Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Abstract

26Brain metastasis is a significant cause of morbidity and mortality in multiple cancer 27 types and represents an unmet clinical need. The mechanisms that mediate metastatic 28 cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the 29 highest rate of brain metastasis among common cancer types, is an ideal model to 30 study how cancer cells adapt to the brain parenchyma. We performed unbiased 31 proteomics analysis of melanoma short-term cultures, a novel model for the study of 32 brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative 33 pathologies are differentially expressed in melanoma cells explanted from brain 34 metastases compared to those derived from extracranial metastases. This raised the 35 exciting hypothesis that molecular pathways implicated in neurodegenerative disorders 36 are critical for metastatic adaptation to the brain. 37 38Here, we show that melanoma cells require amyloid beta (Ab), a polypeptide heavily 39 implicated in Alzheimer's disease, for growth and survival in the brain parenchyma. 40Melanoma cells produce and secrete Ab, which activates surrounding astrocytes to a 41 pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that 42 pharmacological inhibition of Ab decreases brain metastatic burden. 43 44Our results reveal a mechanistic connection between brain metastasis and Alzheimer's 45 disease -two previously unrelated pathologies, establish Ab as a promising therapeutic 46 target for brain metastasis, and demonstrate suppression of neuroinflammation as a 47 critical feature of metastatic adaptation to the brain parenchyma. 48 49 3 Main 50 51Brain metastasis is the most common form of adult intracranial malignancy 1 and results 52 in severe morbidity and mortality. 40-75% of Stage IV melanoma patients develop brain 53 metastasis 2,3 , reflecting melanoma's striking ability to colonize the brain. Brain 54 metastases are less responsive than extracranial metastases to current cancer 55 therapies 4-6 , and the majority of patients succumb to disease in less than one year 7 . 56 Furthermore, patients with brain metastasis are often excluded from clinical trials and 57 urgently need new clinical options. In recent years, research has started to elucidate the 58 molecular mechanisms contributing to the multi-step process of brain metastasis. Most 59 findings have focused on cancer extravasation across the blood-brain barrier (BBB), 60 which cannot be leveraged therapeutically given that the vast majority of brain 61 metastasis patients will present with extravasated cancer cells at the time of cancer 62 diagnosis. The main bottleneck in the brain metastatic process has been shown to be 63 the successful expansion of a single cell in the brain parenchyma to form a macro-64 metastasis 8 . Recent studies have begun to demonstrate the role of the brain 65 microenvironment in this process. In particular, reactive astrocytes have been shown to 66 interact with cancer cells in the brain 9,10 and exhibit both pro-and anti-...

Amyloid aggregates accumulate in melanoma metastasis modulating YAP activity

“…Consistently, we observed that melanoma cells treated with BACE inhibitor become less proliferative and more sensitive to chemotherapy. Our data are consistent with a recent study where BACE inhibition was able to impair melanoma brain metastatic proliferation in vivo (preprint: Kleffman et al, 2019). Indeed, we found that a combined treatment of doxorubicin and NB360 is more effective than doxorubicin alone.…”

The emerging role of β-secretases in cancer

“…In particular, the BACE1/2 dependent maturation of amyloidogenic proteins such as APP or PMEL, has been shown to affect TME cells behavior and to act both in paracrine and autocrine way driving tumor proliferation and progression [44,48,69]. Importantly, it has also to be noted that β-secretases, besides processing amyloidogenic proteins, have a broad range of substrates; for example, it has been shown that BACE1 can process IL6R, inducing macrophages polarization towards a protumoral phenotype [73].…”

“…In details, the authors silenced APP in melanoma cells without affecting melanoma proliferation in vitro but noticed a reduction in brain metastases formation in vivo in a melanoma mouse model. In the same study, they also use a dual BACE1/2 inhibitor to block the production of Aβ in vivo, demonstrating the efficacy of this kind of treatment in reducing the number of brain metastases and tumor burden and suggesting BACE1/2 inhibition as new therapy against melanoma progression [69].…”

“…In this case, it has been shown that melanoma derived brain metastases produce the Aβ40 peptide which, through the cross-talk with astrocytes, induces an immunosuppressive environment that foster brain colonization by melanoma cells (Fig. 5b) [69]. In details, the authors silenced APP in melanoma cells without affecting melanoma proliferation in vitro but noticed a reduction in brain metastases formation in vivo in a melanoma mouse model.…”

“…A second study, underlining the relevant role of BACE1/2 activity in cancer, describes a paracrine effect of amyloid beta in promoting melanoma brain metastases [69]. In this case, it has been shown that melanoma derived brain metastases produce the Aβ40 peptide which, through the cross-talk with astrocytes, induces an immunosuppressive environment that foster brain colonization by melanoma cells (Fig.…”