YAP1 activation by human papillomavirus E7 promotes basal cell identity in squamous epithelia.

Persistent human papillomavirus (HPV) infection of stratified squamous epithelial cells causes nearly 5% of cancer cases worldwide. HPV-positive oropharyngeal cancers harbor few mutations in the Hippo signaling pathway compared to HPV-negative cancers at the same anatomical site, prompting the hypothesis that an HPV-encoded protein inactivates the Hippo pathway and activates the Hippo effector yes-associated protein (YAP1). The HPV E7 oncoprotein is required for HPV infection and for HPV-mediated oncogenic transformation. We investigated the effects of HPV oncoproteins on YAP1 and found that E7 activates YAP1, promoting YAP1 nuclear localization in basal epithelial cells. YAP1 activation by HPV E7 required that E7 binds and degrades the tumor suppressor protein tyrosine phosphatase non-receptor type 14 (PTPN14). E7 required YAP1 transcriptional activity to extend the lifespan of primary keratinocytes, indicating that YAP1 activation contributes to E7 carcinogenic activity. Maintaining infection in basal cells is critical for HPV persistence, and here we demonstrate that YAP1 activation causes HPV E7 expressing cells to be retained in the basal compartment of stratified epithelia. We propose that YAP1 activation resulting from PTPN14 inactivation is an essential, targetable activity of the HPV E7 oncoprotein relevant to HPV infection and carcinogenesis.

The 'epithelial' cells that cover our bodies are in a constant state of turnover. Every few weeks, the outermost layers die and are replaced by new cells from the layers below. For scientists, this raises a difficult question. Cells infected by human papillomaviruses, often known as HPV, can become cancerous over years or even decades. How do infected cells survive while the healthy cells around them mature and get replaced? One clue could lie in PTPN14, a human protein which many papillomaviruses eliminate using their viral E7 protein; this mechanism could be essential for the virus to replicate and cause cancer. To find out the impact of losing PTPN14, Hatterschide et al. used human epithelial cells to make three-dimensional models of infected tissues. These experiments showed that, when papillomaviruses destroy PTPN14, a human protein called YAP1 turns on in the lowest, most long-lived layer of the tissue. Cells in which YAP1 is activated survive while those that carry the inactive version mature and die. This suggests that papillomaviruses turn on YAP1 to remain in tissues for long periods. Papillomaviruses cause about five percent of all human cancers. Finding ways to stop them from activating YAP1 has the potential to prevent disease. Overall, the research by Hatterschide et al. also sheds light on other epithelial cancers which are not caused by viruses.

Primary Laryngectomy Versus Salvage Laryngectomy: A Comparison of Outcomes in the Chemoradiation Era.

OBJECTIVE: To compare primary total laryngectomy (TL) versus salvage TL and analyze the functional outcomes, complications, recurrence rates, and survival. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care center. SUBJECTS AND METHODS: Fifteen-year retrospective analysis of 208 patients with laryngeal squamous cell carcinoma treated by TL was completed. Outcome measures included survival, swallowing rehabilitation, speech rehabilitation, complications, and assessment of comorbidity. Survival estimates were analyzed with Kaplan-Meier method, and regression analysis utilized the Cox proportional hazards model. RESULTS: Alaryngeal speech was not significantly different between primary TL and salvage TL, 68% versus 82% (P = 0.14). Comparing primary and salvage TL, the perioperative complication rate was 33% versus 48% (P = 0.036). Thirty-six percent of primary TL patients had recurrence compared to 26% of salvage patients. Five-year overall survival rates between primary TL and salvage TL were not significantly different (P = 0.68). Comorbidity was an independent predictor of survival. CONCLUSIONS: Development of a functional voice was not significantly different between salvage and primary TL patients, with a majority achieving alaryngeal speech. Perioperative complications were more prevalent in the salvage TL group. Recurrence and survival are significantly associated with comorbidity status. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:2179-2185, 2020.

Impact of Nuclear Interleukin-1 Alpha and EGFR Expression on Recurrence and Survival Outcomes in Oral Squamous Cell Carcinomas.

