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Guo et al. determine the molecular basis of collagen lysyl hydroxylase 2 (LH2) substrate specificity. They further show that LH2 also functions as a collagen glucosyltransferase to promote lung cancer progression.

Summary: Cancer cells function as primary architects of the tumor microenvironment. However, the molecular features of cancer cells that govern stromal cell phenotypes remain unclear. Here, we show that cancer-associated fibroblast (CAF) heterogeneity is driven by lung adenocarcinoma (LUAD) cells at either end of the epithelial-to-mesenchymal transition (EMT) spectrum. LUAD cells that have high expression of the EMT-activating transcription factor ZEB1 reprogram CAFs through a ZEB1-dependent secretory program and direct CAFs to the tips of invasive projections through a ZEB1-driven CAF repulsion process. The EMT, in turn, sensitizes LUAD cells to pro-metastatic signals from CAFs. Thus, CAFs respond to contextual cues from LUAD cells to promote metastasis.

Collagenous stromal accumulations predict a worse clinical outcome in a variety of malignancies. Better tools are needed to elucidate the way in which collagen influences cancer cells. Here, we report a method to generate collagenous matrices that are deficient in key post-translational modifications and evaluate cancer cell behaviors on those matrices. We utilized genetic and biochemical approaches to inhibit lysine hydroxylation and glucosylation on collagen produced by MC-3T3-E1 murine osteoblasts (MC cells). Seeded onto MC cell-derived matrix surface, multicellular aggregates containing lung adenocarcinoma cells alone or in combination with cancer-associated fibroblasts dissociated with temporal and spatial patterns that were influenced by collagen modifications. These findings demonstrate the feasibility of generating defined collagen matrices that are suitable for cell culture studies.

Collagen lysyl hydroxylases promote cancer progression. Here the authors present the crystal structure of the lysyl hydroxylase domain of L230 from Acanthamoeba polyphaga mimivirus, which is of interest for LH inhibitor development, and show that ectopic expression of L230 in tumors promotes collagen cross-linking and metastasis.

Abstract Cancer-associated fibroblasts (CAFs) regulate diverse intratumoral biological programs and can promote or inhibit tumorigenesis, but those CAF populations that negatively impact the clinical outcome of lung cancer patients have not been fully elucidated. Because Thy-1 (CD90) marks CAFs that promote tumor cell invasion in a murine model of KrasG12D–driven lung adenocarcinoma (KrasLA1), here we postulated that human lung adenocarcinomas containing Thy-1+ CAFs have a worse prognosis. We first examined the location of Thy-1+ CAFs within human lung adenocarcinomas. Cells that co-express Thy-1 and α-smooth muscle actin (αSMA), a CAF marker, were located on the tumor periphery surrounding collectively invading tumor cells and in perivascular regions. To interrogate a human lung cancer database for the presence of Thy-1+ CAFs, we isolated Thy-1+ CAFs and normal lung fibroblasts (LFs) from the lungs of KrasLA1 mice and wild-type littermates, respectively, and performed global proteomic analysis on the murine CAFs and LFs, which identified 425 proteins that were differentially expressed. Used as a probe to identify Thy-1+ CAF-enriched tumors in a compendium of 1,586 lung adenocarcinomas, the presence of the 425-gene signature predicted a significantly shorter survival. Thus, Thy-1 marks a CAF population that adversely impacts clinical outcome in human lung cancer.

Extracellular vesicles (EVs), including exosomes, have been widely recognized for their role in intercellular communication of the immune response system. In the past few years, significance has been given to exosomes in the induction and modulation of cell-fate-inducing signalling pathways, such as the Hedgehog (Hh), Wnts, Notch, transforming growth factor (TGF-β), epidermal growth factor (EGF) and fibroblast growth factor (FGF) pathways, placing them in the wider context of development and also of cancer. These protein families induce signalling cascades responsible for tissue specification, homeostasis and maintenance. Exosomes contribute to cell-fate signal secretion, and vice versa exosome secretion can be induced by these proteins. Interestingly, exosomes can also transfer their mRNA to host cells or modulate the signalling pathways directly by the removal of downstream effector molecules from the cell. Surprisingly, much of what we know about the function of exosomes in cell determination is gathered from pathological transformed cancer cells and wound healing while data about their biogenesis and biology in normal developing and adult tissue lag behind. In this report, we will summarize some of the published literature and point to current advances and questions in this fast-developing topic. In a brief foray, we will also update and shortly discuss their potential in diagnosis and targeted cancer treatment.

In the originally published version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to also include support from the National Institutes of Health grant T32GM008280 to Sarah Alvarado.

As the second most common subtype of breast carcinoma, Invasive Lobular Carcinoma (ILC) microenvironment features have not been thoroughly explored. ILC has different histological subtypes and elucidating differences in their microenvironments could lead to a comprehensive development of cancer therapies. We designed a custom-made cancer associated fibroblast (CAFs) panel and used multiplex immunofluorescence to identify the differences in tumor microenvironment between Classic ILC and Pleomorphic ILC.Materials and methodsMultiplex immunofluorescence were performed on formalin fixed paraffin embedded tissues using Opal-7 color kit. The antibodies used for phenotyping CAFs were Pan CK (AE1/AE3), CD45, A-SMA, FAP, S100, Thy-1 with optimized dilutions. The images were acquired and analyzed using Vectra 3.0 imaging system and InForm software respectively.ResultsWe studied 19 different CAFs colocalized phenotypes in the tumor, stroma and overall tissue compartments between classic and pleomorphic ILC. Total A-SMA+, A-SMA+FAP+S100+ and A-SMA+S100+ CAFs demonstrated higher densities in classic ILC cases while FAP+S100+ and S-100+ CAFs were increased in the pleomorphic subtype samples.ConclusionOur study explores multiple CAFs phenotypes between classical and pleomorphic ILC. We showed that CAFs subset differ between Classic ILC and Pleomorphic ILC. A-SMA CAFs are more prevalent in the TME of classic ILCs whereas Pleomorphic ILCs are dominated by CAFs without A-SMA expression. This also iterates the importance of exploring this particular type of breast carcinoma in more detail, paving the way for meaningful translational research.

The way in which metastatic tumour cells control endocytic vesicular trafficking networks to establish a front-rear polarity axis that facilitates motility remains unclear. Here, the authors show that the EMT activator ZEB1 influences vesicular trafficking dynamics to execute cell polarity change.