Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target

New, Jacob; Arnold, Levi; Ananth, Megha; Alvi, Sameer; Thornton, Mackenzie; Werner, Lauryn R.; Tawfik, Ossama; Dai, Hongying; Shnayder, Yelizaveta; Kakarala, Kiran; Tsue, Terance T.; Girod, Douglas A.; Ding, Wen–Xing; Anant, Shrikant; Thomas, Sufi M.

doi:10.1158/0008-5472.can-17-1077

Cited by 150 publications

(136 citation statements)

References 57 publications

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“…CAFs also have a reprogrammed metabolism with high glycolytic flux, autophagy, and senescence, which are cellular processes that provide a nutrient-rich environment for cancer cells (39). Metabolically reprogrammed CAFs have been identified in the tumor stroma of HNSCC and have been shown to promote malignant progression (9,40,41). Here, we demonstrate that CS metabolically reprograms fibroblasts.…”

Section: Discussionmentioning

confidence: 62%

“…Metabolic compartmentalization with high stromal MCT4 and/or high cancer cell MCT1 and TOMM20, markers of mitochondrial metabolism, occurs in HNSCC (9). Coculture models in vitro and coinjection models in vivo are useful to study the influence of the stroma on carcinoma cells (7,11,41). In breast cancer, a coculture model of fibroblasts and human breast adenocarcinoma cells showed that the lactate released by fibroblasts induces mitochondrial biogenesis in adjacent carcinoma cells (46).…”

Section: Discussionmentioning

confidence: 99%

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Cigarette Smoke Induces Metabolic Reprogramming of the Tumor Stroma in Head and Neck Squamous Cell Carcinoma

Domingo‐Vidal

Whitaker‐Menezes

Martos-Rus

et al. 2019

Molecular Cancer Research

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Head and neck squamous cell carcinoma (HNSCC) is comprised of metabolically linked distinct compartments. Cancer-associated fibroblasts (CAF) and nonproliferative carcinoma cells display a glycolytic metabolism, while proliferative carcinoma cells rely on mitochondrial oxidative metabolism fueled by the catabolites provided by the adjacent CAFs. Metabolic coupling between these reprogrammed compartments contributes to HNSCC aggressiveness. In this study, we examined the effects of cigarette smoke–exposed CAFs on metabolic coupling and tumor aggressiveness of HNSCC. Cigarette smoke (CS) extract was generated by dissolving cigarette smoke in growth media. Fibroblasts were cultured in CS or control media. HNSCC cells were cocultured in vitro and coinjected in vivo with CS or control fibroblasts. We found that CS induced oxidative stress, glycolytic flux and MCT4 expression, and senescence in fibroblasts. MCT4 upregulation was critical for fibroblast viability under CS conditions. The effects of CS on fibroblasts were abrogated by antioxidant treatment. Coculture of carcinoma cells with CS fibroblasts induced metabolic coupling with upregulation of the marker of glycolysis MCT4 in fibroblasts and markers of mitochondrial metabolism MCT1 and TOMM20 in carcinoma cells. CS fibroblasts increased CCL2 expression and macrophage migration. Coculture with CS fibroblasts also increased two features of carcinoma cell aggressiveness: resistance to cell death and enhanced cell migration. Coinjection of carcinoma cells with CS fibroblasts generated larger tumors with reduced apoptosis than control coinjections, and upregulation of MCT4 by CS exposure was a driver of these effects. We demonstrate that a tumor microenvironment exposed to CS is sufficient to modulate metabolism and cancer aggressiveness in HNSCC. Implications: CS shifts cancer stroma toward glycolysis and induces head and neck cancer aggressiveness with a mitochondrial profile linked by catabolite transporters and oxidative stress. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/9/1893/F1.large.jpg.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Induces Metabolic Reprogramming of the Tumor Stroma in Head and Neck Squamous Cell Carcinoma

Domingo‐Vidal

Whitaker‐Menezes

Martos-Rus

et al. 2019

Molecular Cancer Research

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“…The induction of the self‐renewal potential in these cells indicated a definite CAF‐driven CSC enrichment in these cells. Although studies on interactions between autologous niche‐dysplastic cells are few, niche‐dependent CSC enrichment has been reported to increase malignancy, migration and invasion in breast, hepatic, oral, and pancreatic cancer, with multiple pathways being implicated . Further, Notch1 inhibition could only lead to a minimal effect on CAF‐induced proliferation suggesting the involvement of multiple pathways in the dysplastic cell‐niche cross talk and the redundancy of the Notch1 pathway.…”

