Tcf3 expression marks both stem and progenitor cells in multiple epithelia.

The Lef/Tcf-family transcription factor Tcf3 has important roles in development, stem cell function and malignancy. Previous gain- and loss-of-function studies have suggested that Tcf3 is a mediator of self-renewal and an undifferentiated state in stem and progenitor cells in skin, but little is known of its role in other postnatal tissues. Here, we explore the distribution and behavior of Tcf3-expressing cells in several adult tissues using a novel Tcf3-CreER knock-in mouse model. By lineage tracing in dorsal skin, we verify that Tcf3-expressing cells in the hair follicle bulge are self-renewing stem cells with multilineage potential. We then demonstrate, for the first time, the presence of Tcf3-expressing cells in the basal layer of several other stratified epithelia, including the paw skin, tongue and esophagus. By lineage tracing, we demonstrate that the Tcf3-expressing population in these tissues includes persistent stem cells, transient progenitors and cells undergoing active differentiation. Our observations here suggest that the role of Tcf3 in cell-fate decision is more complex than previously appreciated and is highly dependent on cellular context.

Foxp1 maintains hair follicle stem cell quiescence through regulation of Fgf18.

Hair follicles cyclically degenerate and regenerate throughout adult life and require regular stem cell activation to drive the cycle. In the resting phase of the hair cycle, hair follicle stem cells are maintained in a quiescent state until they receive signals to proliferate. We found that the forkhead transcription factor Foxp1 is crucial for maintaining the quiescence of hair follicle stem cells. Loss of Foxp1 in skin epithelial cells leads to precocious stem cell activation, resulting in drastic shortening of the quiescent phase of the hair cycle. Conversely, overexpression of Foxp1 in keratinocytes prevents cell proliferation by promoting cell cycle arrest. Finally, through both gain- and loss-of-function studies, we identify fibroblast growth factor 18 (Fgf18) as the key downstream target of Foxp1. We show that exogenously supplied FGF18 can prevent the hair follicle stem cells of Foxp1 null mice from being prematurely activated. As Fgf18 controls the length of the quiescent phase and is a key downstream target of Foxp1, our data strongly suggest that Foxp1 regulates the quiescent stem cell state in the hair follicle stem cell niche by controlling Fgf18 expression.

Testicular Radiomics To Predict Pathology At Time of Postchemotherapy Retroperitoneal Lymph Node Dissection for Nonseminomatous Germ Cell Tumor.

INTRODUCTION: Testicular germ cell tumors are the most common malignancy in young adult males. Patients with metastatic disease receive standard of care chemotherapy followed by retroperitoneal lymph node dissection for residual masses >1cm. However, there is a need for better preoperative tools to discern which patients will have persistent disease after chemotherapy given low rates of metastatic germ cell tumor after chemotherapy. The purpose of this study was to use radiomics to predict which patients would have viable germ cell tumor or teratoma after chemotherapy at time of retroperitoneal lymph node dissection. PATIENTS AND METHODS: Patients with nonseminomatous germ cell tumor undergoing postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) between 2008 and 2019 were queried from our institutional database. Patients were included if prechemotherapy computed tomography (CT) scan and postchemotherapy imaging were available. Semiqualitative and quantitative features of residual masses and nodal regions of interest and radiomic feature extractions were performed by 2 board certified radiologists. Radiomic feature analysis was used to extract first order, shape, and second order statistics from each region of interest. Post-RPLND pathology was compared to the radiomic analysis using multiple t-tests. RESULTS: 45 patients underwent PC-RPLND at our institution, with the majority (28 patients) having stage III disease. 24 (53%) patients had teratoma on RPLND pathology, while 2 (4%) had viable germ cell tumor. After chemotherapy, 78%, 53%, and 33% of patients had cystic regions, fat stranding, and local infiltration present on imaging. After radiomic analysis, first order statistics mean, median, 90th percentile, and root mean squares were significant. Strong correlations were observed between these 4 features;a lower signal was associated with positive pathology at RPND. CONCLUSIONS: Testicular radiomics is an emerging tool that may help predict persistent disease after chemotherapy.

Ex vivo gene transfer for improved adoptive immunotherapy of cancer.

