Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Nicolas, Adele M.; Pešić, Marina; Engel, Esther; Ziegler, Paul; Diefenhardt, Markus; Kennel, Kilian B; Buettner, Florian; Conche, Claire; Petrocelli, Valentina; Elwakeel, Eiman; Weigert, Andreas; Zinoveva, Anna; Fleischmann, Maximilian; Häupl, Björn; Karakütük, Cem; Bohnenberger, Hanibal; Mosa, Mohammed H.; Kaderali, Lars; Gaedcke, Jochen; Ghadimi, Michael; Rödel, Franz; Arkan, Melek C.; Oellerich, Thomas; Rödel, Claus; Fokas, Emmanouil; Greten, Florian R.

doi:10.1016/j.ccell.2022.01.004

Cited by 163 publications

(156 citation statements)

References 50 publications

Supporting

Mentioning

153

Contrasting

Order By: Relevance

“…Colored rectangles and numbers on the left indicate genes upregulated in O _min (1, red), O_ENAS (2, black) or in the co-cultures with NF and CAF (3, orange). (B) Hierarchical clustering of general fibroblast, myofibroblast (myCAF) and inflammatory fibroblast (iCAF) markers (described in published scRNA-seq datasets of patient tumors ( 13, 14, 25 ) in cultured NFs and CAFs grown alone (NF, CAF) or in co-culture with organoids (O_NF, O_CAF).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…One reason might be the lack of the tumor stroma in these models, which evidently is also strongly affected by e.g. chemotherapy (55) and radiotherapy (25,(56)(57)(58). Here we present and thoroughly characterize a CRC PDO model integrating fibroblasts as a highly abundant and important cell type in the TME.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, CXCL1, CXCL8, MMP1, MMP3 and MMP13 were present at higher levels in the co-culture conditions (both NF and CAF), representing genes inducing proinflammatory and ECM degrading phenotypes in fibroblasts. These genes were defined as iCAF markers in scRNA-seq analysis (25). Interestingly, some of the genes involved in collagen organization including decorin (DCN), which has been associated with tumor suppressive activities, and some collagen genes were downregulated upon co-culture with organoids in both NFs and CAFs.…”

Section: Fibroblast Marker Gene Expression In Co-culture With Organoi...mentioning

confidence: 99%

“…In fact, early co-culture experiments have demonstrated that irradiated fibroblasts better support tumor cell growth compared to nonirradiated fibroblasts pointing out that these cells actively affect the tumor and can potentially affect response to therapy (10,(21)(22)(23)(24). Further, a recent report identified an association of iCAFs with poor prognosis in rectal cancer following irradiation (25).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Mimicking tumor cell heterogeneity of colorectal cancer in a patient-derived organoid-fibroblast model

Atanasova

Cardona

Hejret

et al. 2022

Preprint

View full text Add to dashboard Cite

Patient-derived organoid (PDO) cancer models are generated from epithelial tumor cells. Although they reflect the molecular tumor characteristics, they lack the complexity of the tumor microenvironment, which is a key driver of tumorigenesis and therapy response. Here, we present a colorectal cancer (CRC) organoid model that incorporates epithelial cells and stromal fibroblasts from the same patient. Molecular characterization of primary cancer associated fibroblasts (CAFs) and matched normal fibroblasts (NF) revealed proteomic, secretome and gene expression differences in pathways associated with tumor related fibroblast function. Further, CAFs retained higher motility compared to NFs in vitro. Importantly, both CAFs and NFs supported cancer cell proliferation in 3D co-cultures, without the addition of classical niche factors. PDOs grown together with fibroblasts displayed a larger cellular heterogeneity of tumor cells compared to mono-cultures, and closely resembled the in vivo tumor morphology. This was also confirmed by the calculation of cellular proportions of epithelial cell subtypes in organoid mono-versus co-cultures, which were inferred through bioinformatics deconvolution of bulk RNA sequencing data using published single cell RNA sequencing datasets from CRC tissues. Additionally, we observed a mutual crosstalk between tumor cells and fibroblasts in the co-cultures. This was manifested by majorly deregulated pathways such as cell-cell communication and extracellular matrix remodeling in the organoids. For the fibroblasts, we observed enhanced expression of tumor induced marker genes and cytokines characteristic for myo- and immunogenic fibroblasts. This model will be vital as a physiological personalized tumor model to study disease mechanisms and therapy response in CRC.One Sentence SummaryPatient matched fibroblasts support tumor organoid growth in 3D co-culture and maintain intratumoral cellular heterogeneity and histo-morphology.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Fibroblast Marker Gene Expression In Co-culture With Organoi...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mimicking tumor cell heterogeneity of colorectal cancer in a patient-derived organoid-fibroblast model

