Predictive modeling in colorectal cancer: time to move beyond consensus molecular subtypes

Sveen, Anita; Cremolini, Chiara; Dienstmann, Rodrigo

doi:10.1093/annonc/mdz412

Cited by 20 publications

(22 citation statements)

References 20 publications

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“…These findings were further supported by scRNA-seq CMS classification analysis that assigned each CRC sample to multiple CMS subtypes thereby suggesting CMS heterogeneity in each CRC tumor 21,65 . These findings may also explain why CMS-defined populations of tumors have not been readily observed in transcriptomic data from independent CRC cohorts 22,54 .…”

Section: Discussionmentioning

confidence: 61%

“…8-11) . The continuous scores showed no reliability in classifying CRC into immune–stromal rich (CMS1/CMS4) or immune-stromal desert (CMS2/CMS3) subtypes as proposed previously 20 . Thus, confirming continuous scores rather than discrete subtypes may improve classifying CRC tumors and may explain tumor-to-tumor variability, tumor/TME-to-tumor/TME and TME-to-TME variabilities 55 .…”

Section: Mainmentioning

confidence: 57%

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Redefining colorectal cancer classification and clinical stratification through a single-cell atlas

Khaliq

Kurt

et al. 2021

Preprint

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Colorectal cancer (CRC), a disease of high incidence and mortality, exhibits a large degree of inter- and intra-tumoral heterogeneity. The cellular etiology of this heterogeneity is poorly understood. Here, we generated and analyzed a single-cell transcriptome atlas of 49,859 CRC cells from 16 patients, validated with an additional 31,383 cells from an independent CRC patient cohort. We describe subclonal transcriptomic heterogeneity of CRC tumor epithelial cells, as well as discrete stromal populations of cancer-associated fibroblasts (CAFs). Within CRC CAFs, we identify the transcriptional signature of specific subtypes that significantly stratifies overall survival in more than 1,500 CRC patients with bulk transcriptomic data. We demonstrate that scRNA analysis of malignant, stromal, and immune cells exhibit a more complex picture than portrayed by bulk transcriptomic-based Consensus Molecular Subtypes (CMS) classification. By demonstrating an abundant degree of heterogeneity amongst these cell types, our work shows that CRC is best represented in a transcriptomic continuum crossing traditional classification systems boundaries. Overall, this CRC cell map provides a framework to re-evaluate CRC tumor biology with implications for clinical trial design and therapeutic development.

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Section: Discussionmentioning

confidence: 61%

Section: Mainmentioning

confidence: 57%

Redefining colorectal cancer classification and clinical stratification through a single-cell atlas

Khaliq

Kurt

et al. 2021

Preprint

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“…were removed from the distal colon indicating they may be CMS2, whereas LGCA2 was from the proximal colon and is therefore more likely to be CMS3. CRC tumours are known to be heterogeneous and usually do not fit perfectly into a single CMS category but contain aspects of multiple categories, maybe reflecting transition between categories during tumour progression (Guinney et al, 2015;Sveen et al, 2019). Compared to the other 3 HGCA cell lines, untreated HGCA1 cells formed the smallest tumourspheres during passage 1 and 2, and its TMB score (7.75) was more similar to the 3…”

Section: Key Findingsmentioning

confidence: 99%

Characterisation of cancer stem cells and the renin-angiotensin system in colon adenocarcinoma