Interleukin-1 alpha (IL-1α) is a pleiotropic cytokine involved in inflammation and immune response and is upregulated in many solid tumors including head and neck squamous cell carcinomas. Although IL-1α expression is generally associated with poor prognosis, the implications of the subcellular localization of IL-1α expression in patient outcomes are poorly understood. This study is aimed at investigating the prognostic value of nuclear and cytoplasmic immunohistochemical IL-1α expression in oral squamous cell carcinomas (OSCCs). Tissue microarrays containing 146 OSCCs were analyzed for IL-1α and epidermal growth factor receptor (EGFR) expression by immunohistochemistry. IL-1α and EGFR expression scores were correlated with clinicopathological parameters and survival outcomes. IL-1α expression was observed in the nuclear and/or cytoplasmic compartments in 98% of evaluable tumors and 78% of tumors expressed IL-1α in both compartments. There were no differences observed in overall survival or progression-free survival between high, moderate, or negative IL-1α nuclear/cytoplasmic expression scores. When IL-1α nuclear/cytoplasmic expression scores were stratified by positive or negative EGFR expression, tumors with a combined EGFR-positive and high nuclear IL-1α expression profile were significantly more likely to possess perineural invasion and were significantly associated with a high risk of tumor recurrence and worse progression-free survival compared to all other EGFR and combined IL-1α/EGFR expression profiles. Altogether, nuclear IL-1α expression may enhance the prognostic value of EGFR in OSCC and warrants further study as a prognostic biomarker for recurrence.

Impact of PET/CT on Staging and Treatment of Advanced Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: To understand the effects of positron emission tomography/computed tomography (PET/CT) evaluation on patients with previously untreated head and neck squamous cell carcinoma (HNSCC) with clinical evidence of regional lymph node involvement. STUDY DESIGN: Prospective blinded study. SETTING: Tertiary care cancer center. SUBJECTS AND METHODS: Informed consent was obtained and data collected from 52 consecutive previously untreated patients with HNSCC and clinical evidence of cervical metastasis. All patients underwent conventional evaluation for HNSCC and whole body PET/CT. Data were evaluated by 5 independent reviewers, who performed TNM staging per the American Joint Committee on Cancer (seventh edition) manual and proposed a treatment plan prior to viewing, and after reviewing, PET/CT. Cases where at least 3 of 5 reviewers agreed were considered significant. RESULTS: There were 0 patients for whom review of the PET/CT altered the T-class assessment (95% CI, 0-6.8), 12 (23.1%) for whom PET/CT altered N classification (95% CI, 12.5-34.5), and 2 (3.8%) for whom PET/CT altered the M classification (95% CI, 0.5-13.2). For 5 patients (9.6%), overall stage was altered per PET/CT review (95% CI, 3.2-21). For 3 patients (5.8%), PET/CT findings prompted reviewers to alter treatment recommendations (95% CI, 1.2-15.9). CONCLUSION: When added to more conventional patient evaluation, PET/CT results in changes to the TNM categories, but overall staging and treatment were less frequently affected. Whether PET/CT should be used routinely for patients with stage III and IV HNSCC is still subjective and merits further study.

Population analysis of socioeconomic status and otolaryngologist distribution on head and neck cancer outcomes.

BACKGROUND: The relationship between clinical outcomes and geographic determinants is not well known for head and neck cancer. Socioeconomic status (SES) factors and the distribution of health care resources might impact outcomes. METHODS: Head and neck cancer cases in the Surveillance, Epidemiology, and End Results (SEER) database were studied. Patient-level prognostic factors were identified from the SEER, and county-level factors were identified from the Area Health Resource File. Stage at presentation and observed survival were the outcomes of interest, with predictive factors identified by multivariate logistic and Cox proportional hazards regression. RESULTS: On multivariate analysis, tumor site, sex, race, marital status, rural residence, and county poverty level predicted stage at presentation. Sex, race, marital status, county-level poverty, and number of otolaryngologists predicted observed survival. CONCLUSION: Adverse county-level SES predicted advanced cancer stage at presentation and diminished observed survival. SES was a stronger predictor of patient outcomes than rurality or number of otolaryngologists.

Accuracy of the HPV status site-specific factor 10 (SSF-10) variable for patients with oropharyngeal cancers in the Iowa Cancer Registry, 2010-2014.

