Tumor-derived extracellular vesicles convey solute transporters to induce bioenergetic dependence shift contributing to treatment resistance.

Growing evidence points to the tumor microenvironment's role in developing drug resistance. A key element of this microenvironment is inter-cellular communication, which includes the release of membrane-encapsulated vesicles containing various cargo, known as extracellular vesicles (EVs). Understanding how EVs contribute to acquired resistance holds significant clinical implications.

Bioengineered Hydrogels Recapitulate Fibroblast Heterogeneity in Cancer.

Recently mapped transcriptomic landscapes reveal the extent of heterogeneity in cancer-associated fibroblasts (CAFs) beyond previously established single-gene markers. Functional analyses of individual CAF subsets within the tumor microenvironment are critical to develop more accurate CAF-targeting therapeutic strategies. However, there is a lack of robust preclinical models that reflect this heterogeneity in vitro.

Bioengineered hydrogels enhance ex vivo preservation of patient-derived tumor explants for drug evaluation.

Ex vivo patient-derived tumor slices (PDTS) are currently limited by short-term viability in culture. Here, we show how bioengineered hydrogels enable the identification of key matrix parameters that significantly enhance PDTS viability compared to conventional culture systems. As demonstrated using single-cell RNA sequencing and high-dimensional flow cytometry, hydrogel-embedded PDTS tightly preserved cancer, cancer-associated fibroblast, and various immune cell populations and subpopulations in the corresponding original tumor.

Erratum: Publisher's Note: "Magnetic force-based cell manipulation for in vitro tissue engineering" [APL Bioeng. , 031504 (2023)].

[This corrects the article DOI: 10.1063/5.0138732.

Magnetic force-based cell manipulation for tissue engineering.

Cell manipulation techniques such as those based on three-dimensional (3D) bioprinting and microfluidic systems have recently been developed to reconstruct complex 3D tissue structures . Compared to these technologies, magnetic force-based cell manipulation is a simpler, scaffold- and label-free method that minimally affects cell viability and can rapidly manipulate cells into 3D tissue constructs. As such, there is increasing interest in leveraging this technology for cell assembly in tissue engineering.

Making In Vitro Tumor Models Whole Again.

As a reductionist approach, patient-derived in vitro tumor models are inherently still too simplistic for personalized drug testing as they do not capture many characteristics of the tumor microenvironment (TME), such as tumor architecture and stromal heterogeneity. This is especially problematic for assessing stromal-targeting drugs such as immunotherapies in which the density and distribution of immune and other stromal cells determine drug efficacy. On the other end, in vivo models are typically costly, low-throughput, and time-consuming to establish.

Hepatocellular carcinoma organoid co-cultures mimic angiocrine crosstalk to generate inflammatory tumor microenvironment.

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer worldwide. Despite approvals of several therapeutics to treat advanced HCC in the past few years, the impact of anti-angiogenic treatment on HCC patient overall survival remains limited. This suggests there may be alternative, perfusion-independent roles of endothelial cells that support tumor progression.

Clinical translation of patient-derived tumour organoids- bottlenecks and strategies.

Multiple three-dimensional (3D) tumour organoid models assisted by multi-omics and Artificial Intelligence (AI) have contributed greatly to preclinical drug development and precision medicine. The intrinsic ability to maintain genetic and phenotypic heterogeneity of tumours allows for the reconciliation of shortcomings in traditional cancer models. While their utility in preclinical studies have been well established, little progress has been made in translational research and clinical trials.

Organoids.

Organoids have attracted increasing attention because they are simple tissue-engineered cell-based models that recapitulate many aspects of the complex structure and function of the corresponding tissue. They can be dissected and interrogated for fundamental mechanistic studies on development, regeneration, and repair in human tissues. Organoids can also be used in diagnostics, disease modeling, drug discovery, and personalized medicine.

Engineering stromal heterogeneity in cancer.

Based on our exponentially increasing knowledge of stromal heterogeneity from advances in single-cell technologies, the notion that stromal cell types exist as a spectrum of unique subpopulations that have specific functions and spatial distributions in the tumor microenvironment has significant impact on tumor modeling for drug development and personalized drug testing. In this Review, we discuss the importance of incorporating stromal heterogeneity and tumor architecture, and propose an overall approach to guide the reconstruction of stromal heterogeneity in vitro for tumor modeling. These next-generation tumor models may support the development of more precise drugs targeting specific stromal cell subpopulations, as well as enable improved recapitulation of patient tumors in vitro for personalized drug testing.

Hot or cold: Bioengineering immune contextures into in vitro patient-derived tumor models.

In the past decade, immune checkpoint inhibitors (ICI) have proven to be tremendously effective for a subset of cancer patients. However, it is difficult to predict the response of individual patients and efforts are now directed at understanding the mechanisms of ICI resistance. Current models of patient tumors poorly recapitulate the immune contexture, which describe immune parameters that are associated with patient survival.