Section: Discussionmentioning

confidence: 99%

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

Kulsum

Raju²,

Raghavan³

et al. 2019

Molecular Carcinogenesis

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Understanding the cellular interactions during oral carcinogenesis has the potential to identify novel prognostic and therapeutic targets. This study aimed at investigating the cancer stem cell (CSC)‐fibroblast niche interactions using in‐vitro dysplastic cell line models developed from different stages of 4NQO‐induced oral carcinogenic mice model. The spontaneously transformed epithelial cells (DysMSCTR6, 14 and 16) were developed from three time points (mild/moderate/severe), while two fibroblast cell lines (FibroMSCTR12, 16) were developed from moderate and severe dysplastic tissue. The epithelial (Epcam+/Ck+) and the fibroblast cell lines (Vimentin+/α‐SMA+/Ck‐) were authenticated and assessment of cells representing progressive grades of dysplastic severity indicated a significant increase in dysplastic marker profile (P < 0.05). Evaluation of the CSC characteristics showed that an increase in expression of Cd133, Cd44, Aldh1a1, Notch1, and Sox2 was accompanied by an increase in migratory (P > 0.05) and colony formation capacity (P > 0.005). Targeting Notch1 (GSI inhibitor PZ0187; 30 μM), showed a significant reduction in cell proliferation capacity (P < 0.05) and in the dysplastic marker profile. Further, Notch1 inhibition resulted in down regulation of Cd133 and Aldh1a 1 (P < 0.05) and a complete abrogation of colony formation ability (P < 0.0001). The effect of niche interactions evaluated using FibroMSCTR12‐conditioned media studies, revealed an enrichment of ALDH1A1+ cells (P < 0.05), induction of spheroid formation ability (P < 0.0001) and increased proliferation capacity (3.7 fold; P < 0.005). Although PZ0187 reduced cell viability by ∼40%, was unable to abrogate the conditioned‐media induced increase in proliferation capacity completely. This study reports a Notch‐1 dependent enrichment of CSC properties during dysplastic progression and a Notch‐1 independent dysplastic cell‐fibroblast interaction during oral carcinogenesis.

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“…Similarly, stromal cells, including cancerassociated fibroblasts (CAF), have not yet been studied in ASCC, although CAFs have been reported to play a role in cancer progression in other types of squamous cell carcinoma. 9,10 In this study, we provide the first molecular gene expression profile of targets linked to a panel of targeted therapies in ASCC and demonstrate a central role for the targetable IGF2-PI3K axis, involving tumour cell crosstalk with CAFs.…”

Section: Introductionmentioning

confidence: 90%

“…Nevertheless, all of these analyses have identified PI3K/AKT/mTOR as the pathway most commonly altered in ASCC. Similarly, stromal cells, including cancer‐associated fibroblasts (CAF), have not yet been studied in ASCC, although CAFs have been reported to play a role in cancer progression in other types of squamous cell carcinoma …”

Section: Introductionmentioning

confidence: 99%

Interaction between IGF2‐PI3K axis and cancer‐associated‐fibroblasts promotes anal squamous carcinogenesis

Cacheux

Lièvre

Richon

et al. 2019

Intl Journal of Cancer

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Anal squamous cell carcinoma (ASCC) is a rare tumour, but its incidence is increasing. Standard chemoradiotherapy fails to cure 20% of patients and no targeted therapy is currently approved for recurrent ASCC. The PI3K/Akt/mTOR pathway is frequently altered in this poorly characterised carcinoma. IGF2 was identified here as a key factor in ASCC oncogenesis, as IGF2 was shown to play a crucial role in the PI3K pathway with frequent (~60%) and mutually exclusive genomic alterations in IGF2, IGF1R, PTEN and PIK3CA genes. We also demonstrated that IGF2 expression is mainly due to cancer‐associated fibroblasts and that IGF2 secreted by cancer‐associated fibroblasts from ASCC samples promotes proliferation of a human ASCC cell line via IGF2 paracrine signalling. Altogether, these results highlight the key role of the IGF2/PI3K axis, and the major role of cancer‐associated fibroblasts in tumour growth via IGF2 secretion, suggesting a major role of IGF2/IGF1R inhibitors in ASCC therapies.

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Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target

Cited by 150 publications

References 57 publications

Cigarette Smoke Induces Metabolic Reprogramming of the Tumor Stroma in Head and Neck Squamous Cell Carcinoma

Cigarette Smoke Induces Metabolic Reprogramming of the Tumor Stroma in Head and Neck Squamous Cell Carcinoma

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

Interaction between IGF2‐PI3K axis and cancer‐associated‐fibroblasts promotes anal squamous carcinogenesis

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