Adoptive immunotherapy is an appealing approach to cancer treatment, with the potential for more precise targeting and reduced toxicity. While early clinical trial data using adoptive T cells against post-transplant virus-associated hematologic malignancies, lymphoma and melanoma have been promising, treating other solid tumors has proven to be more challenging. Adoptive lymphocytes have been genetically modified in many ways to improve activity and circumvent tumor evasion, including transfer of transgenic T-cell receptors and chimeric antigen receptors to redirect T cell and natural killer cell antigen specificity. Gene transfer may also allow expression of homeostatic cytokines or their receptors to overcome the lack of stimulatory signals or expression of dominant-negative receptors for inhibitory cytokines to compensate for an immunosuppressive tumor milieu. In addition, suicide genes can install a 'safety switch' on adoptively transferred cells to allow ablation if necessary. Although further refinement and validation are necessary, these genetic modification strategies offer hope for significant improvements in cancer immunotherapy.

Impact of testicular cancer stage on semen parameters in patients before orchiectomy.

OBJECTIVE: To study the impact of testicular cancer composite stage and histology with semen parameters in preorchiectomy cryopreservation samples. METHODS: We retrospectively collected semen parameter data, composite stage, and tumor histology for patients who cryopreserved sperm prior to orchiectomy for testicular cancer between 2006 and 2018. Stage I was considered localized disease, and Stages II and III were considered metastatic disease. The World Health Organization (WHO) 2010 semen parameter criteria was used to characterize lab values as normal or subnormal. Categorical and continuous variables were compared using Fisher's exact and Mann Whitney U tests, respectively. RESULTS: Thirty eight patients with testicular cancer underwent preorchiectomy cryopreservation. The median age (IQR) of our cohort was 27 (23-32). Four patients (11%) had azoospermia. No significant differences were found in these semen parameters between Stage I and Stage II/III patients or between seminoma and NSGCT patients. Per WHO 2010 criteria, 7 patients (18%) had abnormal (below reference range) semen volume, 18 patients (47%) had abnormal total sperm counts, and 9 patients (24%) had abnormal motility percentage. Abnormal semen parameters were not significantly associated with tumor histology or stage. CONCLUSION: To our knowledge, this is the first study to show that semen parameters are similar across all stages of testicular cancer. Prior studies have shown that delaying orchiectomy to cryopreserving sperm does not negative affect oncological outcomes. As a result, regardless of staging or histology, sperm banking should be recommended for patients with both localized and metastatic testicular cancer.

Distance to Treatment With Radical Cystectomy in a Rural State: Long Car Rides, Equivalent Outcomes.

INTRODUCTION: Radical cystectomy is a complex surgery with better outcomes reported when performed at high-volume centers. This may lead to patients traveling farther for care. We examined the impact of travel distance on clinical outcomes. METHODS: A total of 220 patients undergoing radical cystectomy from 2015-2021 were retrospectively reviewed. Distance traveled to the treatment center by patient zip codes was classified as <12.5 miles, 12.5-49.9 miles, and ≥50 miles. Multivariable logistic regression was used to assess complications, readmissions, 90-day mortality, and length of stay by distance traveled. Time to treatment based on distance traveled was compared. RESULTS: A total of 220 patients underwent radical cystectomy with complete 90-day follow-up. Of the patients 38.6% (85/220) were readmitted; 62.5% (53/85) presented to the treatment center or were transferred. All patients readmitted to an outside hospital traveled ≥12.5 miles (P < .001). Patients with high-grade complications were likely to be transferred to the treatment center with only 23.7% (9/38) definitively managed by outside hospital. Patients traveling >12.5 miles with low-grade complications were more likely to be managed at an outside hospital (57.5%, P = .01). There was no difference in time to initiation of neoadjuvant chemotherapy (P = .99) or time to radical cystectomy following neoadjuvant chemotherapy (P = .23) by distance traveled. For 49 muscle-invasive bladder cancer patients proceeding directly to surgery without neoadjuvant chemotherapy, time from diagnosis to radical cystectomy was increased if traveling >12.5 miles (P = .04). CONCLUSIONS: Increased travel distance did not impact early postoperative outcomes. Distance traveled may impact access to care, such as time to surgery or location of readmission to the treatment center postoperatively.

Refining the serum miR-371a-3p test for viable germ cell tumor detection.

Circulating miR-371a-3p has excellent performance in the detection of viable (non-teratoma) germ cell tumor (GCT) pre-orchiectomy; however, its ability to detect occult disease is understudied. To refine the serum miR-371a-3p assay in the minimal residual disease setting we compared performance of raw (Cq) and normalized (∆Cq, RQ) values from prior assays, and validated interlaboratory concordance by aliquot swapping. Revised assay performance was determined in a cohort of 32 patients suspected of occult retroperitoneal disease. Assay superiority was determined by comparing resulting receiver-operator characteristic (ROC) curves using the Delong method. Pairwise t-tests were used to test for interlaboratory concordance. Performance was comparable when thresholding based on raw Cq vs. normalized values. Interlaboratory concordance of miR-371a-3p was high, but reference genes miR-30b-5p and cel-miR-39-3p were discordant. Introduction of an indeterminate range of Cq 28-35 with a repeat run for any indeterminate improved assay accuracy from 0.84 to 0.92 in a group of patients suspected of occult GCT. We recommend that serum miR-371a-3p test protocols are updated to (a) utilize threshold-based approaches using raw Cq values, (b) continue to include an endogenous (e.g., miR-30b-5p) and exogenous non-human spike-in (e.g., cel-miR-39-3p) microRNA for quality control, and (c) to re-run any sample with an indeterminate result.