Three-Dimensional Macroporous Sponge for the Culture of Hepatocellular Carcinoma Patient-Derived Xenograft Organoids.

This protocol focuses on the culture of cells harvested from hepatocellular carcinoma (HCC) patient-derived xenografts (PDXs) as organoids using a cellulosic macroporous sponge scaffold. Compared with many other epithelial cancer types, the viability of HCC cells directly derived from patients or PDX models is notoriously challenging to maintain in vitro. We previously developed a macroporous sponge scaffold uniquely designed to provide biochemical and mechanical cues that support the culture of normal hepatocytes as spheroids with maintained functionality.

Hydrogels to engineer tumor microenvironments in vitro.

In recent years, hydrogel-based three-dimensional tumor models have become increasingly mainstream for cancer research. Hydrogels enable recapitulation of biochemical and biophysical cues in the tumor microenvironment (TME) for the culture of cancer and stromal cells. While there is increasing insight into how cancer-stromal interactions support tumor progression and drug resistance, much remains to be understood for the successful development of therapeutic targets that are capable of controlling tumors in patients.

Hydrogel-based colorectal cancer organoid co-culture models.

The lack of cancer-associated fibroblasts (CAFs) in patient-derived organoid (PDO) models is a major limitation as CAFs contribute to tumor progression and drug resistance. In the present study, we addressed this problem by establishing in vitro conditions that enable the co-culture of colorectal cancer (CRC) PDO with patient-derived CAFs. Considering that the CRC extracellular matrix is high in hyaluronan and collagen I, we hypothesized that hyaluronan-gelatin hydrogels may serve as a suitable alternative 3D matrix to traditionally used basement membrane extracts to support the co-culture of CRC PDO and CAFs.

Cleavable cellulosic sponge for functional hepatic cell culture and retrieval.

Interconnected macroporous hydrogel is hydrophilic; it exhibits soft tissue-like mechanical property and aqueous-stable macroporosity for 3D spheroid culture. There is an unmet need to develop cleavable macroporous hydrogel, for the ease of retrieving functional spheroids for further in vitro and in vivo applications. We have developed and comprehensively characterized a hydroxypropyl-cellulose-disulfide sponge by systematically identifying strategies and synthesis schemes to confer cleavability to the sponge under cell-friendly conditions.

Deep learning enables automated scoring of liver fibrosis stages.

Current liver fibrosis scoring by computer-assisted image analytics is not fully automated as it requires manual preprocessing (segmentation and feature extraction) typically based on domain knowledge in liver pathology. Deep learning-based algorithms can potentially classify these images without the need for preprocessing through learning from a large dataset of images. We investigated the performance of classification models built using a deep learning-based algorithm pre-trained using multiple sources of images to score liver fibrosis and compared them against conventional non-deep learning-based algorithms - artificial neural networks (ANN), multinomial logistic regression (MLR), support vector machines (SVM) and random forests (RF).

Datasets describing the growth and molecular features of hepatocellular carcinoma patient-derived xenograft cells grown in a three-dimensional macroporous hydrogel.

This data article presents datasets associated with the research article entitled "Generation of matched patient-derived xenograft models using 3D macroporous hydrogels for the study of liver cancer" (Fong et al., 2018) [1]. A three-dimensional macroporous sponge system was used to generate counterparts to various hepatocellular carcinoma patient-derived xenograft (HCC-PDX) lines.

Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, often manifesting at the advanced stage when cure is no longer possible. The discrepancy between preclinical findings and clinical outcome in HCC is well-recognized. So far, sorafenib is the only targeted therapy approved as first-line therapy for patients with advanced HCC.

Development of a classification model for non-alcoholic steatohepatitis (NASH) using confocal Raman micro-spectroscopy.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in developed countries [1]. A subset of individuals with NAFLD progress to non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD which predisposes individuals to cirrhosis, liver failure and hepatocellular carcinoma. The current gold standard for NASH diagnosis and staging is based on histological evaluation, which is largely semi-quantitative and subjective.

3D Culture as a Clinically Relevant Model for Personalized Medicine.

Advances in understanding many of the fundamental mechanisms of cancer progression have led to the development of molecular targeted therapies. While molecular targeted therapeutics continue to improve the outcome for cancer patients, tumor heterogeneity among patients, as well as intratumoral heterogeneity, limits the efficacy of these drugs to specific patient subtypes, as well as contributes to relapse. Thus, there is a need for a more personalized approach toward drug development and diagnosis that takes into account the diversity of cancer patients, as well as the complex milieu of tumor cells within a single patient.

Actomyosin contractility drives bile regurgitation as an early response during obstructive cholestasis.

Background & Aims: A wide range of liver diseases manifest as biliary obstruction, or cholestasis. However, the sequence of molecular events triggered as part of the early hepatocellular homeostatic response in obstructive cholestasis is poorly elucidated. Pericanalicular actin is known to accumulate during obstructive cholestasis.