Oncogenic collagen I homotrimers from cancer cells bind to α3ß1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer.

In contrast to normal type I collagen (Col1) heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (α1/α1/α1). Col1 homotrimer results from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via α3ß1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Col1 homotrimers increases overall survival of mice with pancreatic ductal adenocarcinoma (PDAC), associated with reprograming of the tumor microbiome with increased microaerophilic Campylobacterales, which can be reversed with broad-spectrum antibiotics. Deletion of Col1 homotrimers enhances T cell infiltration and enables efficacy of anti-PD-1 immunotherapy. This study identifies the functional impact of Col1 homotrimers on tumor microbiome and tumor immunity, implicating Col1 homotrimer-α3ß1 integrin signaling axis as a cancer-specific therapeutic target.

The emerging roles of exosomes in the modulation of immune responses in cancer.

Exosomes are promising tools for improving cancer care, but conversely may also contribute to tumor progression. Here, we highlight recently discovered roles of exosomes in modulating immune responses in cancer, with emphasis on exosomal surface proteins and on RNA and DNA content. We also discuss how exosomes could be exploited as biomarkers and delivery vehicles in cancer therapy.

Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer.

Pancreatic cancer presents with a dismal mortality rate and is in urgent need of methods for early detection with potential for timely intervention. All living cells, including cancer cells, generate exosomes. We previously discovered double stranded genomic DNA in exosomes derived from the circulation of pancreatic cancer patients, which enabled the detection of prevalent mutations associated with the disease. Here, we report a proof-of-concept study that demonstrates the potential clinical utility of circulating exosomal DNA for identification of KRASG12D and TP53R273H mutations in patients with pancreas-associated pathologies, including pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP) and intraductal papillary mucinous neoplasm (IPMN), and in healthy human subjects. In 48 clinically annotated serum samples from PDAC patients, digital PCR analyses of exosomal DNA identified KRASG12D mutation in 39.6% of cases, and TP53R273H mutation in 4.2% of cases. KRASG12D and TP53R273H mutations were also detected in exosomal DNA from IPMN patients (2 out of 7 with KRASG12D, one of which also co-presented with TP53R273H mutation). Circulating exosomal DNA in 5 out of 9 CP patients enabled the detection of KRASG12D mutation. In 114 healthy subject-derived circulating exosomal DNA, 2.6% presented with KRASG12D mutation and none with TP53R273H mutation. This study highlights the value of circulating exosomal DNA for a rapid, low-cost identification of cancer driving mutations. The identification of mutations in IPMN patients and healthy subjects suggests that liquid biopsies may allow potential assessment of cancer risk but with a cautionary note that detection of clinical cancer cannot be assumed.

Extrafoveal Cone Packing in Eyes With a History of Retinopathy of Prematurity.

PURPOSE: To study the density and packing geometry of the extrafoveal cone photoreceptors in eyes with a history of retinopathy of prematurity (ROP). We used a multimodal combination of adaptive optics (AO) scanning light ophthalmoscopy (SLO) and optical coherence tomography (OCT). METHODS: Cones were identified in subjects (aged 14-26 years) with a history of ROP that was either severe and treated by laser ablation of avascular peripheral retina (TROP; n = 5) or mild and spontaneously resolved, untreated (UROP; n = 5), and in term-born controls (CT; n = 8). The AO-SLO images were obtained at temporal eccentricities 4.5°, 9°, 13.5°, and 18° using both confocal and offset apertures with simultaneous, colocal OCT images. Effects of group, eccentricity, and aperture were evaluated and the modalities compared. RESULTS: In the SLO images, cone density was lower and the packing pattern less regular in TROP, relative to CT and UROP retinae. Although SLO image quality appeared lower in TROP, root mean square (RMS) wavefront error did not differ among the groups. In TROP eyes, cone discrimination was easier in offset aperture images. There was no evidence of cone loss in the TROP OCT images. CONCLUSIONS: Low cone density in TROP confocal SLO images may have resulted from lower image quality. Since AO correction in these eyes was equivalent to that of the control group, and OCT imaging showed no significant cone loss, the optical properties of the inner retina or properties of the cones themselves are likely altered in a way that affects photoreceptor imaging.

Temporal summation in children with a history of retinopathy of prematurity.

PURPOSE: To assess temporal summation in children with a history of retinopathy of prematurity (ROP) by determining the critical duration (tCRIT) for complete temporal summation under rod-mediated conditions. From prior ERG studies, it is known that the kinetics of activation of phototransduction are prolonged in the ROP rod photoreceptor. METHODS: Dark-adapted thresholds for detecting 10° diameter stimuli with durations from 10 to 640 ms were measured. A two-alternative, spatial, forced-choice psychophysical procedure was used. The tCRIT for complete summation was estimated in former preterm subjects with a history of severe ROP (n = 7), mild ROP (n = 23), and no ROP (n = 15). The subjects ranged in age from 10.4 to 17.6 (median 15.6) years. Age-similar term-born control subjects (n = 5) were also tested. RESULTS: Critical duration was significantly longer in subjects with a history of ROP than in subjects who never had ROP or who were born at term. Mean tCRIT in the mild ROP group [127.5 (SD = 19.9) ms] and severe group [147.6 (SD = 18.9) ms] did not differ significantly, but both were significantly longer than in former preterms who never had ROP [101.1 (SD = 16.5) ms] and in term-born controls [101.0 (SD = 19.5) ms]. CONCLUSIONS: In ROP subjects, tCRIT is significantly prolonged. This is likely due to abnormal kinetics in the rod outer segment.

Effect of retinopathy of prematurity on scotopic spatial summation.

PURPOSE: To evaluate scotopic retinal organization in retinopathy of prematurity (ROP) through a study of spatial summation. METHODS: Thresholds for a range of stimulus diameters (0.4°-10°) were measured using a two alternative, spatial, forced choice psychophysical procedure. The critical diameter (DCRIT) for complete summation was estimated in subjects with a history of severe ROP (N = 7) and mild ROP (N = 17). Subjects who were born preterm and never had ROP (N = 16) and term-born subjects (N = 7) were also tested. The subjects ranged in age from 9 to 17 (median 13.5) years. RESULTS: Critical diameter for complete spatial summation was significantly larger in ROP subjects than in subjects who never had ROP and in term-born control subjects. Critical diameter varied significantly with severity of ROP. CONCLUSIONS: The larger DCRIT values in ROP are consistent with altered organization of the post receptor retina. This may offer the ROP retina a strategy for achieving noise reduction and good dark-adapted visual sensitivity.