Routine Overnight Vital Signs Are Rarely Associated with Major Clinical Events in Patients Undergoing Radical Cystectomy: A Retrospective Cohort Study.

INTRODUCTION: Evidence has associated patient sleep disruption with adverse clinical outcomes. Overnight vital sign checks are a frequent source of patient sleep disruption. We sought to determine the utility of routine overnight vital sign checks in stable postoperative patients following radical cystectomy for bladder cancer. METHODS: We assembled a database containing all routine vital sign checks from postoperative days 0 through 6 for all patients who underwent radical cystectomy at our institution during a 5-year period (2016-2020). Sets of overnight vital signs were flagged as "abnormal" based on specified criteria and then reviewed by 2 blinded reviewers to determine whether they were associated with significant clinical interventions. RESULTS: A total of 546 patients representing 2,589 patient-nights in the hospital were included. Abnormal vital signs resulting in "moderate" or "major" clinical interventions (corresponding to concern for Clavien-Dindo grade ≥II complications) occurred during 17/2,589 (0.65%) patient-nights. Thus, 152 patient-nights of routine vital sign checks were required to identify a single moderate or major clinical event. Reviewing all overnight-onset complications, we noted that a majority (15/23, 65%) of Clavien-Dindo grade II complications were manifested only by symptoms or laboratory abnormalities without vital sign derangements, whereas all grade ≥III complications had associated vital sign abnormalities. CONCLUSIONS: Routine overnight vital signs were associated with a low frequency of clinically significant events. Reduced intensity of overnight vital sign checks may be a safe addition to enhanced-recovery packages in carefully selected patients.

Decreased Muscle Mass Prior to and Following Chemotherapy Predicts Morbidity in Testicular Cancer Patients Undergoing Post-Chemotherapy Retroperitoneal Lymph Node Dissection.

INTRODUCTION/BACKGROUND: The importance of nutritional status before oncologic surgery has been demonstrated in several solid malignancies. Testicular cancer primarily effects young men, and therefore clinicians may not consider sarcopenia as a factor in this population. We therefore sought to determine the impact of decreased muscle mass, measured by psoas muscle diameter, on outcomes in patients undergoing post-chemotherapy retroperitoneal lymphadenectomy (PC-RPLND) for metastatic germ cell tumors (mGCTs). MATERIALS AND METHODS: Records of all patients undergoing PC-RPLND for mGCTs at our institution were reviewed. Muscle mass was assessed by measuring cross-sectional area of the psoas muscle on pre-chemotherapy and pre-operative computerized tomography. Psoas Index (PSI) was calculated by adjusting total psoas area for patient height (cm2/m2). Univariate and multivariate analysis was performed to assess the predictive value of sarcopenia for morbidity and mortality following PC-RPLND. RESULTS: From 2014-2019, 95 patients underwent PC-RPLND, of whom 64 patients had both pre-chemo and pre-operative cross-sectional imaging. Prior to chemotherapy, mean PSI was 7.36 cm2/m2, which decreased to 7.06 cm2/m2 (P = .041) following chemotherapy. Patients with Stage III disease had a lower mean PSI than patients with Stage I disease (6.84 cm2/m2 vs 7.46 cm2/m2, P = .047). Patients who suffered post-operative complications had a lower mean PSI (6.39 cm2/m2 vs 7.37 cm2/m2, P = .020). CONCLUSION: Decreased muscle mass was predictive of morbidity in patients undergoing PC-RPLND. Patients with higher disease burden had lower pre-operative muscle mass. Further assessment of pre-operative nutritional status in this population may reduce morbidity following PC-RPLND.

The early impact of medicaid expansion on urologic malignancies in the United States.

