune system regulation.

APOE gene polymorphisms are a major genetic risk determinant of Alzheimer’s disease. In 2012, scientists at the Tavaozie lab at Rockefeller University, established a link between cancer and the APOE gene while studying miRNA networks involved in cancer². They discovered that the APOE gene was negatively regulated in cancer, and its activation suppressed endothelial invasion and metastasis. A second study in 2018 by the same group threw light on the anticancer mechanism of the gene³. APOE reduces the number of myeloid-derived suppressor cells, which have immune-suppressive functions in cancer populations.

Role of APOE in Skin Cancer

In a recent study published in the journal Nature Medicine, the group performed studies on mouse melanoma models and analyzed genetic data from cancer patients to understand the role of the polymorphic gene in cancer progression, immune upregulation, and median times of survival in patients¹. The key findings are as follows.

1. APOE allele 4 has the best outcome for tumor metastasis in mice skin cancer model

The murine APOE gene in mouse melanoma models (YUMM1.7, YUMM 3, and YUMMER 1.7) was replaced with the human isoforms APOE2 and 4 to study tumor growth and progression. APOE4 mice had significantly smaller tumor sizes and volumes when compared to APOE2 mice. Tail vein migrations to study metastasis also showed similar results with APOE4 mice having lower metastasis than APOE2 mice.

2. APOE4 also positively influences the immune response to cancer cells

APOE regulates the myeloid immune cell function in cancers. Immune profiling was done by FACS to understand the differences between the tumor microenvironments in APOE2 and APOE4 mice. Higher numbers of CD45+ leukocytes cells were found in the tumors of APOE4 mice than in APOE2. There was an increase in the number of anti-cancers cells like NK-cells and CD8+T cells resulting from the production of granzyme B and interferon-γ. In APOE4 mice, immunosuppressive cells like Ly6G+ and granulocytic myeloid-derived suppressor cells (G-MDSCs) were reduced in number when compared to APOE2 mice. Also, single-cell RNA sequence data showed the upregulation of myeloid cells and antitumorigenic pathways and downregulation of cancer pathways like angiogenesis.

3. Study in humans show that those carrying APOE4 have good outcomes for cancer spread and length of survival

Genetic analysis from The Cancer Genome Atlas (TCGA) of patients diagnosed with stage II and III melanoma showed that neither APOE4 nor APOE2 were involved in cancer incidence. However, patients with the APOE4 variant had better survival outcomes with a median time of 10.1 years, while APOE3 and APOE2 have 5.2 and 2.5 years, respectively. Analysis of the MDACC data from an independent study by Amos et al. also matched the TGCA study.

4. Immunotherapy and APOE

Since immunotherapy is used in treating melanoma, the scientists investigated whether the APOE genotype influenced cancer progression in YUMMER 1.7 mouse melanoma model when treated with Anti-PD1 inhibitors. The survival rate was higher in mice treated with anti-PD1. A higher probability of prolonged survival was also observed in patients with the APOE4 variant post anti-PD1 treatment in the TGCA and MDACC genetic studies. It was also observed that further activation of the APOE gene by a transcription factor Liver X receptor augmented the anticancer progression properties seen in APOE4 mice compared to the APOE2 mice.

Role of APOE in Neurodegenerative Disorders

APOE4 gene has a negative effect on Alzheimer’s in contrast to cancer⁴. It has also been associated with shorter lifespan⁵. Currently, there are no answers to explain the effect of the APOE4 gene on disease progression of Alzheimer’s. It is also not known how APOE functions in other types of cancers. It would be interesting to study how the APOE4 gene is mediating pleiotropic effects in different disease conditions.

Implications of the Study

This study has implications for diagnostics development and cancer treatments. APOE can be used as a biomarker to screen for relapse of the disease. Patients with the APOE4 gene responded well to immune therapy even though they had a poor prognosis with prior treatments. Also, the mouse melanoma model responded well to the pharmacologic activation of APOE. These results suggest that there is scope for developing better drugs to treat cancer. Rgenix, a biopharmaceutical company, has developed a small molecule agonist (RGX-104) of LXR, which activates the APOE gene. It is currently in phase 1/2b clinical study⁶.

Related Article: CRISPR-Edited T cells Evaluated in Combating Lung Cancer

References

1. https://www.nature.com/articles/s41591-020-0879-3
2. https://pubmed.ncbi.nlm.nih.gov/23142051/
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846344/
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120741/
5. https://www.nature.com/articles/s41467-019-11558-2
6. https://rgenix.com/rgx-104/
7. https://www.rockefeller.edu/news/28096-first-evidence-inherited-genetics-can-drive-metastasis/

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