Search

Cancer-associated fibroblasts (CAFs) and their extracellular matrix are active participants in cancer progression. While it is known that functionally different subpopulations of CAFs co-exist in ovarian cancer, it is unclear whether certain CAF subsets are enriched during metastatic progression and/or chemotherapy. Using computational image analyses of patient-matched primary high-grade serous ovarian carcinomas, synchronous pre-chemotherapy metastases, and metachronous post-chemotherapy metastases from 42 patients, we documented the dynamic spatiotemporal changes in the extracellular matrix, fibroblasts, epithelial cells, immune cells, and CAF subsets expressing different extracellular matrix components. Among the different CAF subsets, COL11A1+ CAFs were associated with linearized collagen fibers and exhibited the greatest enrichment in pre- and post-chemotherapy metastases compared to matched primary tumors. Although pre- and post-chemotherapy metastases were associated with increased CD8+ T cell infiltration, the infiltrate was not always evenly distributed between the stroma and cancer cells, leading to an increased frequency of the immune-excluded phenotype where the majority of CD8+ T cells are present in the tumor stroma but absent from the tumor parenchyma. Overall, most of the differences in the tumor microenvironment were observed between primary tumors and metastases, while fewer differences were observed between pre- and post-treatment metastases. These data suggest that the tumor microenvironment is largely determined by the primary vs. metastatic location of the tumor while chemotherapy does not have a significant impact on the host microenvironment.

Iodine (I) abundance in marine carbonates (measured as an elemental ratio with calcium, I / Ca) is of broad interest as a proxy for local/regional ocean redox. This connection arises because the speciation of iodine in seawater, the balance between iodate (IO 3-) and iodide (I−), is sensitive to the prevalence of oxic vs. anoxic conditions. However, although I / Ca ratios are increasingly commonly being measured in ancient carbonate samples, a fully quantitative interpretation of this proxy requires the availability of a mechanistic interpretative framework for the marine iodine cycle that can account for the extent and intensity of ocean deoxygenation in the past. Here we present and evaluate a representation of marine iodine cycling embedded in an Earth system model ("cGENIE") against both modern and paleo-observations. In this framework, we account for IO 3- uptake and release of I− through the biological pump, the reduction in ambient IO 3- to I− in the water column, and the re-oxidation of I− to IO 3-. We develop and test a variety of different plausible mechanisms for iodine reduction and oxidation transformation and contrast model projections against an updated compilation of observed dissolved IO 3- and I− concentrations in the present-day ocean. By optimizing the parameters controlling previously proposed mechanisms involved in marine iodine cycling, we find that we can obtain broad matches to observed iodine speciation gradients in zonal surface distribution, depth profiles, and oxygen-deficient zones (ODZs). However, we also identify alternative, equally well performing mechanisms which assume a more explicit mechanistic link between iodine transformation and environment – an ambiguity that highlights the need for more process-based studies on modern marine iodine cycling. Finally, to help distinguish between competing representations of the marine iodine cycle and because our ultimate motivation is to further our ability to reconstruct ocean oxygenation in the geological past, we conducted "plausibility tests" of different model schemes against available I / Ca measurements made on Cretaceous carbonates – a time of substantially depleted ocean oxygen availability compared to modern and hence a strong test of our model. Overall, the simultaneous broad match we can achieve between modeled iodine speciation and modern observations, and between forward proxy modeled I / Ca and geological elemental ratios, supports the application of our Earth system modeling in simulating the marine iodine cycle to help interpret and constrain the redox evolution of past oceans. [ABSTRACT FROM AUTHOR]