BACKGROUND: Surveillance, Epidemiology, and End Results Cancer Registries (SEER) began collecting human papillomavirus (HPV) status for upper aerodigestive tract cancers in 2010. However, classification of p16-testing was not included in the Collaborative Stage coding guidelines, potentially leading to inconsistent coding. METHODS: The HPV values for Iowa patients with oropharyngeal cancers (n = 824) were recoded based on modified guidelines that included p16 test results, and compared with the original guidelines. RESULTS: Forty percent of patients were recoded to a different value, and the HPV testing rate increased from 45% to 55%; 56% received p16-testing only. Of those originally coded as HPV-type 16 (n = 187), 89% were recoded to HPV-not otherwise specified (NOS). When comparing high-level positive/negative/not done categories, original coding captured 81% of patients with HPV-positive cancers. CONCLUSION: p16 was the most common HPV test but was inconsistently coded as HPV-testing. p16-positivity was also erroneously equated with HPV-type 16. Adding a separate p16 variable would improve consistency and accuracy of HPV coding.

Independent Predictors of Prognosis Based on Oral Cavity Squamous Cell Carcinoma Surgical Margins.

Objective To conduct a multivariate analysis of a large cohort of oral cavity squamous cell carcinoma (OCSCC) cases for independent predictors of local recurrence (LR) and overall survival (OS), with emphasis on the relationship between (1) prognosis and (2) main specimen permanent margins and intraoperative tumor bed frozen margins. Study Design Retrospective cohort study. Setting Tertiary academic head and neck cancer program. Subjects and Methods This study included 426 patients treated with OCSCC resection between 2005 and 2014 at University of Iowa Hospitals and Clinics. Patients underwent excision of OCSCC with intraoperative tumor bed frozen margin sampling and main specimen permanent margin assessment. Multivariate analysis of the data set to predict LR and OS was performed. Results Independent predictors of LR included nodal involvement, histologic grade, and main specimen permanent margin status. Specifically, the presence of a positive margin (odds ratio, 6.21; 95% CI, 3.3-11.9) or <1-mm/carcinoma in situ margin (odds ratio, 2.41; 95% CI, 1.19-4.87) on the main specimen was an independent predictor of LR, whereas intraoperative tumor bed margins were not predictive of LR on multivariate analysis. Similarly, independent predictors of OS on multivariate analysis included nodal involvement, extracapsular extension, and a positive main specimen margin. Tumor bed margins did not independently predict OS. Conclusion The main specimen margin is a strong independent predictor of LR and OS on multivariate analysis. Intraoperative tumor bed frozen margins do not independently predict prognosis. We conclude that emphasis should be placed on evaluating the main specimen margins when estimating prognosis after OCSCC resection.

A Hairy Situation: Laser Hair Removal after Oral Reconstruction.

OBJECTIVES: To present a case series of 4 patients who underwent postoperative hair removal using the long-pulsed Alexandrite or Nd:YAG laser following intraoral cutaneous flap reconstruction. METHODS: Patients underwent epilation in dermatology clinic with long-pulsed Alexandrite or Nd:YAG lasers, spaced 8 weeks apart, until hair removal was achieved. RESULTS: All patients achieved improvement in hair removal regardless of initial flap donor site with significant improvement in quality of life and minimal side effects. CONCLUSIONS: The long-pulsed Alexandrite and Nd:YAG represent safe and effective treatment options to improve patient quality of life following intraoral flap repair following excision of malignancy.

Longitudinal Perioperative Pain Assessment in Head and Neck Cancer Surgery.

OBJECTIVE: To evaluate perioperative pain in patients undergoing major head and neck cancer surgery and identify associations between preoperative and postoperative pain characteristics. METHODS: Patients undergoing head and neck surgery with regional/free tissue transfer were enrolled. Preoperative pain and validated screens for symptoms (neuropathic pain, anxiety, depression, fibromyalgia) were assessed. Postoperatively, patients completed a pain diary for 4 weeks. RESULTS: Twenty-seven patients were enrolled. Seventy-eight percent had pain prior to surgery, and for 38%, the pain had neuropathic characteristics. Thirteen patients (48%) completed at least 2 weeks of the postoperative pain diary. Patients with moderate/severe preoperative pain report significantly greater pain scores postoperatively, though daily pain decreased at a similar linear rate for all patients. Patients with more severe preoperative pain consumed greater amounts of opioids postoperatively, and this correlated with daily postoperative pain scores. Patients who screened positive for neuropathic pain also reported worse postoperative pain. CONCLUSION: Longitudinal perioperative pain assessment in head and neck patients undergoing surgery suggests that patients with worse preoperative pain continue to endorse worse pain postoperatively and require more narcotics. Patients with preoperative neuropathic pain also report poor pain control postoperatively, suggesting an opportunity to identify these patients and intervene with empiric neuropathic pain treatment.

