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Original citation: J Clin Invest. 2022;132(19):1-18. https://doi.org/10.n72/JCI157399. https://doi.org/10.1172/JCI168771 After the publication of this article, the authors became aware that the [beta]-actin blot shown in Supplemental Figure 11A was incorrect. The [...]

Vessel co-option has been demonstrated to mediate colorectal cancer liver metastasis (CRCLM) resistance to antiangiogenic therapy. The current mechanisms underlying vessel co-option have mainly focused on 'hijacker' tumor cells, whereas the function of the 'hijackee' sinusoidal blood vessels has not been explored. Here, we found that the occurrence of vessel co-option in bevacizumab-resistant CRCLM xenografts was associated with increased expression of fibroblast activation protein [alpha] (FAP[alpha]) in the co-opted hepatic stellate cells (HSCs), which was dramatically attenuated in HSC-specific conditional Fop-knockout mice bearing CRCLM allografts. Mechanistically, bevacizumab treatment induced hypoxia to upregulate the expression of fibroblast growth factor-binding protein 1 (FGFBP1) in tumor cells. Gain- or lossof-function experiments revealed that the bevacizumab-resistant tumor cell-derived FGFBP1 induced FAP[alpha] expression by enhancing the paracrine FGF2/FGFR1/ERK1/-2/EGR1 signaling pathway in HSCs. FAP[alpha] promoted CXCL5 secretion in HSCs, which activated CXCR2 to promote the epithelial-mesenchymal transition of tumor cells and the recruitment of myeloid-derived suppressor cells. These findings were further validated in tumor tissues derived from patients with CRCLM. Targeting FAP[alpha]+ HSCs effectively disrupted the co-opted sinusoidal blood vessels and overcame bevacizumab resistance. Our study highlights the role of FAP[alpha]+ HSCs in vessel co-option and provides an effective strategy to overcome the vessel co-option-mediated bevacizumab resistance., Introduction Colorectal cancer (CRC) is the third most common and the second most fatal malignancy in the world (1). Specifically, CRC liver metastasis (CRCLM) contributes to more than 70% of [...]

Hematogenous metastasis is the main approach for colorectal cancer liver metastasis (CRCLM). However, as the gatekeepers in the tumor vessels, the role of TPCs in hematogenous metastasis remains largely unknown, which may be attributed to the lack of specific biomarkers for TPC isolation. Here, microdissection combined with a pericyte medium‐based approach is developed to obtain TPCs from CRC patients. Proteomic analysis reveals that TRP channel‐associated factor 2 (TCAF2), a partner protein of the transient receptor potential cation channel subfamily M member 8 (TRPM8), is overexpressed in TPCs from patients with CRCLM. TCAF2 in TPCs is correlated with liver metastasis, short overall survival, and disease‐free survival in CRC patients. Gain‐ and loss‐of‐function experiments validate that TCAF2 in TPCs promotes tumor cell motility, epithelial‐mesenchymal transition (EMT), and CRCLM, which is attenuated in pericyte‐conditional Tcaf2‐knockout mice. Mechanistically, TCAF2 inhibits the expression and activity of TRPM8, leading to Wnt5a secretion in TPCs, which facilitates EMT via the activation of the STAT3 signaling pathway in tumor cells. Menthol, a TRPM8 agonist, significantly suppresses Wnt5a secretion in TPCs and CRCLM. This study reveals the previously unidentified pro‐metastatic effects of TPCs from the perspective of cold‐sensory receptors, providing a promising diagnostic biomarker and therapeutic target for CRCLM. [ABSTRACT FROM AUTHOR]

Data from an airborne vertically pointing millimeter-wave Doppler radar are used to study the cloud microphysical effect of glaciogenic seeding of cold-season orographic clouds. Fixed flight tracks were flown downstream of ground-based silver iodide (AgI) generators in the Medicine Bow Mountains of Wyoming. Composite data from seven flights, each with a no-seeding period followed by a seeding period, indicate that radar reflectivity was higher near the ground during the seeding periods. Several physical considerations argue in favor of the hypothesis that the increase in near-surface reflectivity is attributed to AgI seeding. While the increase in near-surface reflectivity and thus snowfall rate are statistically significant, caution is warranted in view of the large natural variability of weather conditions and the small size of the dataset. DOI: 10.1175/2010JAS3496.1