Abstract B13: High-content imaging to quantitate colorectal cancer associated fibroblast heterogeneity

Cancer-associated fibroblasts (CAFs) are important, highly heterogeneous components of the tumor extracellular matrix that have different origins and express a diverse set of biomarkers. Different subtypes of CAFs participate in the immune regulation of the tumor microenvironment (TME). In addition to their role in supporting stromal cells, CAFs have multiple immunosuppressive functions, via membrane and secretory patterns, against anti-tumor immunity. The inhibition of CAFs function and anti-TME therapy targeting CAFs provides new adjuvant means for immunotherapy. In this review, we outline the emerging understanding of CAFs with a particular emphasis on their origin and heterogeneity, different mechanisms of their regulation, as well as their direct or indirect effect on immune cells that leads to immunosuppression.

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Hypoxia Facilitates the Proliferation of Colorectal Cancer Cells by Inducing Cancer-associated Fibroblast-derived IL6.

10.21203/rs.3.rs-259724/v1 ◽

2021 ◽

Author(s):

Ying Xu ◽

Rong Kuai ◽

Yimin Chu ◽

Lu Zhou ◽

Hai-qin Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Tumor Development ◽

Cancer Associated Fibroblast ◽

Stat3 Signaling ◽

Colorectal Cancer Cells ◽

Cancer Tissues ◽

Development Methods ◽

Multiplex Cytokine ◽

Common Malignancy

Abstract Background: Colorectal cancer (CRC) is most common malignancy worldwide, and its underlying molecular mechanisms remain largely unexplored. Accumulating evidences indicate Cancer-Associated Fibroblasts (CAFs), abundant stromal cell population in the tumor microenvironment, play a key role in tumor development. Methods: We have successfully isolated CAFs and paired normal fibroblasts (NFs) from colorectal cancer tissues (n=10). By using multiplex cytokine profiling assay, we have identified IL-6 as a major cytokine released by CAFs. Coculturing of CAFs with CRC cell lines HCT116 or SW480 increase IL-6 release, and the secretion by CAFs can be further enhanced under hypoxia. By using CCK-8 assay, we have found HCT116 or SW480 cells treated with culture medium from CAFs, IL-6 or hypoxia showed a significant cell growth compared to control cells (P<0.01). Results: Mechanistically, we have found hypoxia can enhanced effect of IL-6/STAT3 signaling on CRC cells, in part, throughHIF-1a targets PKM2. Conclusions: In conclusion, our data clearly proposes the interconnected mechanisms for a constitutive activation of STAT3 signalby CAFs-derived IL-6 under hypoxia in colorectal cancer. The pharmacological inhibition of STAT3, PKM2 or HIF-1α can significantly reduce oncogenic effect of IL-6, providing a potential therapeutic target for CRC patients.Trail registration: Not applicable

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Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer

Nature Communications ◽

10.1038/s41467-021-24687-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Wenyu Wang ◽

Yen-An Tang ◽

Qian Xiao ◽

Wee Chyan Lee ◽

Bing Cheng ◽

...

Keyword(s):

Colorectal Cancer ◽

Chromatin Remodeling ◽

Cancer Drug ◽

Bet Inhibitor ◽

Cancer Associated Fibroblast ◽

Bet Inhibitors ◽

Inhibitor Resistance ◽

Bet Protein

AbstractBRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively.

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PO-304 Three-dimensional co-culture of colorectal cancer spheroid with cancer-associated fibroblast as a model to study immune cell modulation

10.1136/esmoopen-2018-eacr25.817 ◽

2018 ◽

Author(s):

S Susanti ◽

TP Raposo ◽

A Arsalan ◽

A Tchoryk ◽

L Martinez-Pomares ◽

...

Keyword(s):

Colorectal Cancer ◽

Immune Cell ◽

Three Dimensional ◽

Cancer Associated Fibroblast

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Oxidative stress induced autophagy in cancer associated fibroblast enhances proliferation and metabolism of colorectal cancer cells

Cell Cycle ◽

10.1080/15384101.2016.1252882 ◽

2016 ◽

Vol 16 (1) ◽

pp. 73-81 ◽

Cited By ~ 22

Author(s):

Wenjing Zhou ◽

Gang Xu ◽

Yunqiu Wang ◽

Ziao Xu ◽

Xiaofei Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Cancer Cells ◽

Cancer Associated Fibroblast ◽

Colorectal Cancer Cells

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Hypoxia facilitates the proliferation of colorectal cancer cells by inducing cancer-associated fibroblast-derived IL6

Neoplasma ◽

10.4149/neo_2021_210308n296 ◽

2021 ◽

Author(s):

Ying Xu ◽

Rong Kuai ◽

Yi-Min Chu ◽

Lu Zhou ◽

Hai-Qin Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Cancer Associated Fibroblast ◽

Colorectal Cancer Cells

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Genome-wide analysis indicating cancer associated fibroblast (CAF) impacts on colorectal cancer (CRC) prognosis via immunosuppression.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3543 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3543-3543

Author(s):

Yu-feng Chen ◽

Xiaojian Wu ◽

Feng Gao

Keyword(s):

Colorectal Cancer ◽

Immune Response ◽

Adjuvant Chemotherapy ◽

Tumor Microenvironment ◽

Prognostic Value ◽

Enrichment Analysis ◽

Gene Signature ◽

Stage Ii ◽

Training Cohort ◽

Cancer Associated Fibroblast

3543 Background: Cancer associated fibroblast (CAF) in tumor microenvironment is associated with poor prognosis and chemo-resistance in multiple solid tumors, however, there is lack of universal measure of CAF in colorectal cancer (CRC). The aim of this study was to assess fibroblast-signature for predicting outcome and analyze relevant mechanism. Methods: A dataset including 316 CRC patients without adjuvant chemotherapy was used as the discovery cohort for the identification of prognostic fibroblast-related genes (FRGs). A total of 1,352 CRC patients were then divided into one training cohort (n = 461) and two validation cohorts (n = 338, n = 553, respectively) for the construction of fibroblast-related gene signature (FRGS) and the verification of its prognostic value in stage II/III CRC patients. Functional annotation and analysis were performed to reveal the relevant mechanism. Results: A 11-gene signature was derived, which was prognostic for stage II/III CRC patients in two validation cohort (Validation-1 cohort: HR = 1.90, 95%CI = 1.16-3.12, P< 0.01; Validation-2 cohort: HR = 1.95, 95%CI = 1.39-2.73, P< 0.001). High CAF risk was correlated with worse prognosis in CRC patients without adjuvant chemotherapy (HR = 3.63, 95%CI = 2.24-5.88, P< 0.001), but not in patients who received adjuvant chemotherapy ( P= 0.154). Similar trends were found in Validation-1 cohort. After integrated with clinical characteristics, FRGS was confirmed as an independent prognostic factor after adjusted for TNM stage of tumor in multivariate analysis (Training cohort: HR = 3.19, 95%CI = 1.88-5.41, P< 0.001; Validation-1 cohort: HR = 5.00, 95%CI = 1.58-15.85, P= 0.007; Validation-2 cohort: HR = 2.99, 95%CI = 1.44-6.21, P= 0.003). Furthermore, enrichment analysis found that anti-tumor immune response was suppressed in the high CAF risk group. Conclusions: The 11-gene FRGS had independent prognostic value for CRC patients, as well as in prediction of benefit from chemotherapy. CAF in tumor microenvironment might impact on the prognosis of CRC patients via inhibiting immune response.

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