bims-instec 2022-08-07 papers

Cell Stem Cell. 2022 Aug 04. pii: S1934-5909(22)00303-4. [Epub ahead of print]29(8): 1213-1228.e8

Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia.

Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5-ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures.

Keywords: cell plasticity; colorectal cancer; colorectal neoplasia; intestinal polyps; intestinal stem cells; molecular phenotyping; stem cells

DOI: https://doi.org/10.1016/j.stem.2022.07.008

Cell Stem Cell. 2022 Aug 04. pii: S1934-5909(22)00262-4. [Epub ahead of print]29(8): 1246-1261.e6

Lymphatics and fibroblasts support intestinal stem cells in homeostasis and injury.

Norihiro Goto, Saori Goto, Shinya Imada, Sahar Hosseini, Vikram Deshpande, Ömer H Yilmaz.

Lgr5+ intestinal stem cells (ISCs) depend on niche factors for their proper function. However, the source of these ISC niche factors and how they support ISCs in vivo remain controversial. Here, we report that ISCs depend on lymphatic endothelial cells (LECs) and RSPO3+GREM1+ fibroblasts (RGFs). In the intestine and colon, LECs are surrounded by RGFs and are located near ISCs at the crypt base. Both LECs and RGFs provide the critical ISC niche factor RSPO3 to support ISCs, where RSPO3 loss in both cell types drastically compromises ISC numbers, villi length, and repair after injury. In response to injury, LEC and RGF numbers expand and produce greater amounts of RSPO3 and other growth/angiocrine factors to foster intestinal repair. We propose that LECs represent a novel niche component for ISCs, which together with RGFs serve as the major in vivo RSPO3 source for ISCs in homeostasis and injury-mediated regeneration.

Keywords: Lgr5; RSPO3; fibroblast; intestinal stem cell; lymphatic endothelial cell

DOI: https://doi.org/10.1016/j.stem.2022.06.013

Front Cell Dev Biol. 2022 ;10 894737

The Hippo-YAP/TAZ Signaling Pathway in Intestinal Self-Renewal and Regeneration After Injury.

Feihong Deng, Zengrong Wu, Fei Zou, Su Wang, Xuehong Wang.

The Hippo pathway and its downstream effectors, the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), control stem cell fate and cell proliferation and differentiation and are essential for tissue self-renewal and regeneration. YAP/TAZ are the core components of the Hippo pathway and they coregulate transcription when localized in the nucleus. The intestinal epithelium undergoes well-regulated self-renewal and regeneration programs to maintain the structural and functional integrity of the epithelial barrier. This prevents luminal pathogen attack, and facilitates daily nutrient absorption and immune balance. Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the entire digestive tract. Impaired mucosal healing is a prominent biological feature of IBD. Intestinal self-renewal is primarily dependent on functional intestinal stem cells (ISCs), especially Lgr5+ crypt base columnar (CBC) cells and transient-amplifying (TA) cells in the crypt base. However, intestinal wound healing is a complicated process that is often associated with epithelial cells, and mesenchymal and immune cells in the mucosal microenvironment. Upon intestinal injury, nonproliferative cells rapidly migrate towards the wound bed to reseal the damaged epithelium, which is followed by cell proliferation and differentiation. YAP is generally localized in the nucleus of Lgr5+ CBC cells, where it transcriptionally regulates the expression of the ISC marker Lgr5 and plays an important role in intestinal self-renewal. YAP/TAZ are the primary mechanical sensors of the cellular microenvironment. Their functions include expanding progenitor and stem cell populations, reprogramming differentiated cells into a primitive state, and mediating the regenerative function of reserve stem cells. Thus, YAP/TAZ play extremely crucial roles in epithelial repair after damage. This review provides an overview of the Hippo-YAP/TAZ signaling pathway and the processes of intestinal self-renewal and regeneration. In particular, we summarize the roles of YAP/TAZ in the phases of intestinal self-renewal and regeneration to suggest a potential strategy for IBD treatment.

Keywords: hippo–YAP/TAZ pathway; inflammatory bowel disease; intestinal regeneration; intestinal self-renewal; intestinal stem cell

DOI: https://doi.org/10.3389/fcell.2022.894737

Cell Stem Cell. 2022 Aug 04. pii: S1934-5909(22)00302-2. [Epub ahead of print]29(8): 1262-1272.e5

Lymphangiocrine signals are required for proper intestinal repair after cytotoxic injury.

Brisa Palikuqi, Jérémie Rispal, Efren A Reyes, Dedeepya Vaka, Dario Boffelli, Ophir Klein.

The intestinal epithelium undergoes continuous renewal and has an exceptional capacity to regenerate after injury. Maintenance and proliferation of intestinal stem cells (ISCs) are regulated by their surrounding niche, largely through Wnt signaling. However, it remains unclear which niche cells produce signals during different injury states, and the role of endothelial cells (ECs) as a component of the ISC niche during homeostasis and after injury has been underappreciated. Here, we show that lymphatic endothelial cells (LECs) reside in proximity to crypt epithelial cells and secrete molecules that support epithelial renewal and repair. LECs are an essential source of Wnt signaling in the small intestine, as loss of LEC-derived Rspo3 leads to a lower number of stem and progenitor cells and hinders recovery after cytotoxic injury. Together, our findings identify LECs as an essential niche component for optimal intestinal recovery after cytotoxic injury.

Keywords: Rspo3; Sca1; endothelial; intestine; lymphangiocrine; lymphatics; mucus; regeneration; stem cells

DOI: https://doi.org/10.1016/j.stem.2022.07.007

Nat Commun. 2022 Aug 04. 13(1): 4443

Molecular characterization of colorectal cancer related peritoneal metastatic disease.

A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity.

DOI: https://doi.org/10.1038/s41467-022-32198-z

Nat Rev Cancer. 2022 Aug 02.

Hidden epithelial subtypes refine colorectal cancer classification.

Joseph Willson.

DOI: https://doi.org/10.1038/s41568-022-00501-1

Nat Genet. 2022 Aug;54(8): 1192-1201

Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment.

Dalia Barkley, Reuben Moncada, Maayan Pour, Deborah A Liberman, Ian Dryg, Gregor Werba, Wei Wang, Maayan Baron, Anjali Rao, Bo Xia, Gustavo S França, Alejandro Weil, Deborah F Delair, Cristina Hajdu, Amanda W Lund, Iman Osman, Itai Yanai.

Transcriptional heterogeneity among malignant cells of a tumor has been studied in individual cancer types and shown to be organized into cancer cell states; however, it remains unclear to what extent these states span tumor types, constituting general features of cancer. Here, we perform a pan-cancer single-cell RNA-sequencing analysis across 15 cancer types and identify a catalog of gene modules whose expression defines recurrent cancer cell states including 'stress', 'interferon response', 'epithelial-mesenchymal transition', 'metal response', 'basal' and 'ciliated'. Spatial transcriptomic analysis linked the interferon response in cancer cells to T cells and macrophages in the tumor microenvironment. Using mouse models, we further found that induction of the interferon response module varies by tumor location and is diminished upon elimination of lymphocytes. Our work provides a framework for studying how cancer cell states interact with the tumor microenvironment to form organized systems capable of immune evasion, drug resistance and metastasis.

DOI: https://doi.org/10.1038/s41588-022-01141-9