Trop-2 is a calcium signal transducer that is associated with transformed cell growth in experimental systems. However, its role in human cancer remains essentially unknown. In this study, we profiled Trop-2 expression in normal human tissues at the mRNA and protein levels. We then systematically compared Trop-2 mRNA and protein levels in tumours with their tissues of origin. We find that Trop-2 expression is invariably upregulated in tumours, regardless of baseline expression in normal tissues, which suggests a corresponding selective advantage. Thus, we investigated the outcome of Trop-2 upregulation on tumour growth. Overexpression of wild-type Trop-2 was shown to be necessary and sufficient to drive cancer growth in a widely invariant manner across cell type and species. Upregulation of Trop-2 was shown to quantitatively stimulate tumour growth, as proportional to expression levels in vivo, and tumour cell growth was abrogated by somatic knockdown of Trop-2 expression. On the other hand, we found no evidence of tumour-associated TROP2 mutations, nor of TROP2 induction of oncogenic transformation per se. Our data support a model where above-baseline expression of wild-type Trop-2 is a key driver of human cancer growth.

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2–driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from β-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of β-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/β-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2–centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.

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The process of organomineralization is increasingly well understood with respect to modern carbonate sediments accumulating adjacent to tropical reef atolls and reef caves. Mineralization related to non-living organic substrates results in autochthonous micrite production (`automicrites').`Automicrites' are the main constructive element of Lower Cretaceous (Albian) carbonate mud mounds in northern Spain. These slope mud mounds occur within transgressive and early highstand system tracts encompassing several macrobenthic ecological zones. They are clearly separated from the biocalcifying carbonate factory (Urgonian carbonate platforms), in both space and time. Within these build-ups, most`automicrites' were initially indurated and accreted to form a medium-relief growth framework.`Automicrites' have a uniform, presumably high-Mg-calcite precursor mineralogy. They show an inorganic stable-isotope signature ( ¶ 13 C around +3á3&) within the range of early marine cements, and skeletal compounds lacking major vital effects. Epi¯uorescence microscopy shows that they have facies-speci®c¯uorescence, which is similar to skeletal compounds of Acanthochaetetes, but clearly different from allomicritic sediment and cements, which are mostly nonuorescent. The EDTA-soluble intracrystalline organic fraction (SIOF) of Albian automicrites shows an amino acid spectrum that is similar to shallow subsurface samples from their modern counterparts. Gel electrophoresis of the SIOF demonstrates an exclusively acidic character, and a mean molecular size range between 20 and 30 kDa. Experiments in vitro (inhibition tests) indicate that the SIOF has a signi®cant Ca 2+ -binding capacity. Fluorescence and chemical characteristics of SIOF point to a main substance class, such as humic and fulvic acids, compounds that form from pristine organic matter during early diagenesis. Biomarker analyses provide evidence for the crucial role of biodegradation by heterotrophic microorganisms, but no biomarker for cyanobacteria has been found. Primary sources of organic material should have been manifold, including major contributions by metazoans such as sponges. It is concluded that many carbonate mud mounds are essentially organomineralic in origin and that the resulting fabric of polygenetic muds (`polymuds') may represent ancestral metazoan reef ecosystems, which possibly originated during the Neoproterozoic.

The white blood cell (WBC) elements and the bone marrow myeloid progenitor cell populations were analyzed to ascertain adaptation to micro-gravity and subsequent readaptation to 1 G in rats flown on the 14-day Spacelab Life Sciences-2 (SLS-2) mission. Bone marrow cells were harvested from one group of rats killed inflight (FD13) and blood was drawn from three other groups at various times. The WBC level was normal on FD14 with the exception of neutrophilia. On FD13, numbers of colony-forming units-granulocyte (CFU-G), CFU-GM, and CFU-M from flight animals were decreased compared with ground controls when incubated with recombinant rat interleukin-3 (rrIL-3) alone or in combination with recombinant human erythropoietin (rhEpo). On recovery (R + 0), flight rats had decreased numbers of total leukocytes and absolute numbers of lymphocytes and monocytes with elevated neutrophils compared with control rats. They had lower numbers of CD4, CD8, CD2, CD3, and B cells in the peripheral blood but no differences in spleen lymphocytes.