Subjugation of TGFβ Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End-Joining

Liu, Qi; Ma, Lin; Jones, Trevor; Palomero, Luís; Pujana, Miquel Àngel; Martinez-Ruiz, Haydeliz; Ha, Patrick K.; Murnane, John P.; Cuartas, Isabel; Seoane, Joan; Baumann, Michaël; Linge, Annett; Barcellos‐Hoff, Mary Helen

doi:10.1101/353441

Cited by 13 publications

(32 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies reported that low HRR capacity of the HPV‐positive HNSCC could explain the sensitivity to PARP inhibition alone or in combination with RT . Others have hypothesized that the reliance of HPV‐positive HNSCC on alternative EJ could provide a mechanistic explanation for the sensitivity to PARP inhibitors . In addition, dependency of PARP inhibition alone or in combination with RT is also reported to be independent of HPV‐status, but related to defects in HRR, impaired or DSB repair or increased ROS production …”

Section: Discussionmentioning

confidence: 99%

“…29,30 Others have hypothesized that the reliance of HPV-positive HNSCC on alternative EJ could provide a mechanistic explanation for the sensitivity to PARP inhibitors. 15 In addition, dependency of PARP inhibition alone or in combination with RT is also reported to be independent of HPV-status, 31 but related to defects in HRR, 32 impaired or DSB repair 33 or increased ROS production. 34 Here, we show that the enhanced sensitivity to PARP inhibition could be linked to higher activity of the BER pathway in HPV-positive HNSCCs.…”

Section: Discussionmentioning

confidence: 99%

“…8 Several studies showed that HPV-positive HNSCC are characterized by decreased double-strand break (DSB) repair capacity [9][10][11][12] probably because of malfunctions in nonhomologous end-joining (NHEJ) and homologous recombination repair (HRR) pathways. 8,[13][14][15] These observations strongly suggest that different approaches should be employed for radiosensitization of different groups of HNSCC patients.…”

Section: Introductionmentioning

confidence: 99%

“…Although no profound investigations on differences in DNA repair pathways between both groups of HNSCC was performed, several preclinical studies—ours included—ascribed increased RT response in HPV‐positive cancers due to defects in DDR pathways . Several studies showed that HPV‐positive HNSCC are characterized by decreased double‐strand break (DSB) repair capacity probably because of malfunctions in nonhomologous end‐joining (NHEJ) and homologous recombination repair (HRR) pathways . These observations strongly suggest that different approaches should be employed for radiosensitization of different groups of HNSCC patients.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Radiosensitization approaches for HPV‐positive and HPV‐negative head and neck squamous carcinomas

Dok

Bamps

Glorieux

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

Radiotherapy is one of the most used treatment approaches for head and neck squamous cell carcinoma (HNSCC). Targeted inhibition of DNA repair machinery has the potential to improve treatment response by tailoring treatment to cancer cells lacking specific DNA repair pathways. Human papillomavirus (HPV)‐negative and HPV‐positive HNSCCs respond differently to radiotherapy treatment, suggesting that different approaches of DNA repair inhibition should be employed for these HNSCC groups. Here, we searched for optimal radiosensitization approaches for HPV‐positive and HPV‐negative HNSCCs by performing a targeted CRISPR‐Cas9 screen. We found that inhibition of base excision repair resulted in a better radiotherapy response in HPV‐positive HNSCC, which is correlated with upregulation of genes involved in base excision repair. In contrast, inhibition of nonhomologous end‐joining and mismatch repair showed strong effects in both HNSCC groups. We validated the screen results by combining radiotherapy with targeted inhibition of DNA repair in several preclinical models including primary and recurrent patient‐derived HNSCC xenografts. These findings underline the importance of stratifying HNSCC patients for combination treatments.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Radiosensitization approaches for HPV‐positive and HPV‐negative head and neck squamous carcinomas

Dok

Bamps

Glorieux

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…HPV is an important risk factor for HNSCC, and is associated with tumor biology and clinical characteristics including response to radiation (3,6,20). Recently, the involvement of HPV in the radiosensitivity of cancers has been established through altered tumor immune microenvironment.…”

Section: Figurementioning

confidence: 99%

HPV-positive head and neck cancer derived exosomal miR-9 induces M1 macrophage polarization and increases tumor radiosensitivity

