The adenomatous polyposis coli protein 30 years on.

Mutations in the gene encoding the Adenomatous polyposis coli protein (APC) were discovered as driver mutations in colorectal cancers almost 30 years ago. Since then, the importance of APC in normal tissue homeostasis has been confirmed in a plethora of other (model) organisms spanning a large evolutionary space. APC is a multifunctional protein, with roles as a key scaffold protein in complexes involved in diverse signalling pathways, most prominently the Wnt signalling pathway.

The Oligomerization Domains of the APC Protein Mediate Liquid-Liquid Phase Separation That Is Phosphorylation Controlled.

One of the most important properties of intrinsically disordered proteins is their ability to undergo liquid-liquid phase separation and form droplets. The Adenomatous Polyposis Coli (APC) protein is an IDP that plays a key role in Wnt signaling and mutations in initiate cancer. APC forms droplets via its 20R domains and self-association domain (ASAD) and in the context of Axin.

Ultrasound mediated delivery of quantum dots from a proof of concept capsule endoscope to the gastrointestinal wall.

Biologic drugs, defined as therapeutic agents produced from or containing components of a living organism, are of growing importance to the pharmaceutical industry. Though oral delivery of medicine is convenient, biologics require invasive injections because of their poor bioavailability via oral routes. Delivery of biologics to the small intestine using electronic delivery with devices that are similar to capsule endoscopes is a promising means of overcoming this limitation and does not require reformulation of the therapeutic agent.

A Learning-Based Microultrasound System for the Detection of Inflammation of the Gastrointestinal Tract.

Inflammation of the gastrointestinal (GI) tract accompanies several diseases, including Crohn's disease. Currently, video capsule endoscopy and deep bowel enteroscopy are the main means for direct visualisation of the bowel surface. However, the use of optical imaging limits visualisation to the luminal surface only, which makes early-stage diagnosis difficult.

Loss of adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22.

Interleukin-22 (IL-22) is a critical immune defence cytokine that maintains intestinal homeostasis and promotes wound healing and tissue regeneration, which can support the growth of colorectal tumours. Mutations in the adenomatous polyposis coli gene (Apc) are a major driver of familial colorectal cancers (CRCs). How IL-22 contributes to APC-mediated tumorigenesis is poorly understood.

Identification of Endogenous Adenomatous Polyposis Coli Interaction Partners and β-Catenin-Independent Targets by Proteomics.

() is the most frequently mutated gene in colorectal cancer. APC negatively regulates the Wnt signaling pathway by promoting the degradation of β-catenin, but the extent to which APC exerts Wnt/β-catenin-independent tumor-suppressive activity is unclear. To identify interaction partners and β-catenin-independent targets of endogenous, full-length APC, we applied label-free and multiplexed tandem mass tag-based mass spectrometry.

Lgr5 intestinal stem cells reside in an unlicensed G phase.

During late mitosis and the early G phase, the origins of replication are licensed by binding to double hexamers of MCM2-7. In this study, we investigated how licensing and proliferative commitment are coupled in the epithelium of the small intestine. We developed a method for identifying cells in intact tissue containing DNA-bound MCM2-7.

Chir99021 and Valproic acid reduce the proliferative advantage of Apc mutant cells.

More than 90% of colorectal cancers carry mutations in Apc that drive tumourigenesis. A 'just-right' signalling model proposes that Apc mutations stimulate optimal, but not excessive Wnt signalling, resulting in a growth advantage of Apc mutant over wild-type cells. Reversal of this growth advantage constitutes a potential therapeutic approach.

A Multicellular Model of Intestinal Crypt Buckling and Fission.

Crypt fission is an in vivo tissue deformation process that is involved in both intestinal homeostasis and colorectal tumourigenesis. Despite its importance, the mechanics underlying crypt fission are currently poorly understood. Recent experimental development of organoids, organ-like buds cultured from crypt stem cells in vitro, has shown promise in shedding light on crypt fission.

Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer.

Objective: Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes.

Design: RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71).

SAP97 Binding Partner CRIPT Promotes Dendrite Growth and .

The dendritic tree is a key determinant of neuronal information processing. In the motor system, the dendritic tree of spinal cord neurons undergoes dramatic remodeling in an activity-dependent manner during early postnatal life. This leads to the proper segmental spinal cord connectivity that subserves normal locomotor behavior.

Interkinetic nuclear migration and basal tethering facilitates post-mitotic daughter separation in intestinal organoids.

Homeostasis of renewing tissues requires balanced proliferation, differentiation and movement. This is particularly important in the intestinal epithelium where lineage tracing suggests that stochastic differentiation choices are intricately coupled to the position of a cell relative to a niche. To determine how position is achieved, we followed proliferating cells in intestinal organoids and discovered that the behaviour of mitotic sisters predicted long-term positioning.