PURPOSE: To assess the effects of variable adoption of Medicaid Expansion (ME) of the Affordable Care Act among different states on urologic malignancies using a new variable that defines ME status of patient's residence in a nationwide cancer registry. BASIC PROCEDURES: The National Cancer Database was queried for urologic malignancies (bladder, prostate, kidney and testis) from 2011 to 2016, spanning the period surrounding the primary ME which took place in 2014. Trends in insurance status at time of diagnosis and effects on stage at presentation and survival after ME were evaluated using a difference-in-differences estimator and stratified Cox proportional hazards regression model. MAIN FINDINGS: The percentage of patients with Medicaid coverage at the time of diagnosis increased significantly after adoption of ME in ME states across all urologic malignancies. Concurrently, there was a significant decrease in percentage of uninsured patients diagnosed with testis cancer, but not other urologic malignancies, in ME states. A change in the stage at presentation was not observed across all urologic malignancies for patients in ME states after adoption of ME. No difference in overall survival was noted among patients living in a ME state compared to non-ME states with adoption of ME in 2014. PRINCIPAL CONCLUSIONS: Despite increases in the proportion of patients with Medicaid coverage after 2014 in states that enrolled in ME, there was not an associated change in stage at presentation or survival for patients with genitourinary malignancy.

Outcomes of patients undergoing concurrent radical cystectomy and nephroureterectomy: A single-institution series.

INTRODUCTION: Radical cystectomy (RC) and radical nephroureterectomy (RNU) are commonly performed in urological oncology. Concurrent disease in the upper tract and bladder is rare, so performing both procedures in the same setting is uncommon. Here, we report the perioperative and oncological outcomes of a single-institution series of concurrent RC+RNU. METHODS: We retrospectively reviewed the charts of patients who underwent concurrent RC+RNU for bladder and/or upper tract urothelial carcinoma between 2006 and 2020. Patient demographic and clinical factors, perioperative parameters, and oncological outcomes were obtained. RESULTS: Twenty-seven patients underwent RC+RNU during the study period; 22 (81%) were male. Median (interquartile range) patient age was 71 (67-75) years. All had a diagnosis of bladder cancer. Concurrent upper tract urothelial carcinoma (UTUC) was the indication for RNU in 12 cases (44%) and non-functional renal unit in the remainder. Two patients (7%) experienced early postoperative mortality. Eight patients (30%) experienced major complications (Clavien-Dindo >3). Complications did not vary significantly between those rendered anephric (5/16, 31%) and those who were not (3/11, 27%) (p=0.82, Chi-squared test). Median (95% confidence interval) and five-year overall survival were 47 (41-52) months and 42%, respectively. Six of 22 male patients (27%) experienced a urethral recurrence and three of 14 patients (21%) with non-functional kidneys had occult UTUC discovered on final pathology. CONCLUSIONS: Combined RC+RNU carries an elevated perioperative risk, primarily in highly comorbid patients. Striking rates of occult UTUC in non-functional kidneys and of urethral recurrence after cystectomy were noted. RC+RNU is an appropriate option in select patients.

Outcomes of Patients with Bacillus Calmette-Guérin (BCG)-Unresponsive Non-Muscle Invasive Bladder Cancer as Defined by the U.S. Food and Drug Administration.

BACKGROUND: Limited data are available on the outcomes of patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to intravesical bacillus Calmette-Guérin (BCG), as defined by the United States Food and Drug Administration. OBJECTIVE: To define the outcomes of patients with BCG-unresponsive NMIBC. METHODS: This was a retrospective, single-institution observational cohort study. Records of patients managed at our institution for BCG-unresponsive NMIBC between 2005 and 2020 were reviewed and clinical outcomes evaluated. RESULTS: The study included 149 patients. Management was with initial radical cystectomy in 60 patients (40%) and initial bladder-sparing therapy (BST) in 89 patients (60%). Overall survival was greater among patients undergoing RC than BST (HR 1.83, 95% CI 1.04-3.22, p = 0.036), potentially due to patient selection, as no significant difference was noted for metastasis-free or cancer-specific survival. Patients opting for initial BST had high rates of treatment failure, with estimated 5-year cystectomy-free survival of only 42%. Patients who received additional lines of BST after a subsequent failure were at increased risk of having ≥pT3 or pN+ disease at cystectomy (42% for ≥2 lines BST, versus 18% for 1 line BST and 15% for initial cystectomy, p = 0.038). CONCLUSION: Among patients who underwent initial BST for BCG-unresponsive NMIBC, rates of treatment failure were very high. Patients who underwent delayed cystectomy after ≥2 lines of BST had elevated rates of extravesical disease. Our observations emphasize the importance of recent and ongoing clinical trials in this clinical space.

Disparities in Pre-Orchiectomy Sperm Cryopreservation Among Testicular Cancer Patients at a Public Safety Net Hospital and a Private Tertiary Care Center.