Tong

Xie

et al. 2019

Preprint

View full text Add to dashboard Cite

Human papillomavirus (HPV) is an etiological risk factor for a subset of head and neck squamous cell carcinoma (HNSCC). HPV+ HNSCC is significant more radiosensitive than HPV-HNSCC, but the underlying mechanism is still unknown. Tumor microenvironment can affect tumor response to radiation therapy. Cancer secreted exosomes are emerging as crosstalk mediators between tumor cells and the tumor microenvironment. The main objectives of this study were to determine the role of HPV+ HNSCC-derived exosomes in increased radiation sensitivity. Here, we found that exosomes derived from HPV+ HNSCC cells activate macrophages into the M1 phenotype, which then increases the radiosensitivity of HNSCC cells. miR-9 was enriched in exosomes released from HPV+ HNSCC cells and it could be transported to macrophages, leading to altered cellular functions. Overexpression of miR-9 in macrophages induced polarization into the M1 phenotype via downregulation of PPARδ. Increased radiosensitivity was observed for HNSCC cells co-cultured with macrophages in which miR-9 was upregulated or treated with M1 macrophages. These observations suggest that HPV+ HNSCC cells secrete miR-9-rich exosomes, which then polarize macrophages into M1 phenotype and lead to increased radiosensitivity of HNSCC cells. Hence, miR-9 may be a potential treatment strategy for HNSCC. Statement of significanceHPV+ HNSCC through the release of miR-9-rich exosomes polarize macrophages into M1 phenotype and lead to increased radiosensitivity of HNSCC.

show abstract

Doc, I feel tired… oh really, so how‘s your mucositis?

Kober

Yom

2021

Cancer

View full text Add to dashboard Cite

For the past 40 years, 1 cancer-related fatigue (CRF) has been the subject of intense but sequestered investigation. CRF is commonly defined as a subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or its treatment that is distressing, persistent, not proportional to recent activity, and which interferes with the patient's usual functioning. 2 Excess CRF is known to occur in virtually all patients with head and neck cancer (HNC) who receive chemoradiation, 3 and one-half of these patients have sustained elevations in fatigue as long as 2 years later. 4 CRF has significant affects in terms of lost productivity, lost days from work, and decreased quality of life. 5 In addition, CRF may be associated with decreased survival. 6 However, despite its high prevalence rate and negative effects on patients and society, 5 limited progress has been made in clinical assessment and treatment.In the day-to-day whirlwind of clinical oncology practice, the assessment of CRF is usually not perceived as a priority, particularly among patients with HNC. Patients' frequent reporting of this symptom is simply lost in the busy shuffle of handling their many other severe and complex medical problems. The reasons for this lack of attention are multifactorial. They may include a de-prioritization of what is perceived as a primarily subjective concern, a generally poor medical and clinical understanding of CRF in the oncology community, a lack of training in standardized assessment or treatment options for CRF, or a perception that CRF has little meaningful bearing on patients' oncologic outcomes. In addition, a comprehensive treatment plan for CRF may require multidimensional assessment and multiple routes of intervention, with no rapidly delivered magic bullet. For these reasons, CRF has been called the forgotten symptom in oncology. 7 It is fair to say that the underlying mechanisms for CRF remain under investigation. 8 The most commonly cited of these include interacting alterations in: immune function or inflammation, energy metabolism, neurotransmission, anemia, and circadian rhythm. Variations in genotype, gene expression levels, and methylation patterns related to inflammatory mechanisms are associated with CRF severity in patients treated with chemotherapy and radiation. 5 However, the lack of a clinically applicable risk prediction model is a barrier hindering any impetus to develop more effective management. 9 A widely accepted and accurate risk prediction model could assist clinicians in identifying high-risk patients who could be targeted for interventions to prevent or reduce CRF.The study by Xiao and colleagues in this issue of Cancer 10 provides a clinically accessible demonstration of the importance of assessing and treating CRF in the context of treating HNC. This research maps out the relative contributions of chemotherapy and/or radiation to CRF and CRF's associations with elevated measures of epigenetic aging and chronic inflammation in this specific population of patien...

show abstract

Subjugation of TGFβ Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End-Joining

Cited by 13 publications

References 57 publications

Radiosensitization approaches for HPV‐positive and HPV‐negative head and neck squamous carcinomas

Radiosensitization approaches for HPV‐positive and HPV‐negative head and neck squamous carcinomas

HPV-positive head and neck cancer derived exosomal miR-9 induces M1 macrophage polarization and increases tumor radiosensitivity

Doc, I feel tired… oh really, so how‘s your mucositis?

Contact Info

Product

Resources

About