Survival outcomes in elderly patients with untreated upper aerodigestive tract cancer.

BACKGROUND: This study is an evaluation of survival in patients with upper aerodigestive tract (UADT) cancer who did not receive guideline-directed therapy. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was examined to identify patients with invasive cancer of the UADT. Patients were classified as "untreated" if they received neither surgery nor radiotherapy. Kaplan-Meier observed survival estimates were computed and stage-specific actuarial estimates of relative survival were computed. RESULTS: Of 3589 untreated patients, 13.7% were black, compared to 9.5% white, and 9.2% all other races (p <.0001). Patients with stage IV disease were more likely to be untreated than those with stage I disease (11.9% vs 3.8%; p <.0001). Median survival was 39 months for treated patients and 4 months for untreated patients. CONCLUSION: The median survival for untreated patients was 4 months. Stage, race, and primary site were independently associated with untreated status. © 2016 Wiley Periodicals, Inc. Head Neck 39: 215-218, 2017.

Association of Main Specimen and Tumor Bed Margin Status With Local Recurrence and Survival in Oral Cancer Surgery.

Importance: There is controversy surrounding surgical margins in oral cavity squamous cell carcinoma (OCSCC), with debate regarding the assessment and prognostic value of margins. Objective: To analyze a large cohort of OCSCC cases for correlation between tumor specimen margins and intraoperative tumor bed frozen margins and evaluate how margin status associates with local recurrence and survival. Design, Setting, and Participants: Retrospective cohort study of 406 patients treated with OCSCC resection between 2005 and 2014 at the University of Iowa Hospitals and Clinics. Included cases underwent margin evaluation on the tumor specimen and intraoperative frozen margin assessment from the tumor bed. Main Outcomes and Measures: Findings of intraoperative frozen margin analysis as a test of tumor specimen margins; local recurrence and survival based on margin findings; prognosis based on clearance of positive frozen margins. To evaluate whether additional resection to "clear" positive frozen margins affected prognosis, we compared local recurrence rates for patients in 3 groups: group A included those patients with negative margins on both intraoperative and permanent specimens; group B included those with positive intraoperative margins subsequently cleared by additional resection to negative margins; and group C included those with negative intraoperative but positive permanent specimen margins. Results: The median age of the 406 patients (234 men and 172 women) was 61 years (interquartile range, 53-72 years). When frozen margins were correlated with tumor specimen margins, frozen margin accuracy was 65%, with a 46% false-negative rate. We observed a local recurrence rate of 36% (95% CI, 24%-49%) when invasive carcinoma was present at an intraoperative frozen margin and 45% (95% CI, 34%-57%) when invasive carcinoma was found on the permanent specimen margin compared with 19% (95% CI, 14%-26%) and 13% (95% CI, 7%-22%) for completely negative frozen and permanent margin findings, respectively. There was a significant difference in local recurrence between group A (13%) and group B (27%) (absolute difference, 14%; 95% CI, 3%-26%) and between group A and group C (34%) (absolute difference, 21%; 95% CI, 8%-34%), but there was no difference between groups B and C (absolute difference, 7%; 95% CI, -8% to 22%), suggesting that additional resection to clear positive frozen margins does not improve prognosis. Conclusions and Relevance: Intraoperative frozen margins from the tumor bed are not ideal predictors of positive margins on the main specimen. Both frozen and specimen margins are associated with local recurrence, but the specimen margin has the stronger association. Importantly, we demonstrate that clearing positive frozen margins from the tumor bed is not associated with improved outcomes.

Correlating thyroid cytology and histopathology: Implications for molecular testing.

