Single-cell deconvolution reveals high lineage- and location-dependent heterogeneity in mesenchymal multivisceral stage 4 colorectal cancer.

Metastasized colorectal cancer (CRC) is associated with a poor prognosis and rapid disease progression. Besides hepatic metastasis, peritoneal carcinomatosis is the major cause of death in Union for International Cancer Control (UICC) stage IV CRC patients. Insights into differential site-specific reconstitution of tumor cells and the corresponding tumor microenvironment are still missing. Here, we analyzed the transcriptome of single cells derived from murine multivisceral CRC and delineated the intermetastatic cellular heterogeneity regarding tumor epithelium, stroma, and immune cells. Interestingly, we found an intercellular site-specific network of cancer-associated fibroblasts and tumor epithelium during peritoneal metastasis as well as an autologous feed-forward loop in cancer stem cells. We furthermore deciphered a metastatic dysfunctional adaptive immunity by a loss of B cell-dependent antigen presentation and consecutive effector T cell exhaustion. Furthermore, we demonstrated major similarities of this murine metastatic CRC model with human disease and - based on the results of our analysis - provided an auspicious site-specific immunomodulatory treatment approach for stage IV CRC by intraperitoneal checkpoint inhibition.

Partial link between the seasonal acquisition of cold-tolerance and desiccation resistance in the goldenrod gall fly Eurosta solidaginis (Diptera: Tephritidae).

Possible links between seasonal increases in cold-tolerance and desiccation resistance were examined in field-collected larvae of the goldenrod gall fly, Eurosta solidaginis. From 20 September to 30 October 2001, larvae exhibited a gradual increase in cold-tolerance culminating in 100% survival of freezing at -20 degrees C for 24 h. The increase in cold-tolerance was probably due to a concomitant increase in cryoprotectants as measured by hemolymph osmolality (488-695 mOsmol kg(-1)). In contrast to the gradual increase in cold-tolerance, larvae exhibited two distinct phases of reduced rates of water loss. The first phase was an abrupt sixfold decrease to 0.57 microg mm(-2) h(-1) between 3 and 16 October. The first phase of reduced rates of water loss was not correlated with changes in cold-tolerance; nor was it correlated with hemolymph osmolality and body water content, which remained constant throughout the study. The reduction in rates of water loss during the first phase were probably the result of decreased respiratory water loss as the larvae entered diapause, and possibly reduced cuticular water loss as larvae increased the amount of their cuticular hydrocarbons. Interestingly, the first phase of reduced water loss was associated with, and may have been cued by, a reduction in the water potential of the gall tissues surrounding the larvae. The second phase was a more subtle fourfold reduction in rates of water loss occurring between 16 October and 11 December. In contrast to the first phase, the second phase of increased desiccation resistance correlated closely with increases in hemolymph osmolality (568-870 mOsmol kg(-1)). The correlation between seasonal increases in hemolymph osmolality and reduction in rates of water loss may represent a link between desiccation resistance and cold-tolerance in this species.