Munro¹

2021

Preprint

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Colorectal cancer (CRC) is the third most common cancer and the second highest cause of cancer deaths globally. More than 70% of CRC-related deaths are due to metastasis to the liver. The cancer stem cell (CSC) concept hypothesises that CSCs drive tumour growth, chemoresistance, recurrence and metastasis. Markers such as CD133, LGR5 and EpCAM, have been used to identify and isolate CSCs in CRC. However, these markers are often expressed by cells with no stem cell properties and are not expressed by all tumour-initiating cells. An improved range of markers to define CSCs is needed. In 2007, adult mouse and human fibroblasts were reprogrammed into a stem cell state and defined as induced pluripotent stem cells (iPSCs) using transcription factors OCT4, SOX2, NANOG, KLF4 and c-MYC. These genes have well-documented roles in embryonic development and the maintenance of pluripotency, and their expression has been investigated in a range of cancers. <br><br>The renin-angiotensin system (RAS) physiologically maintains blood pressure and volume and is also acknowledged to play a role in cancer. Over-expression of (pro)renin receptor (PRR), angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R), and angiotensin-converting enzyme (ACE) have been reported in cancer. Epidemiological studies investigating the effect of RAS inhibitors on cancer outcomes have shown contradictory results.<br><br>This thesis investigates the expression of iPSC markers and RAS components in colon adenocarcinoma (CA) with three specific aims: (1) to compare CA-derived primary cell lines to their original CA tissues; (2) to investigate the expression profiles of iPSC markers in CA; and (3) to investigate expression of RAS components by CA CSCs and to determine whether CSCs can be targeted by RAS modulators. <br><br>DNA sequencing was carried out to compare the mutational profiles of formalin-fixed paraffin-embedded (FFPE) CA tissues and CA-derived cell lines to confirm whether the cell lines were a suitable in vitro model for the parent tumours.<br><br><div>Proteomics was performed to determine proteomic differences between CA tissues and patient-matched normal colon (NC) tissues, CA-derived cell lines and NC-derived cells, and between low grade CA (LGCA) tissues and cell lines and high grade CA (HGCA) tissues and cell lines. Biological processes which may link the RAS and CA were investigated, revealing enrichment of various signalling pathways that may play roles in CA onset and progression directly or via the RAS.</div><div><br></div>Western blotting and immunohistochemical staining showed elevated protein levels of OCT4, SOX2, NANOG, c-MYC, AT2R, PRR and cathepsin D in CA tissues relative to their patient-matched NC tissues, with SOX2, ACE and cathepsin B at similar levels and KLF4 less abundant in CA compared with NC tissues. Co-expression analysis by immunofluorescence staining showed a small number of epithelial cells co-expressed NANOG, SOX2, KLF4, c-MYC and CD133, as well as PRR, ACE2 and AT2R, while a small number of stromal cells co-expressed OCT4 and AT2R. This indicates the presence of at least one CSC subpopulation in CA, which expresses RAS components. HGCA tissue-derived cell lines expressed higher levels of OCT4 and SOX2 than LGCA-derived cell lines. The primary cell lines were sorted based on EpCAM expression. These EpCAM High and EpCAM Low cell subpopulations could undergo directed differentiation down the three embryonic lineages. A small number of CA-derived cells, particularly within the HGCA-derived cells, formed tumourspheres. Treatment of HGCA-derived cell lines with RAS modulators revealed that β-blockers and AT2R antagonists consistently reduced their metabolism, tumoursphere formation and iPSC marker expression. <br><br>The findings of this thesis suggest that CA-derived cell lines expressing iPSC markers have stem cell function and express RAS components. Furthermore, RAS modulators may directly influence CSCs in CA by reducing iPSC marker gene expression. This indicates a potential role for RAS modulators in regulating CSCs, which merits further investigation.

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“…For an extensive discussion of the various intricacies that should be considered for the interpretation of these studies, we would like to point to refs. 138 – 140 . Nevertheless, clinically relevant patterns in terms of therapy response can be distilled from these analyses, and we will highlight them in this section.…”

Section: Translation Of Cms To the Clinicmentioning

confidence: 99%

Exploring and modelling colon cancer inter-tumour heterogeneity: opportunities and challenges

2020

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Colon cancer inter-tumour heterogeneity is installed on multiple levels, ranging from (epi)genetic driver events to signalling pathway rewiring reflected by differential gene expression patterns. Although the existence of heterogeneity in colon cancer has been recognised for a longer period of time, it is sparingly incorporated as a determining factor in current clinical practice. Here we describe how unsupervised gene expression-based classification efforts, amongst which the consensus molecular subtypes (CMS), can stratify patients in biological subgroups associated with distinct disease outcome and responses to therapy. We will discuss what is needed to extend these subtyping efforts to the clinic and we will argue that preclinical models recapitulate CMS subtypes and can be of vital use to increase our understanding of treatment response and resistance and to discover novel targets for therapy.

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Predictive modeling in colorectal cancer: time to move beyond consensus molecular subtypes

Cited by 20 publications

References 20 publications

Redefining colorectal cancer classification and clinical stratification through a single-cell atlas

Redefining colorectal cancer classification and clinical stratification through a single-cell atlas

Characterisation of cancer stem cells and the renin-angiotensin system in colon adenocarcinoma

Exploring and modelling colon cancer inter-tumour heterogeneity: opportunities and challenges

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