Common germline variants of the human APOE gene modulate melanoma progression and survival

Abstract

We report the surprising finding that common germline polymorphisms of APOE, present in approximately 39% of Caucasians, predict survival outcomes in human melanoma. Analysis of The Cancer Genome Atlas revealed that carriers of the APOE2 variant experienced shorter survival relative to APOE3 homozygotes, while APOE4 variant carriers exhibited increased survival.Consistent with this, melanoma growth in human APOE knock-in mice followed the order of APOE2 > APOE3 > APOE4, revealing causal regulation of progression by APOE variants. Mechanistically, recombinant ApoE protein variants differentially suppressed melanoma cell invasion and endothelial recruitment phenotypes. Moreover, tumors in APOE4 mice exhibited greater immune cell infiltration and activation relative to tumors of APOE2 mice. These findings support the notion that human germline genetic makeup can impact the trajectory of a future malignancy.The secreted glycoprotein Apolipoprotein E (ApoE) was previously found to suppress melanoma progression and metastasis through cancer cell autonomous and non-autonomous mechanisms (1-3). In humans there are three prevalent ApoE variants termed ApoE2, ApoE3, and ApoE4, which differ in only two amino acids and exhibit differential binding to ApoE receptors (Fig. 1a)(4-7). The APOE4 variant is the strongest monogenetic risk factor for Alzheimer's disease, while APOE2 confers reduced risk for this disease (8,9). APOE variants also modulate the risk for cardiovascular disease (reviewed in ( 10)). Given their high prevalence in the general population, the association of APOE variants with a number of human phenotypic outcomes has been investigated. However, a causal role for these variants in disease pathogenesis has only been demonstrated for Alzheimer's disease and atherosclerosis through the use of murine models (11,12). The potential association between APOE status and cancer outcomes has remained inconclusive (13,14).Given prior evidence supporting a role for ApoE in melanoma progression, we investigated the association between germline APOE variant status and clinical outcome of patients with advanced localized melanoma (stages II-III) by determining APOE genotypes from normal tissue whole exome sequencing data of

Amyloid aggregates accumulate in melanoma metastasis modulating YAP activity

“…APOE is a lipoprotein, whose primitive function is transporting cholesterol, but it is also involved in the stabilization of amyloid-b fibrils in AD and of PMEL fibrils in melanocyte maturation (Bissig et al, 2016). Recently, APOE variants were found to be involved in melanoma progression and survival (Ostendorf et al, 2020). APOE expression is regulated by the nuclear LXR activation.…”

Identification of Ferroptosis Genes In Immune Infiltration and Prognosis In Thyroid Papillary Carcinoma Using Network Analysis

“…It is classi ed as an oncogene and has been implicated in breast cancer cell migration [72,73]. Apoe is associated with tumorigenesis in many cancers, including lung, gastric and thyroid cancer, and a higher risk of metastasis [74][75][76].…”

Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer

“…173 Strikingly, APOE4 was associated with increased anti-tumor immunity in mouse models of melanoma and to favorable patient outcomes, while the low-affinity APOE2 variant was anti-correlated to the latter parameters. 174 Expression of the complement component C1Q by TAM was found to play a role in clear cell renal cell carcinoma (ccRCC) patients and to correlate with poor prognosis. 174,175 More specifically, tumor cells elicited C1Q production by a subset of immune suppressive TAMs expressing high levels of PD-L1 and PD-L2.…”

“…174 Expression of the complement component C1Q by TAM was found to play a role in clear cell renal cell carcinoma (ccRCC) patients and to correlate with poor prognosis. 174,175 More specifically, tumor cells elicited C1Q production by a subset of immune suppressive TAMs expressing high levels of PD-L1 and PD-L2. 176 Deletion of the long pentraxin (PTX)3, an interactor of C1Q, was associated with higher susceptibility to carcinogenesis via amplification of the complement cascade and of cancer-related inflammation.…”

“…The germline APOE4 variant encodes for a mutated form of APOE that binds with high affinity to its receptors—including TREM2—and represents a major risk factor for Alzheimer's disease 173 . Strikingly, APOE4 was associated with increased anti‐tumor immunity in mouse models of melanoma and to favorable patient outcomes, while the low‐affinity APOE2 variant was anti‐correlated to the latter parameters 174 . Expression of the complement component C1Q by TAM was found to play a role in clear cell renal cell carcinoma (ccRCC) patients and to correlate with poor prognosis 174,175 .…”