Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

Vazquez, Ester Gil; Nasreddin, Nadia; Valbuena, Gabriel N.; Mulholland, Eoghan; Belnoue-Davis, Hayley L.; Eggington, Holly R; Schenck, Ryan O.; Wouters, Valérie M; Wirapati, Pratyaksha; Gilroy, Kathryn; Lannagan, Tamsin R.M.; Flanagan, Dustin J.; Najumudeen, Arafath K.; Omwenga, Sulochana; McCorry, Amy M B; Easton, Alistair; Koelzer, Viktor H.; East, James E.; Morton, Dion; Trusolino, Livio; Maughan, Tim; Campbell, Andrew D.; Loughrey, Maurice B.; Dunne, Philip D.; Tsantoulis, Petros; Huels, David J.; Tejpar, Sabine; Sansom, Owen J.; Leedham, Simon J.

doi:10.1016/j.stem.2022.09.005

Cited by 5 publications

(12 citation statements)

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“…Furthermore, PDS1 and PDS2 tumors were associated with tubular and serrated gene signatures, respectively 20 , but PDS3 tumors had no clear association with these precursor features. This was confirmed using a cohort of transcriptionally profiled polyp samples (S:CORT polyp cohort 19 ) pathologically defined as tubulovillous adenomas, sessile serrated lesions and traditional serrated adenomas, in which tubulovillous adenomas were predominantly PDS1 and sessile serrated lesions associated with PDS2, but PDS3 tumors lacked any precursor association (Fig. 4c and Extended Data Fig.…”

Section: Resultsmentioning

confidence: 61%

“…The lack of robust morphological patterns in PDS3 tumors prompted us to next assess their stem cell and precursor associations. Using the intestinal stem cell (ISC) index 19 , we observed an association between PDS1 tumors and the canonical LGR5 + crypt-base columnar cell (CBC) signature, PDS2 tumors aligned strongly with LGR5 − /ANXA1 + regenerative stem cell (RSC) signature and PDS3 tumors scored low for both stem signatures (Fig. 4a and Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

“… a , Scatter gradient-density plot representing LGR5 + CBC and LGR5 − /ANXA1 + RSC ssGSEA scores with PDS sample annotations in the SPINAL cohort (top). Stem cell plasticity landscape schematic highlighting the PDS1 association with CBC and the PDS2 association with RSC gene signatures along the stem cell index proposed in a previous study 19 (bottom). b , In situ hybridization multiplex staining with LGR5, ANXA1 and DAPI across PDS samples in the SPINAL (PDS1, n = 7; PDS2, n = 7; PDS3, n = 6) cohort.…”

Section: Resultsmentioning

confidence: 99%

“…m , Heatmap visualization of the differentiation, PRC targets and MYC targets gene expressions in the FOCUS cohort, with annotated PDS prediction probabilities, PDS and SMI. n , In addition to the stem phenotypic landscape described in a previous work 19 , an overall tumor epithelial landscape describes the stem–differentiation cellular dynamics along the SMI, in which PDS3 tumors are highly enriched for differentiated-like traits that correspond to high PRC target expression. AbsPro, absorptive progenitor; SecPDG, secretory progenitor/deep crypt secretory cells/goblet, Ent, enterocytes; EEC, enteroendocrine cell.…”

Section: Resultsmentioning

confidence: 99%

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Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer

Malla,

Byrne,

Lafarge

et al. 2024

Nat Genet

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Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1+ stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers.

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Section: Resultsmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer

Malla,

Byrne,

Lafarge

et al. 2024

Nat Genet

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“…(i)RECs closely resemble a cancer state driving metastatic recurrence after surgical resection in a CRC mouse model 25 , implicating them as metastasis-initiating CRC cells required for tumour regeneration. They also share an expression profile with a state enriched in early micrometastasis CRC mouse models 13 that upregulates a foetal intestinal signature and is characterised by high YAP signalling [21][22][23][24] (Fig. 1e).…”

Section: Heterogeneous Cancer Cell States In Primary Crcmentioning

confidence: 99%

Phenotypic plasticity mediates colorectal cancer metastasis

Efremova,

Ogden,

Metic

et al. 2024

Preprint

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A major challenge for inhibiting metastasis is the ability of cancer cells to reversibly switch states in response to microenvironmental cues along the metastatic cascade. The regulatory factors and signals from the microenvironment enabling colorectal cancer (CRC) cells to transition into an invasive state and to establish metastasis in the liver remain unknown. Using a combination of single-cell multiomics and spatial transcriptomics data from primary and metastatic CRC patients, we reveal putative metastasis-initiating cancer states with regenerative and inflammatory signatures, driven by transcription factors AP-1, NF-κB and YAP. We demonstrate the existence of an intermediate population with a hybrid regenerative and stem phenotype, indicating phenotypic transitions between stem and pro-metastatic cells. Our spatial analyses show localisation of the regenerative states at the invasive edge in primary CRC and in an immunosuppressive niche in liver metastasis, surrounded by immune and stromal cells that sustain these cells. We uncover putative ligand-receptor interactions driven by cancer-associated fibroblasts (CAFs), macrophages and CD8 T cells that activate the regenerative and inflammatory invasive phenotype in cancer cells. Together, our findings reveal regulatory and signalling factors that can be targeted to restrict transition into invasive states to impair metastasis.

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Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines

Ogasawara,

Kano,

Yoneyama

et al. 2024

iScience

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Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

Cited by 5 publications

References 0 publications

Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer

Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer

Phenotypic plasticity mediates colorectal cancer metastasis

Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines

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