Candida albicans drives colorectal cancer progression by inducing hypoxia signaling
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Curated by eLife
eLife Assessment
This study examines the role of the fungal pathogen Candida albicans in the progression of colorectal cancer, a relevant and urgent topic given the global incidence of colon cancer. While the findings are useful and provide solid experimental work and insight into how Candida may contribute to tumor progression, the small patient sample size, reliance on in vitro models, and absence of in vivo validation may limit its impact. This work will interest scientists studying cancer progression and the role played by pathogens.
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Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related mortality worldwide. Gut microbiota, including fungal species, are increasingly implicated in CRC progression, while the molecular mechanisms underlying host-fungal interactions in this context remain poorly understood. Here, we show that Candida albicans (C. albicans) activates pro-metastatic signaling pathways, MAPK and NF-κB, leading to upregulation of oncogenic transcription factors c-Jun and c-Myc. This cascade stabilizes and activates hypoxia-inducible factor 1α (HIF-1α), a central regulator of tumor metabolic reprogramming and angiogenesis, ultimately fostering a pro-tumorigenic microenvironment. Mechanistically, we identify candidalysin, a secreted peptide toxin of C. albicans, as a critical effector that engages epidermal growth factor receptor (EGFR) and toll-like receptor 2 (TLR2) in a species- and cancer cell type-dependent manner. These findings are further supported by patient-derived colonic organoids. Collectively, our study delineates a C. albicans-EGFR/TLR2-ERK/NF-κB-HIF-1α axis that promotes hypoxia-like responses in CRC, revealing a previously underappreciated role of fungal pathogens in shaping the tumor microenvironment and offering potential targets for therapeutic interventions.
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eLife Assessment
This study examines the role of the fungal pathogen Candida albicans in the progression of colorectal cancer, a relevant and urgent topic given the global incidence of colon cancer. While the findings are useful and provide solid experimental work and insight into how Candida may contribute to tumor progression, the small patient sample size, reliance on in vitro models, and absence of in vivo validation may limit its impact. This work will interest scientists studying cancer progression and the role played by pathogens.
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Reviewer #1 (Public review):
Summary:
This study addresses the emerging role of fungal pathogens in colorectal cancer and provides mechanistic insights into how Candida albicans may influence tumor-promoting pathways. While the work is potentially impactful and the experiments are carefully executed, the strength of evidence is limited by reliance on in vitro models, small patient sample size, and the absence of in vivo validation, which reduces the translational significance of the findings.
Strengths:
(1) Comprehensive mechanistic dissection of intracellular signaling pathways.
(2) Broad use of pharmacological inhibitors and cell line models.
(3) Inclusion of patient-derived organoids, which increases relevance to human disease.
(4) Focus on an emerging and underexplored aspect of the tumor microenvironment, namely fungal pathogens.
We…
Reviewer #1 (Public review):
Summary:
This study addresses the emerging role of fungal pathogens in colorectal cancer and provides mechanistic insights into how Candida albicans may influence tumor-promoting pathways. While the work is potentially impactful and the experiments are carefully executed, the strength of evidence is limited by reliance on in vitro models, small patient sample size, and the absence of in vivo validation, which reduces the translational significance of the findings.
Strengths:
(1) Comprehensive mechanistic dissection of intracellular signaling pathways.
(2) Broad use of pharmacological inhibitors and cell line models.
(3) Inclusion of patient-derived organoids, which increases relevance to human disease.
(4) Focus on an emerging and underexplored aspect of the tumor microenvironment, namely fungal pathogens.
Weaknesses:
(1) Clinical association data are inconsistent and based on very small sample numbers.
(2) No in vivo validation, which limits the translational significance.
(3) Species- and cell type-specificity claims are not well supported by the presented controls.
(4) Reliance on colorectal cancer cell lines alone makes it difficult to judge whether findings are specific or general epithelial responses.
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Reviewer #2 (Public review):
The authors in this manuscript studied the role of Candida albicans in Colorectal cancer progression. The authors have undertaken a thorough investigation and used several methods to investigate the role of Candida albicans in Colorectal cancer progression. The topic is highly relevant, given the increasing burden of colon cancer globally and the urgent need for innovative treatment options.
However, there are some inconsistencies in the figures and some missing details in the figures, including:
(1) The authors should clearly explain in the results section which patient samples are shown in Figure 1B.
(2) What do a, ab, b, b written above the bars in Figure 1F represent? Maybe authors should consider removing them, because they create confusion. Also, there is no explanation for those letters in the figure …
Reviewer #2 (Public review):
The authors in this manuscript studied the role of Candida albicans in Colorectal cancer progression. The authors have undertaken a thorough investigation and used several methods to investigate the role of Candida albicans in Colorectal cancer progression. The topic is highly relevant, given the increasing burden of colon cancer globally and the urgent need for innovative treatment options.
However, there are some inconsistencies in the figures and some missing details in the figures, including:
(1) The authors should clearly explain in the results section which patient samples are shown in Figure 1B.
(2) What do a, ab, b, b written above the bars in Figure 1F represent? Maybe authors should consider removing them, because they create confusion. Also, there is no explanation for those letters in the figure legend.
(3) The authors should submit all the raw images of Western blot with appropriate labels to indicate the bands of protein of interest along with molecular weight markers.
(4) The authors should do the quantification of data in Figure 2d and include it in the figure.
(5) In Figure 2h, the authors should indicate if the quantification represents VEGF expression after 6h or 12h of C. albicans co-culture with cells.
(6) In Figure 2i, quantification of VEGF should be done and data from three independent experiments should be submitted. The authors should also mention the time point.
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