The success of targeted therapies in cancer treatment has been impeded by various mechanisms of resistance. Besides the acquisition of resistance-conferring genetic mutations, reversible mechanisms ...that lead to drug tolerance have emerged. Plasticity in tumour cells drives their transformation towards a phenotypic state that no longer depends on the drug-targeted pathway. These drug-refractory cells constitute a pool of slow-cycling cells that can either regain drug sensitivity upon treatment discontinuation or acquire permanent resistance to therapy and drive relapse. In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in various cancers, ranging from prostate and lung adenocarcinoma to melanoma and basal cell carcinoma. Our understanding of the mechanisms that control this phenotypic switch has also expanded, revealing the crucial role of reprogramming factors and chromatin remodelling. Further deciphering the molecular basis of tumour cell plasticity has the potential to contribute to new therapeutic strategies which, combined with existing anticancer treatments, could lead to deeper and longer-lasting clinical responses.
Tumour formation involves the co-evolution of neoplastic cells together with extracellular matrix, tumour vasculature and immune cells. Successful outgrowth of tumours and eventual metastasis is not ...determined solely by genetic alterations in tumour cells, but also by the fitness advantage such mutations confer in a given environment. As fitness is context dependent, evaluating tumours as complete organs, and not simply as masses of transformed epithelial cells, becomes paramount. The dynamic tumour topography varies drastically even throughout the same lesion. Heterologous cell types within tumours can actively influence therapeutic response and shape resistance.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The intestinal epithelium is one the fastest renewing tissues in mammals and is endowed with extensive adaptability. The more traditional view of a hierarchical organization of the gut has recently ...given way to a more dynamic model in which various cell types within the intestinal epithelium can de-differentiate and function as an alternative source of stem cells upon tissue damage and stress conditions such as inflammation and tumorigenesis. Here, we will review the mechanistic principles and key players involved in intestinal plasticity and discuss potential therapeutic implications of cellular plasticity in regenerative medicine and cancer.
Emerging evidence supports a dynamic model of the intestine, where the epithelium can de-differentiate and function as an alternative source of stem cells upon tissue damage and stress. de Sousa e Melo and de Sauvage discuss the mechanistic principles and key players involved in intestinal plasticity as well as potential therapeutic implications of cellular plasticity in regenerative medicine and cancer.
Epithelial surfaces form critical barriers to the outside world and are continuously renewed by adult stem cells
. Whereas dynamics of epithelial stem cells during homeostasis are increasingly well ...understood, how stem cells are redirected from a tissue-maintenance program to initiate repair after injury remains unclear. Here we examined infection by Heligmosomoides polygyrus, a co-evolved pathosymbiont of mice, to assess the epithelial response to disruption of the mucosal barrier. H. polygyrus disrupts tissue integrity by penetrating the duodenal mucosa, where it develops while surrounded by a multicellular granulomatous infiltrate
. Crypts overlying larvae-associated granulomas did not express intestinal stem cell markers, including Lgr5
, in spite of continued epithelial proliferation. Granuloma-associated Lgr5
crypt epithelium activated an interferon-gamma (IFN-γ)-dependent transcriptional program, highlighted by Sca-1 expression, and IFN-γ-producing immune cells were found in granulomas. A similar epithelial response accompanied systemic activation of immune cells, intestinal irradiation, or ablation of Lgr5
intestinal stem cells. When cultured in vitro, granuloma-associated crypt cells formed spheroids similar to those formed by fetal epithelium, and a sub-population of H. polygyrus-induced cells activated a fetal-like transcriptional program, demonstrating that adult intestinal tissues can repurpose aspects of fetal development. Therefore, re-initiation of the developmental program represents a fundamental mechanism by which the intestinal crypt can remodel itself to sustain function after injury.
Cancer stem cells (CSCs) have been hypothesized to represent the driving force behind tumour progression and metastasis, making them attractive cancer targets. However, conclusive experimental ...evidence for their functional relevance is still lacking for most malignancies. Here we show that the leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) identifies intestinal CSCs in mouse tumours engineered to recapitulate the clinical progression of human colorectal cancer. We demonstrate that selective Lgr5
cell ablation restricts primary tumour growth, but does not result in tumour regression. Instead, tumours are maintained by proliferative Lgr5
cells that continuously attempt to replenish the Lgr5
CSC pool, leading to rapid re-initiation of tumour growth upon treatment cessation. Notably, CSCs are critical for the formation and maintenance of liver metastasis derived from colorectal cancers. Together, our data highlight distinct CSC dependencies for primary versus metastasic tumour growth, and suggest that targeting CSCs may represent a therapeutic opportunity for managing metastatic disease.
Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma ...(BCC). Most BCC patients experience significant clinical benefit on vismodegib, but some develop resistance. Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.
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•Recurrent mechanisms reactivate the Hh pathway in SMO inhibitor-resistant BCC•Drug-binding pocket and activating SMO mutations reduce sensitivity to vismodegib•Downstream SUFU variants co-occur with alterations predicted to increase GLI2 levels•A relapsed tumor can harbor multiple resistance mechanisms
Sharpe et al. identify SMO mutations in the binding pocket for SMO inhibitors or that constitutively activate SMO in vismodegib-resistant basal cell carcinoma. They demonstrate that a single relapsed tumor can harbor clones with different resistance mutations.
Acquired resistance to targeted therapies threatens the value of these otherwise very promising agents. The recent description of resistance to the Hedgehog pathway inhibitor vismodegib (GDC-0449) in ...a medulloblastoma patient who had a dramatic initial response has spurred efforts to understand potential mechanisms of drug resistance. Elucidating these mechanisms will play a significant role in informing strategies to overcome this meaningful limitation.
The Hedgehog (Hh) signaling pathway regulates body patterning and organ development during embryogenesis. In adults the Hh pathway is mainly quiescent, with the exception of roles in tissue ...maintenance and repair, and its inappropriate reactivation has been linked to several disparate human cancers. In addition to cancers with mutations in components of the Hh pathway, Hh ligand-dependent cancers have been proposed to respond to Hh in an autocrine manner. More recent findings that Hh might instead signal in a paracrine manner from the tumor to the surrounding stroma or in cancer stem cells alter our understanding of Hh mechanisms in cancer, with important implications for choice of preclinical tumor models, drug screening, patient selection and therapeutic intervention. We review here the roles of the Hh pathway in cancer, Hh pathway inhibitors (HPIs) and early clinical trial results using a novel small molecule HPI, GDC-0449.
The intestinal epithelium is a structured organ composed of crypts harboring Lgr5+ stem cells, and villi harboring differentiated cells. Spatial transcriptomics have demonstrated profound zonation of ...epithelial gene expression along the villus axis, but the mechanisms shaping this spatial variability are unknown. Here, we combine laser capture micro-dissection and single cell RNA sequencing to uncover spatially zonated populations of mesenchymal cells along the crypt-villus axis. These include villus tip telocytes (VTTs) that express Lgr5, a gene previously considered a specific crypt epithelial stem cell marker. VTTs are elongated cells that line the villus tip epithelium and signal through Bmp morphogens and the non-canonical Wnt5a ligand. Their ablation is associated with perturbed zonation of enterocyte genes induced at the villus tip. Our study provides a spatially-resolved cell atlas of the small intestinal stroma and exposes Lgr5+ villus tip telocytes as regulators of the epithelial spatial expression programs along the villus axis.
Tissue regeneration: Reserve or reverse? Shivdasani, Ramesh A; Clevers, Hans; de Sauvage, Frederic J
Science (American Association for the Advancement of Science),
2021-Feb-19, 2021-02-19, 20210219, Letnik:
371, Številka:
6531
Journal Article
Recenzirano
Stem cells recover from injury by tissue dedifferentiation, not from dedicated reserves
Tissues with high intrinsic turnover, such as the skin and intestinal lining, rely on resident stem cells, ...which generate all native cell types. Intestinal stem cells (ISCs) are highly sensitive to damage, although they recover quickly. It is unclear whether this recovery (i.e., regeneration) occurs from less sensitive pools of “reserve” stem cells (
1
) or whether ISC progeny undergo “reverse” differentiation into stem cells (
2
). Recent studies in diverse organs highlight that dedifferentiation of specified cell types is a pervasive and dominant means for tissue regeneration. The findings have broad implications because all tissues experience some cell attrition over a lifetime, and knowing how tissues replenish those losses may help in preventing or treating organ failure. Moreover, it remains unclear whether incomplete differentiation, a common feature of cancer, reflects normal tissue plasticity, and it is unclear whether stem cells that arise by dedifferentiation may spawn cancers.
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