Immunotherapy and Systemic Treatment of Cutaneous Squamous Cell Carcinoma

Aboul-Fettouh, Nader; Morse, Daniel C; Patel, Jigar; Migden, Michael R.

doi:10.5826/dpc.11s2a169s

Cited by 15 publications

(21 citation statements)

References 81 publications

(67 reference statements)

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“…The activating effects of EGF and VEGF-A on downstream genes including PLAU/R highlights the potential for anti-EGFR- and/or anti-VEGF- with anti-uPA/uPAR-targeting approaches for metastatic cSCC. EGFR inhibition as monotherapy for metastatic cSCC has had moderate success ( 5 ), even though EGFR is often overexpressed in cSCC, with one study showing an association with EGFR levels and lymph node progression and tumor cell proliferation ( 83 ). In our study, EGFR mRNA counts were generally equally high across all tumor cohorts and SES suggesting no relationship with tumor status (data not shown) but rather that the presence of high levels of active EGF (and VEGF-A) in the pericellular space of metastatic tumors may be responsible for enhanced stimulation of EGFR-mediated signaling pathways ( Figure 7 ).…”

Section: Discussionmentioning

confidence: 99%

“…In our study, EGFR mRNA counts were generally equally high across all tumor cohorts and SES suggesting no relationship with tumor status (data not shown) but rather that the presence of high levels of active EGF (and VEGF-A) in the pericellular space of metastatic tumors may be responsible for enhanced stimulation of EGFR-mediated signaling pathways ( Figure 7 ). This would contribute to EGFR drug resistance mechanisms through stimulation of compensatory signaling pathways ( 5 ) in metastatic cSCC and drive overexpression of downstream targets, including PLAU/R and MMP genes, promoting functions linked to cell invasion such as cell motility. The latter was functionally validated in our EGFR-expressing cell line models.…”

Section: Discussionmentioning

confidence: 99%

“…Metastasis to regional lymph nodes in the head neck occurs in <5% of cases but imparts significant morbidity and mortality ( 4 ). Notwithstanding conventional systemic treatment options such as chemotherapy and, more recently, epidermal growth factor receptor inhibitors or immunotherapy, for a substantial proportion of advanced cSCC patients there are still no valid second-line therapies ( 5 ), indicating a need for alternate targeted therapy options and strategies.…”

Section: Introductionmentioning

confidence: 99%

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Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma

et al. 2022

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Cutaneous squamous cell carcinoma (cSCC) of the head and neck region is the second most prevalent skin cancer, with metastases to regional lymph nodes occurring in 2%–5% of cases. To further our understanding of the molecular events characterizing cSCC invasion and metastasis, we conducted targeted cancer progression gene expression and pathway analysis in non-metastasizing (PRI-) and metastasizing primary (PRI+) cSCC tumors of the head and neck region, cognate lymph node metastases (MET), and matched sun-exposed skin (SES). The highest differentially expressed genes in metastatic (MET and PRI+) versus non-metastatic tumors (PRI-) and SES included PLAU, PLAUR, MMP1, MMP10, MMP13, ITGA5, VEGFA, and various inflammatory cytokine genes. Pathway enrichment analyses implicated these genes in cellular pathways and functions promoting matrix remodeling, cell survival and migration, and epithelial to mesenchymal transition, which were all significantly activated in metastatic compared to non-metastatic tumors (PRI-) and SES. We validated the overexpression of urokinase plasminogen activator receptor (uPAR, encoded by PLAUR) in an extended patient cohort by demonstrating higher uPAR staining intensity in metastasizing tumors. As pathway analyses identified epidermal growth factor (EGF) as a potential upstream regulator of PLAUR, the effect of EGF on uPAR expression levels and cell motility was functionally validated in human metastatic cSCC cells. In conclusion, we propose that uPAR is an important driver of metastasis in cSCC and represents a potential therapeutic target in this disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma

et al. 2022

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“…Most patients with regional metastases from CSCC of the head and neck are managed with a multimodality approach, which usually involves surgery (parotidectomy and neck dissection) and adjuvant external beam radiotherapy depending on the site and stage at the time of diagnosis ( 7 – 9 ). More recently immunotherapy has attracted great interest as a potential alternative for unresectable or distant metastatic disease ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma

et al. 2022

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Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3′ untranslated region (3′UTR) regions of EVC (48% of specimens), PPP1R1A (48% of specimens), and ABCA4 (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene PTPRD was observed. Gene amplification was much less frequent, and few genes were recurrently amplified. Single nucleotide variants driver analyses from three tools confirmed TP53 and CDKN2A as recurrently mutated genes but also identified C9 as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of “TGF-beta regulation of extracellular matrix” and “cell cycle G1 to S check points.” These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC.

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“…Most patients with regional metastases from cSCC of the head and neck are managed with a multimodality approach, which usually involves surgery (parotidectomy and neck dissection) and adjuvant external beam radiotherapy depending on the site and stage at the time of diagnosis [7][8][9]. More recently immunotherapy has attracted great interest as a potential alternative for unresectable or distant metastatic disease [10,11].…”

Section: Introductionmentioning

confidence: 99%

Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma

Thind

Ashford

Strbenac

et al. 2022

Preprint

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Metastatic cutaneous squamous cell carcinoma (cSCC) is associated with a high risk of recurrence and poor prognosis. There is limited published data exploring whole genome sequencing (WGS). The aim of this project was to provide the first comprehensive genomic understanding of the state of metastatic cSCC. In this study, we used WGS on matched tumor and blood DNA to detect somatic genetic alterations from 25 patients with regional metastases of head and neck cSCC. Our computational analyses interrogate clinical impacts of these genetic alterations on metastatic cSCC across the cohort for both the coding and non-coding genome. In the non-coding genome, 3UTR regions of EVC (48%), PPP1R1A (48%) and LUM (16%) were significantly functionally altered (Q-value < 0.05). Further, significant functional alterations are observed in the tumor suppressing lncRNA LINC01003 ( 68% of specimens, Q-value: 0.0158). In addition, significant recurrent copy number loss in tumor suppressor genes KANSL1 and PTPRD and gain in CALR, CCND1 and FGF3 was observed for coding regions. SNVs driver analyses predicted TP53, CDKN2A, as potential drivers of the metastasis cSCC (using 3 different tools). Indel signature analysis highlight dominance of ID signature 13 followed by ID8 & ID9. Interestingly, ID 9 has previously been shown to have no association with skin melanoma, unlike ID 13 and 8, suggesting some point of difference between these two skin-based diseases. The overall landscape of variation in metastatic cSCC is dominated by cell cycle and DNA repair disruption.

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Immunotherapy and Systemic Treatment of Cutaneous Squamous Cell Carcinoma

Cited by 15 publications

References 81 publications

Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma

Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma

Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma

Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma

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