Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.

Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA-protein complexes) and activation of cGAS-STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS-STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS-STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria-endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.

A Cancer Health Needs Assessment Reveals Important Differences Between US-Born and Foreign-Born Latinos in California.

Background: Cancer is the leading cause of death among Latinos, the largest minority population in the United States (US). To address cancer challenges experienced by Latinos, we conducted a catchment area population assessment (CAPA) using validated questions from the National Cancer Institute (NCI) population health assessment supplement at our NCI-designated cancer center in California. Methods: A mixed-methods CAPA was administered by bilingual-bicultural staff, with a focus on understanding the differences between foreign-born and US-born Latinos. Results: 255 Latinos responded to the survey conducted between August 2019 and May 2020. Most respondents were foreign-born (63.9%), female (78.2%), and monolingual Spanish speakers (63.2%). Results showed that compared to US-born Latinos, foreign-born individuals were older, had lower educational attainment, were most likely to be monolingual Spanish speakers, were low-income, and were more likely to be uninsured. Foreign-born Latinos had lower levels of alcohol consumption and higher consumption of fruits and vegetables. The rate of preventive cancer screenings for breast, cervical and colorectal cancer did not differ by birthplace, although a low fraction (35.3%) of foreign-born Latinas who were up-to-date compared to US-born Latinas (83.3%) with colorectal cancer screening was observed. Time since the last routine check-up for all preventable cancers (cervical p=0.0002, breast p=0.0039, and colorectal p=0.0196) is significantly associated with being up to date with cancer screening. Individuals who had a check-up of two or more years ago are 84% less likely to be up to date with pap smears than those who had a check-up within the year (p=0.0060). Individuals without health insurance are 94% less likely to be up to date with mammograms and colonoscopy/FIT tests (p=0.0016 and p=0.0133, respectively) than those who are insured. There is no significant association between screening and nativity. Conclusions: Considerable differences in socio-economic and environmental determinants of health and colorectal cancer screening rates were observed between US-born and foreign-born Latinos. The present study represents the foundation for future targeted intervention among immigrant populations at our cancer center's catchment area.

Multiregional Sequencing Analysis Reveals Extensive Genetic Heterogeneity in Gastric Tumors from Latinos.

Gastric cancer is a leading cause of cancer mortality and health disparities in Latinos. We evaluated gastric intratumoral heterogeneity using multiregional sequencing of >700 cancer genes in 115 tumor biopsies from 32 patients, 29 who were Latinos. Analyses focused on comparisons with The Cancer Genome Atlas (TCGA) and on mutation clonality, druggability, and signatures. We found that only approximately 30% of all mutations were clonal and that only 61% of the known TCGA gastric cancer drivers harbored clonal mutations. Multiple clonal mutations were found in new candidate gastric cancer drivers such as EYS, FAT4, PCDHA1, RAD50, EXO1, RECQL4, and FSIP2. The genomically stable (GS) molecular subtype, which has the worse prognosis, was identified in 48% of our Latino patients, a fraction that was >2.3-fold higher than in TCGA Asian and White patients. Only a third of all tumors harbored clonal pathogenic mutations in druggable genes, with most (93%) GS tumors lacking actionable clonal mutations. Mutation signature analyses revealed that, in microsatellite-stable (MSS) tumors, DNA repair mutations were common for both tumor initiation and progression, while tobacco, POLE, and inflammation signatures likely initiate carcinogenesis. MSS tumor progression was likely driven by aging- and aflatoxin-associated mutations, as these latter changes were usually nonclonal. In microsatellite-unstable tumors, nonclonal tobacco-associated mutations were common. Our study, therefore, contributed to advancing gastric cancer molecular diagnostics and suggests clonal status is important to understanding gastric tumorigenesis. Our findings of a higher frequency of a poor prognosis associated molecular subtype in Latinos and a possible new aflatoxin gastric cancer etiology also advance cancer disparities research. Significance: Our study contributes to advancing our knowledge of gastric carcinogenesis, diagnostics, and cancer health disparities.