Atanasova

Cardona

Hejret

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

Transcriptomic Analyses of Pretreatment Tumor Biopsy Samples, Response to Neoadjuvant Chemoradiotherapy, and Survival in Patients With Advanced Rectal Cancer

et al. 2023

View full text Add to dashboard Cite

ImportanceNeoadjuvant chemoradiotherapy (CRT) is the standard of care for advanced rectal cancer. Yet, estimating response to CRT remains an unmet clinical challenge.ObjectiveTo investigate and better understand the transcriptomic factors associated with response to neoadjuvant CRT and survival in patients with advanced rectal cancer.Design, Setting, and ParticipantsA single-center, retrospective, case series was conducted at a comprehensive cancer center. Pretreatment biopsies from 298 patients with rectal cancer who were later treated with neoadjuvant CRT between April 1, 2004, and September 30, 2020, were analyzed by RNA sequencing. Data analysis was performed from July 1, 2021, to May 31, 2022.ExposuresChemoradiotherapy followed by total mesorectal excision or watch-and-wait management.Main Outcomes and MeasuresTranscriptional subtyping was performed by consensus molecular subtype (CMS) classification. Immune cell infiltration was assessed using microenvironment cell populations-counter (MCP-counter) scores and single-sample gene set enrichment analysis (ssGSEA). Patients with surgical specimens of tumor regression grade 3 to 4 or whose care was managed by the watch-and-wait approach for more than 3 years were defined as good responders.ResultsOf the 298 patients in the study, 205 patients (68.8%) were men, and the median age was 61 (IQR, 52-67) years. Patients classified as CMS1 (6.4%) had a significantly higher rate of good response, albeit survival was comparable among the 4 subtypes. Good responders exhibited an enrichment in various immune-related pathways, as determined by ssGSEA. Microenvironment cell populations-counter scores for cytotoxic lymphocytes were significantly higher for good responders than nonresponders (median, 0.76 [IQR, 0.53-1.01] vs 0.58 [IQR, 0.43-0.83]; P &lt; .001). Cytotoxic lymphocyte MCP-counter score was independently associated with response to CRT, as determined in the multivariable analysis (odds ratio, 3.81; 95% CI, 1.82-7.97; P &lt; .001). Multivariable Cox proportional hazards regression analysis, including postoperative pathologic factors, revealed the cytotoxic lymphocyte MCP-counter score to be independently associated with recurrence-free survival (hazard ratio [HR], 0.38; 95% CI, 0.16-0.92; P = .03) and overall survival (HR, 0.16; 95% CI, 0.03-0.83; P = .03).Conclusions and RelevanceIn this case series of patients with rectal cancer treated with neoadjuvant CRT, the cytotoxic lymphocyte score in pretreatment biopsy samples, as computed by RNA sequencing, was associated with response to CRT and survival. This finding suggests that the cytotoxic lymphocyte score might serve as a biomarker in personalized multimodal rectal cancer treatment.

show abstract

Cellular senescence and the tumour microenvironment

2022

View full text Add to dashboard Cite

The senescence‐associated secretory phenotype (SASP), where senescent cells produce a variety of secreted proteins including inflammatory cytokines, chemokines, matrix remodelling factors, growth factors and so on, plays pivotal but varying roles in the tumour microenvironment. The effects of SASP on the surrounding microenvironment depend on the cell type and process of cellular senescence induction, which is often associated with innate immunity. Via SASP‐mediated paracrine effects, senescent cells can remodel the surrounding tissues by modulating the character of adjacent cells, such as stromal, immune cells, as well as cancer cells. The SASP is associated with both tumour‐suppressive and tumour‐promoting effects, as observed in senescence surveillance effects (tumour‐suppressive) and suppression of anti‐tumour immunity in most senescent cancer‐associated fibroblasts and senescent T cells (tumour‐promoting). In this review, we discuss the features and roles of senescent cells in tumour microenvironment with emphasis on their context‐dependency that determines whether they promote or suppress cancer development. Potential usage of recently developed drugs that suppress the SASP (senomorphics) or selectively kill senescence cells (senolytics) in cancer therapy are also discussed.

show abstract

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Cited by 163 publications

References 50 publications

Mimicking tumor cell heterogeneity of colorectal cancer in a patient-derived organoid-fibroblast model

Mimicking tumor cell heterogeneity of colorectal cancer in a patient-derived organoid-fibroblast model

Transcriptomic Analyses of Pretreatment Tumor Biopsy Samples, Response to Neoadjuvant Chemoradiotherapy, and Survival in Patients With Advanced Rectal Cancer

Cellular senescence and the tumour microenvironment

Contact Info

Product

Resources

About