Cancer Biology: APC Delivers Kiss of Death to Focal Adhesions.

New work shows that the actin-nucleating ability of the adenomatous polyposis coli protein is required for disassembly of focal adhesions. Loss of this function in Apc mutant cells reduces directed cell migration, potentially explaining the decreased migration of colon cancer cells.

Acoustic Sensing and Ultrasonic Drug Delivery in Multimodal Theranostic Capsule Endoscopy.

Video capsule endoscopy (VCE) is now a clinically accepted diagnostic modality in which miniaturized technology, an on-board power supply and wireless telemetry stand as technological foundations for other capsule endoscopy (CE) devices. However, VCE does not provide therapeutic functionality, and research towards therapeutic CE (TCE) has been limited. In this paper, a route towards viable TCE is proposed, based on multiple CE devices including important acoustic sensing and drug delivery components.

Ultrasound capsule endoscopy: sounding out the future.

Video capsule endoscopy (VCE) has been of immense benefit in the diagnosis and management of gastrointestinal (GI) disorders since its introduction in 2001. However, it suffers from a number of well recognized deficiencies. Amongst these is the limited capability of white light imaging, which is restricted to analysis of the mucosal surface.

Paneth Cell-Rich Regions Separated by a Cluster of Lgr5+ Cells Initiate Crypt Fission in the Intestinal Stem Cell Niche.

The crypts of the intestinal epithelium house the stem cells that ensure the continual renewal of the epithelial cells that line the intestinal tract. Crypt number increases by a process called crypt fission, the division of a single crypt into two daughter crypts. Fission drives normal tissue growth and maintenance.

Promoting microtubule assembly: A hypothesis for the functional significance of the +TIP network.

Regulation of microtubule (MT) dynamics is essential for many cellular processes, but the machinery that controls MT dynamics remains poorly understood. MT plus-end tracking proteins (+TIPs) are a set of MT-associated proteins that dynamically track growing MT ends and are uniquely positioned to govern MT dynamics. +TIPs associate with each other in a complex array of inter- and intra-molecular interactions known as the "+TIP network.

Stem cell decisions: a twist of fate or a niche market?

Establishing and maintaining cell fate in the right place at the right time is a key requirement for normal tissue maintenance. Stem cells are at the core of this process. Understanding how stem cells balance self-renewal and production of differentiating cells is key for understanding the defects that underpin many diseases.

Changes in cell and tissue organization in cancer of the breast and colon.

Most cancers arise in epithelia, the tissue type that lines all body cavities. The organization of epithelia enables them to act as a barrier and perform vectorial transport of molecules between body compartments. Crucial for their organization and function is a highly specialized network of cell adhesion and polarity proteins aligned along the apical-basal axis.

High-energy particle-induced tumorigenesis throughout the gastrointestinal tract.

Epidemiological data reveals the gastrointestinal (GI) tract as one of the main sites for low-LET radiation-induced cancers. Importantly, the use of particle therapy is increasing, but cancer risk by high-LET particles is still poorly understood. This gap in our knowledge also remains a major limiting factor in planning long-term space missions.

Computational models reveal a passive mechanism for cell migration in the crypt.

Cell migration in the intestinal crypt is essential for the regular renewal of the epithelium, and the continued upward movement of cells is a key characteristic of healthy crypt dynamics. However, the driving force behind this migration is unknown. Possibilities include mitotic pressure, active movement driven by motility cues, or negative pressure arising from cell loss at the crypt collar.

Cell and tissue polarity in the intestinal tract during tumourigenesis: cells still know the right way up, but tissue organization is lost.

Cell and tissue polarity are tightly coupled and are vital for normal tissue homeostasis. Changes in cellular and tissue organization are common to even early stages of disease, particularly cancer. The digestive tract is the site of the second most common cause of cancer deaths in the developed world.

DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA damage.

Ubiquitin-binding domains (UBDs) are crucial for recruiting many proteins to sites of DNA damage. Here we characterize C1orf124 (Spartan; referred to as DVC1), which has an UBZ4-type UBD found predominantly in DNA repair proteins. DVC1 associates with DNA replication factories and localizes to sites of DNA damage in human cells, in a manner that requires the ability of the DVC1 UBZ domain to bind to ubiquitin polymers in vitro and a conserved PCNA-interacting motif.

The adenomatous polyposis coli protein contributes to normal compaction of mitotic chromatin.

The tumour suppressor Adenomatous Polyposis Coli (APC) is required for proper mitosis; however, the exact role of APC in mitosis is not understood. Using demembranated sperm chromatin exposed to meiotic Xenopus egg extract and HeLa cells expressing fluorescently labelled histones, we established that APC contributes to chromatin compaction. Sperm chromatin in APC-depleted Xenopus egg extract frequently formed tight round or elongated structures.