Comment on “GRP94 promotes brain metastasis by engaging pro-survival autophagy”

I read with great interest the work of Santana-Codina et al¹ in which the authors showed GRP94 (94-kDa glycoprotein), which confers endoplasmic reticulum (ER) stress resistance phenotype on metastasis-initiating cancer cells, determines the organ-specific nature of breast cancer metastasis by activating the protective Atg5/7-dependent autophagy. Given the pre-metastatic niche in the brain with the low level of glucose, GRP94 overexpression is expected to be essential for brain metastasis of breast cancer by regulating both ER stress and pro-survival autophagy.¹

A brain-tropism cancer stem-like cell (CSC) population exhibits enhanced adaptive potential in the hypoxic and/or hyponutrient tumor microenvironment (TME), which is why patients with human epidermal growth factor receptor 2–positive or triple-negative breast cancer whose tumors contain more CSCs than other breast cancers are more likely to develop brain metastases.² Indeed, pathological examinations of the patients with brain metastasis showed in Figure 5 that light chain 3-II–positive cancer cells were enriched at the invasive front and in perinecrotic TME, where hypoxia-inducible factor 1α–positive CSCs activate selective autophagy.^1,2 Strictly speaking, however, the authors should also perform immunohistochemistry analysis of p62/SQSTM1 because of the possibility of impaired autophagy flux in metastatic tumor cells.

It has been recently shown that the metastatic niche in the brain endows an enhanced protocadherin 7 (PCDH7) expression on the survived metastatic CSCs of triple-negative breast cancer, which retains self-renewal potential.³ Mechanistically, the direct interactions between astrocytes and CSCs activate the PCDH7-phospholipase C (PLC) β-Ca²⁺-CaMKII/S100A4 axis to promote tumor colonization in the pre-metastatic niche. In the clinical settings, edelfosine, which is a synthetic alkyl-lysophospholipid and a selective PLC inhibitor, has been clinically trialed in a phase II investigation for the treatment of brain tumor and shown encouraging results in preventing tumor growth.³ However, given that both suppression of mammalian target of rapamycin/unc-51 like autophagy activating kinase 1 signaling and dissociation of Beclin1-IP3R-Bcl-2 complex are responsible for autophagy induction via PLCγ1 inhibition in colorectal and hepatic cancer cells,⁴ it is plausible that metastatic CSCs in the brain cause autophagic cell death (ACD) mediated by PLCγ1 blockage by edelfosine. ACD is accompanied by c-Jun N-terminal kinase signal hyperactivation and excessive accumulation of autophagosomes in the cytoplasm.⁵ By striking contrast, the authors showed a preventive effect of hydroxychloroquine (HCQ), which inhibits the fusion of autophagosomes and lysosome, on brain metastatic lesion.¹ In fact, multiple clinical trials have now reported on the therapeutic efficacy of combining HCQ with conventional chemotherapies, such as in glioblastoma multiforme treatment, where HCQ in combination with temozolomide more than doubled patient survival times compared with temozolomide alone.² Importantly, autophagy is a “double-edged sword” for cancer cells because it can either promote or suppress their survival and proliferation, depending on TME.

Furthermore, the authors clarified that the brain metastatic variant of MDA-MB-435 exhibited upregulation of a mitochondrial BH3-only protein, Bcl-2 nineteen-kilodalton interacting protein 3 (BNIP3), essential for phosphatase and tensin homolog (PTEN)–induced kinase 1 (PINK1)/Parkin-mediated mitophagy.¹ BNIP3 interacts with PINK1 to promote accumulation of full-length PINK1 on the outer membrane of mitochondria and facilitates Parkin recruitment.⁶ Notably, mounting evidence suggests that mitophagy, which is the selective autophagy-dependent degradation of dysfunctional mitochondria under hypoxic and/or hyponutrient TME, is specifically implicated in maintaining CSC phenotype by promoting the turnover of mitochondria and limiting the capacity of CSCs for the tricarboxylic acid cycle and instead making CSCs more dependent on aerobic glycolysis (Warburg effect).² Suppression of PINK1/Parkin-mediated mitophagy or enhanced mitochondrial biogenesis via peroxisome proliferator-activated receptor γ coactivator 1-α leads to downregulation of CD44, one of the breast CSC markers, and promotes the translocation of p53 into the nucleus, where it has been reported to antagonize expression of stem cell genes such as Oct4 and Sox2.² Taken together, further investigations are warranted to identify the effect of GRP94 on mitophagy in metastasis-initiating CSCs existing in the brain.

Funding

No funding supported this work. No potential conflict of interest relevant to this letter is reported.