Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types is lacking. Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. By integrating transcriptional and genetic information, we identify known and previously unidentified vulnerable populations in cortical layer 5 and show that ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity.

Effect of early-stage autophagy inhibition in BRAF autophagy-dependent brain tumor cells.

Autophagy is a multistage process. Progress within the field has led to the development of agents targeting both early (initiation) and late (fusion) stages of this process. The specific stage of autophagy targeted may influence cancer treatment outcomes.

Cancer Cells Upregulate NRF2 Signaling to Adapt to Autophagy Inhibition.

While autophagy is thought to be an essential process in some cancer cells, it is unknown if or how such cancer cells can circumvent autophagy inhibition. To address this, we developed a CRISPR/Cas9 assay with dynamic live-cell imaging to measure acute effects of knockout (KO) of autophagy genes compared to known essential and non-essential genes. In some cancer cells, autophagy is as essential for cancer cell growth as mRNA transcription or translation or DNA replication.

ZZ-dependent regulation of p62/SQSTM1 in autophagy.

Autophagic receptor p62 is a critical mediator of cell detoxification, stress response, and metabolic programs and is commonly deregulated in human diseases. The diverse functions of p62 arise from its ability to interact with a large set of ligands, such as arginylated (Nt-R) substrates. Here, we describe the structural mechanism for selective recognition of Nt-R by the ZZ domain of p62 (p62).

Metastatic cells are preferentially vulnerable to lysosomal inhibition.

Molecular alterations that confer phenotypic advantages to tumors can also expose specific therapeutic vulnerabilities. To search for potential treatments that would selectively affect metastatic cells, we examined the sensitivity of lineage-related human bladder cancer cell lines with different lung colonization abilities to chloroquine (CQ) or bafilomycin A, which are inhibitors of lysosome function and autophagy. Both CQ and bafilomycin A were more cytotoxic in vitro to highly metastatic cells compared with their less metastatic counterparts.

FOXO3 links autophagy to apoptosis.

The molecular machinery linking macroautophagy (autophagy hereafter) to apoptosis is still being elucidated. A recent study found that the transcription factor FOXO3/FOXO3A (forkhead box O3), which regulates autophagy, is itself regulated by basal autophagy to determine apoptosis sensitivity. Autophagy inhibition confers cell sensitivity to anti-cancer agents, and this effect is explained by the ability of FOXO3 to transactivate the pro-apoptotic gene BBC3/PUMA.

Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover.

Macroautophagy (autophagy) is intimately linked with cell death and allows cells to evade apoptosis. This has prompted clinical trials to combine autophagy inhibitors with other drugs with the aim of increasing the likelihood of cancer cells dying. However, the molecular basis for such effects is unknown.

A caspase-independent way to kill cancer cells.

Cancer treatments often focus on killing tumour cells through apoptosis, which is thought to typically require mitochondrial outer membrane permeabilization (MOMP) and subsequent caspase activation. A study now shows that MOMP can trigger TNF-dependent, but caspase-independent cell death, suggesting a different approach to improve cancer therapy.

Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors.

Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors.

The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis.

Although autophagy controls cell death and survival, underlying mechanisms are poorly understood, and it is unknown whether autophagy affects only whether or not cells die or also controls other aspects of programmed cell death. MAP3K7 is a tumor suppressor gene associated with poor disease-free survival in prostate cancer. Here, we report that Map3k7 deletion in mouse prostate cells sensitizes to cell death by TRAIL (TNF-related apoptosis-inducing ligand).

Recent insights into cell death and autophagy.

Macroautophagy (hereafter autophagy) is an evolutionarily-ancient mechanism by which cellular material is delivered to lysosomes for degradation. Autophagy and cell death are intimately linked. For example, both processes often use the same molecular machinery and recent work suggests that autophagy has great influence over a cell's decision to live or die.