BACKGROUND: A gene expression classifier (GEC) has been advocated in management of some indeterminate nodules without surgery. We assessed the potential negative predictive value (NPV) of the GEC at our academic center. METHODS: Retrospectively, all cytologically indeterminate fine-needle aspirates (FNAs) diagnosed by University of Iowa cytopathologists over a 3-year period were identified. Histopathologic findings were recorded. Using published sensitivity and specificity, NPVs were calculated. RESULTS: Of 178 nodules (17, 135, and 26 in classes III, IV, and V, respectively), 71 (40%) were malignant. Prevalence of malignancy was 41%, 29%, and 96% for classes III, IV, and V, respectively. Using sensitivities and specificities for the GEC, NPVs were 91% for the cohort: 88%, 92%, and 26% for classes III, IV, and V, respectively. CONCLUSION: Molecular testing should be associated with an NPV no lower than that from clinical criteria alone. With the prevalences reported, GEC use may result in more missed cancer diagnoses. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1104-1106, 2016.

Influence of body composition on survival in patients with head and neck cancer.

BACKGROUND: Recent evidence has suggested links between obesity and outcomes for various types of cancer. This study investigates the impact that body composition has on survival in patients with head and neck cancer. METHODS: Data prospectively collected from 578 patients were analyzed using Cox regression models to determine independent associations that pretreatment body mass index (BMI) and 3-month weight change have on observed survival. RESULTS: Higher BMIs were associated with better survival (p < .001). Five-year rates ranged from 33.8% for underweight to 75.3% for overweight/obese patients. Patients with stable weight had the highest 5-year rate (72.6%; p = .019), whereas patients who gained ≥5% had worse survival (45.8%) than those who lost ≥5% (65.8%). BMI independently predicted survival, whereas weight change was not an independent predictor. CONCLUSION: This demonstrated association between BMI and survival provides useful information when offering prognoses and investigating optimal treatments © 2015 Wiley Periodicals, Inc. Head Neck 38: E261-E267, 2016.

Association of sentinel lymph node biopsy with survival for head and neck melanoma: survival analysis using the SEER database.

IMPORTANCE: Sentinel lymph node biopsy (SLNB) provides prognostic information for melanoma; however, a survival benefit has not been demonstrated. OBJECTIVE: To assess the association of SLNB with survival for melanoma arising in head and neck subsites (HNM). DESIGN, SETTING, AND PARTICIPANTS: Propensity score-matched retrospective cohort study using the Surveillance Epidemiology and End Results (SEER) database to compare US patients with HNM meeting current recommendations for SLNB, treated from 2004 to 2011 with either (1) SLNB with or without neck dissection, or (2) no SLNB or neck dissection. INTERVENTIONS: SLNB with or without neck dissection. MAIN OUTCOMES AND MEASURES: Disease-specific survival (DSS) estimates based on the Kaplan-Meier method, and Cox proportional hazards modeling to compare survival outcomes between matched pair cohorts. RESULTS: A total of 7266 patients with HNM meeting study criteria were identified from the SEER database. Matching of treatment cohorts was performed using propensity scores modeled on 10 covariates known to be associated with SLNB treatment or melanoma survival. Cohorts were stratified by tumor thickness (thin, >0.75-1.00 mm Breslow thickness; intermediate, >1.00-4.00 mm; and thick, >4.00 mm) and exactly matched within 5 age categories. In the intermediate-thickness cohort, 2808 patients with HNM were matched and balanced by propensity score for SLNB treatment; the 5-year DSS estimate for those treated by SLNB was 89% vs 88% for nodal observation (log-rank P = .30). The hazard ratio for melanoma-specific death was 0.87 for those undergoing SLNB (95% CI, 0.66-1.14; P = .31). In each of the other cohorts analyzed, including those with thin and thick melanomas, and cohorts with melanoma overall, no significant difference in DSS was demonstrated. CONCLUSIONS AND RELEVANCE: This SEER cohort analysis demonstrates no significant association between SLNB and improved disease-specific survival for patients with HNM.

The University of Pennsylvania curriculum for training otorhinolaryngology residents in transoral robotic surgery.

PURPOSE: To define a curriculum for the development of robotic surgical skills in otorhinolaryngology residency training. METHODS: A systematic review of the current literature on robotic surgery training was performed. Based on prior reports in other specialties, a curriculum for otorhinolaryngology residents was created that progresses through several modules, including didactics, inanimate skills laboratory, and operative experience. RESULTS: The curriculum for residents in otorhinolaryngology was designed as follows: didactics include an overview of the robotic device and instruments, a tutorial in basic controls and function, and a room setup and positioning. The anatomy and steps of transoral procedures are taught through books, videos, operative observations, and cadaver dissections. Skills are developed with a virtual reality robotic simulator and robotics labs. The operative experience progresses from case observation to bedside assistant to console surgeon. The role of the console surgeon progresses in a stepwise fashion, and the procedures of radical tonsillectomy, supraglottic partial laryngectomy, and base of tongue resection have been organized as a series of steps. CONCLUSION: A structured curriculum for training residents in transoral robotic surgery was developed. This training is important for otorhinolaryngology residents to acquire the knowledge and skills to perform robotic surgery safely.

