Cancer-Associated Fibroblasts Drive Glycolysis in a Targetable Signaling Loop Implicated in Head and Neck Squamous Cell Carcinoma Progression

Kumar, Dhruv; New, Jacob; Vishwakarma, Vikalp; Joshi, Radhika; Enders, Jonathan; Lin, Fangchen; Dasari, Sumana; Gutierrez, Wade R.; Leef, George; Ponnurangam, Sivapriya; Chavan, Hemantkumar; Ganaden, Lydia; Thornton, Mackenzie; Dai, Hongying; Tawfik, Ossama; Straub, Jeffrey; Shnayder, Yelizaveta; Kakarala, Kiran; Tsue, Terance T.; Girod, Douglas A.; Houten, Bennett Van; Anant, Shrikant; Krishnamurthy, Partha; Thomas, Sufi M.

doi:10.1158/0008-5472.can-17-1076

Cited by 109 publications

(102 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our findings confirm the results of a study from Kumar and colleagues [29]. They recently reported on HGF-related upregulation of glycolysis in HNSCC cells and further investigated the role of HGF/Met signaling in an in vivo model.…”

Section: Discussionsupporting

confidence: 92%

The Influence of Met Receptor Level on HGF-Induced Glycolytic Reprogramming in Head and Neck Squamous Cell Carcinoma

Boschert

Klenk

Abt

et al. 2020

IJMS

View full text Add to dashboard Cite

Head and neck squamous cell carcinoma (HNSCC) is known to overexpress a variety of receptor tyrosine kinases, such as the HGF receptor Met. Like other malignancies, HNSCC involves a mutual interaction between the tumor cells and surrounding tissues and cells. We hypothesized that activation of HGF/Met signaling in HNSCC influences glucose metabolism and therefore substantially changes the tumor microenvironment. To determine the effect of HGF, we submitted three established HNSCC cell lines to mRNA sequencing. Dynamic changes in glucose metabolism were measured in real time by an extracellular flux analyzer. As expected, the cell lines exhibited different levels of Met and responded differently to HGF stimulation. As confirmed by mRNA sequencing, the level of Met expression was associated with the number of upregulated HGF-dependent genes. Overall, Met stimulation by HGF leads to increased glycolysis, presumably mediated by higher expression of three key enzymes of glycolysis. These effects appear to be stronger in Methigh-expressing HNSCC cells. Collectively, our data support the hypothesized role of HGF/Met signaling in metabolic reprogramming of HNSCC.

show abstract

Section: Discussionsupporting

confidence: 92%

The Influence of Met Receptor Level on HGF-Induced Glycolytic Reprogramming in Head and Neck Squamous Cell Carcinoma

Boschert

Klenk

Abt

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown the influence of CAFs on the development of SCCHN, associating the expression of α-SMA with aggressive anaplastic tumours, advanced clinical stages, regional lymph node involvement, and recurrence of the disease (20,23). Moreover, CAFs has been outlined as a possible prognostic factor, considering that the inhibition of its activity has been shown to limit the progression of SCC in vitro and in vivo (24,25). Additionally, in our sample we observed a significant association between the expression of α-SMA and the primary tumour site, where cases of laryngeal SCC showed a greater presence of CAFs compared with oral SCC and nasosinusal SCC.…”

Section: Resultsmentioning

confidence: 99%

Immunohistochemical analysis of cancer-associated fibroblasts and podoplanin in head and neck cancer

Ramos-Vega

Rojas²,

Torres³

2020

Med Oral

View full text Add to dashboard Cite

Background: To immunohistochemically evaluate the association between the presence of cancer-associated fibroblasts (CAFs) and the tumour expression of podoplanin (PDPN) in head and neck squamous cell carcinoma (HNSCC) and their association with clinicopathological variables. Material and Methods: A tissue microarray (TMA) with biopsy sections from patients diagnosed with HNSCC was stained with antibodies against the CAFs marker, α-smooth muscle actin (α-SMA), and PDPN. We subsequently evaluated their expression to determine the association between them and with clinicopathological variables including age, primary tumour site, TNM stage, and tumour differentiation grade. Results: Positive reaction to α-SMA was observed in the tumour stroma, revealing spindle-shaped cells compatible with CAFs, which showed a high expression in 62% of cases and a significant association with laryngeal carcinomas, advanced clinical stages, and lower tumour differentiation (P ≤ 0.05). PDPN staining on tumour cells showed low expression in 72% of cases, and it was not associated with any clinicopathological variable or with the presence of CAFs. Conclusions: The presence of CAFs in the tumour stroma is related to an aggressive phenotype and could increase as the disease progresses, although based on our findings, it would have no relationship, at least directly, with the expression of PDPN.

show abstract

“…Interestingly, bFGF induces OXPHOS in CAFs, leading to HGF production, thus closing the vicious circle. 58 In a clinical study, breast cancer patients with stage 0/1 tumors were treated with N-acetylcysteine (NAC) to reduce oxidative stress in stromal cells and decrease tumor growth. Interestingly, post-treatment biopsies showed that stromal (but not tumor) cells decreased expression of the lactate exporter MCT4 as a result of NAC treatment, while the proliferative index of tumor cells was reduced.…”

Section: Warburg Effec T In Tumor S Tromal Cell Smentioning

confidence: 99%

The immunological Warburg effect: Can a metabolic‐tumor‐stroma score (MeTS) guide cancer immunotherapy?

Siska

Singer

Evert

et al. 2020

Immunological Reviews

View full text Add to dashboard Cite

The "glycolytic switch" also known as the "Warburg effect" is a key feature of tumor cells and leads to the accumulation of lactate and protons in the tumor environment.Intriguingly, non-malignant lymphocytes or stromal cells such as tumor-associated macrophages and cancer-associated fibroblasts contribute to the lactate accumulation in the tumor environment, a phenomenon described as the "Reverse Warburg effect." Localized lactic acidosis has a strong immunosuppressive effect and mediates an immune escape of tumors. However, some tumors do not display the Warburg phenotype and either rely on respiration or appear as a mosaic of cells with different metabolic properties. Based on these findings and on the knowledge that T cell infiltration is predictive for patient outcome, we suggest a metabolic-tumor-stroma score to determine the likelihood of a successful anti-tumor immune response: (a) a respiring tumor with high T cell infiltration ("hot"); (b) a reverse Warburg type with respiring tumor cells but glycolytic stromal cells; (c) a mixed type with glycolytic and respiring compartments; and (d) a glycolytic (Warburg) tumor with low T cell infiltration ("cold"). Here, we provide evidence that these types can be independent of the organ of origin, prognostically relevant and might help select the appropriate immunotherapy approach. K E Y W O R D Sacidification, GLUT, immunotherapies, lactate, T cell, Warburg

show abstract

Cancer-Associated Fibroblasts Drive Glycolysis in a Targetable Signaling Loop Implicated in Head and Neck Squamous Cell Carcinoma Progression

Cited by 109 publications

References 51 publications

The Influence of Met Receptor Level on HGF-Induced Glycolytic Reprogramming in Head and Neck Squamous Cell Carcinoma

The Influence of Met Receptor Level on HGF-Induced Glycolytic Reprogramming in Head and Neck Squamous Cell Carcinoma

Immunohistochemical analysis of cancer-associated fibroblasts and podoplanin in head and neck cancer

The immunological Warburg effect: Can a metabolic‐tumor‐stroma score (MeTS) guide cancer immunotherapy?

Contact Info

Product

Resources

About