Supracricoid partial laryngectomy for primary and recurrent laryngeal cancer.

IMPORTANCE: Supracricoid partial laryngectomy (SCPL) is an essential technique in the armamentarium of modern laryngeal organ preservation surgery. OBJECTIVE, DESIGN, SETTING: Retrospective case series to review the oncologic outcomes following SCPL in a large US-based cohort treated by a single surgeon in a tertiary-care university hospital. PARTICIPANTS: A total of 96 consecutive patients with primary or recurrent squamous cell carcinoma of the larynx undergoing SCPL from 1992 to 2010. INTERVENTIONS: Supracricoid partial laryngectomy surgery. MAIN OUTCOMES AND MEASURES: Five-year local control and laryngeal preservation, using the Kaplan-Meier method. RESULTS: There were 54 primary laryngeal carcinomas and 42 previously treated with radiation to the larynx; 23% were supraglottic or transglottic tumors (n = 22). The overall 5-year local control rate for the series was 94%. For T2 and T3 primary tumors, the 5-year local control was 100% and 96%, respectively. In patients previously treated with radiation, the 5-year local control was 89%, with an 89% laryngeal preservation rate. Among stage III or IV primary laryngeal tumors for which concurrent chemoradiation was a treatment alternative, the 5-year local and locoregional control was 96% and 83%, respectively, and the 5-year larynx preservation was 91%. Ultimate local control was achieved for all patients in the series. A significant postoperative complication occurred in 19% (n = 18) and 1 anesthesia-related perioperative death occurred. No total laryngectomies were performed for laryngeal dysfunction. CONCLUSIONS AND RELEVANCE: This series demonstrates excellent local control for both primary and recurrent laryngeal cancers, with functional larynx preservation. In appropriately staged and selected patients with T2 or T3 primary laryngeal cancer or laryngeal cancer following prior radiation treatment, SCPL should be considered as a treatment alternative to non-surgical treatment or total laryngectomy.

EGFR inhibition promotes an aggressive invasion pattern mediated by mesenchymal-like tumor cells within squamous cell carcinomas.

Squamous cell carcinomas (SCC) with an infiltrative invasion pattern carry a higher risk of treatment failure. Such infiltrative invasion may be mediated by a mesenchymal-like subpopulation of malignant cells that we have previously shown to arise from epithelial-mesenchymal transition (EMT) and resist epidermal growth factor receptor (EGFR) targeting. Here, we show that SCCs with infiltrative, high-risk invasion patterns contain abundant mesenchymal-like cells, which are rare in tumors with low-risk patterns. This cellular heterogeneity was modeled accurately in three-dimensional culture using collagen-embedded SCC spheroids, which revealed distinct invasive fronts created by collective migration of E-cadherin-positive cells versus infiltrative migration of individual mesenchymal-like cells. Because EGFR expression by mesenchymal-like cells was diminished in the spheroid model and in human SCCs, we hypothesized that SCCs shift toward infiltrative invasion mediated by this subpopulation during anti-EGFR therapy. Anti-EGFR treatment of spheroids using erlotinib or cetuximab enhanced infiltrative invasion by targeting collective migration by E-cadherin-positive cells while sparing mesenchymal-like cells; by contrast, spheroid invasion in absence of mesenchymal-like cells was abrogated by erlotinib. Similarly, cetuximab treatment of xenografts containing mesenchymal-like cells created an infiltrative invasive front composed of this subpopulation, whereas no such shift was observed upon treating xenografts lacking these cells. These results implicate mesenchymal-like SCC cells as key mediators of the infiltrative invasion seen in tumors with locally aggressive behavior. They further show that EGFR inhibition can promote an infiltrative invasion front composed of mesenchymal-like cells preferentially in tumors where they are abundant before therapy.