OBJECTIVE: To compare pre-orchiectomy sperm cryopreservation use in testicular cancer patients at a private tertiary care academic center and an affiliated public safety-net hospital. METHODS: This was a retrospective cohort study of patients who underwent radical orchiectomy for testicular cancer at a private tertiary-care hospital, which cared primarily for patients with private health insurance, and at a public "safety-net" facility, which cared for patients regardless of insurance status. Clinical and demographic predictors of cryopreservation use prior to orchiectomy were determined by chart review. RESULTS: A total of 201 patients formed the study cohort, 106 (53%) at the safety-net hospital and 95 (47%) at the private hospital. Safety net patients were more likely to be non-White (82% vs 15%, P < 0.001), uninsured (80% vs 12%, P < 0.001), Spanish speaking (38% vs 5.6%, P < 0.001), and to reside in areas in the bottom quartile of income (41% vs 5.6%, P < 0.001). On multivariable analysis, treatment at the private tertiary care center was strongly associated with use of cryopreservation (OR 5.60, 95% CI 1.74 - 20.4, P = 0.005, though the effects of specific demographic factors could not be elucidated due to collinearity. CONCLUSION: Among patients with testicular cancer, disparities exist in use of sperm cryopreservation between the private and safety-net settings. Barriers to the use of cryopreservation in the safety-net population should be sought and addressed.

Demographic Factors Associated With Non-Guideline-Based Treatment of Kidney Cancer in the United States.

Importance: Significant demographic disparities have been found to exist in the delivery of health care. Demographic factors associated with clinical decision-making in kidney cancer have not been thoroughly studied. Objective: To determine whether demographic factors, including sex and race/ethnicity, are associated with receipt of non-guideline-based treatment for kidney cancer. Design, Setting, and Participants: This retrospective cohort study was conducted using data from the National Cancer Database for the years 2010 through 2017. Included patients were individuals aged 30 to 70 years with localized (ie, cT1-2, N0, M0) kidney cancer and no major medical comorbidities (ie, Charlson-Deyo Comorbidity Index score of 0 or 1) treated at Commission on Cancer-accredited health care institutions in the United States. Data were analyzed from November 2020 through March 2021. Exposures: Demographic factors, including sex, race/ethnicity, and insurance status. Main Outcomes and Measures: Receipt of non-guideline-based treatment (undertreatment or overtreatment) for kidney cancer, as defined by accepted clinical guidelines, was determined. Results: Among 158 445 patients treated for localized kidney cancer, 99 563 (62.8%) were men, 120 001 individuals (75.7%) were White, and 91 218 individuals (57.6%) had private insurance. The median (interquartile range) age was 58 (50-64) years. Of the study population, 48 544 individuals (30.6%) received non-guideline-based treatment. Female sex was associated with lower adjusted odds of undertreatment (odds ratio [OR], 0.82; 95% CI, 0.77-0.88; P < .001) and higher adjusted odds of overtreatment (OR, 1.27; 95% CI, 1.24-1.30; P < .001) compared with male sex. Compared with White patients, Black and Hispanic patients had higher adjusted odds of undertreatment (Black patients: OR, 1.42; 95% CI, 1.29-1.55; P < .001; Hispanic patients: OR, 1.20; 95% CI, 1.06-1.36; P = .004) and overtreatment (Black patients: OR, 1.09; 95% CI, 1.05-1.13; P < .001; Hispanic patients: OR, 1.06; 95% CI, 1.01-1.11, P = .01). Individuals who were uninsured, compared with those who had insurance, had statistically significantly higher adjusted odds of undertreatment (OR, 2.63; 95% CI, 2.29-3.01; P < .001) and lower adjusted odds of overtreatment (OR, 0.72; 95% CI, 0.67-0.77; P < .001). Conclusions and Relevance: This study found that there were significant disparities in treatment decision-making for patients with kidney cancer, with increased rates of non-guideline-based treatment for women and Black and Hispanic patients. These findings suggest that further research into the mechanisms underlying these disparities is warranted and that clinical and policy decision-making should take these disparities into account.

Enhanced Endoscopy with IMAGE1 S CHROMA Improves Detection of Nonmuscle Invasive Bladder Cancer During Transurethral Resection.

Purpose: We assessed the ability of enhanced cystoscopy with CHROMA image enhancement (Karl Storz SE & Co. KG, Tuttlingen, Germany) to improve cancer detection during transurethral resection of bladder tumors (TURBT) in patients with known or suspected nonmuscle invasive bladder cancer (NMIBC). Patients and Methods: A total of 49 patients (82% men) with a median age of 71 years underwent TURBT for known or suspected NMIBC. Bladders were assessed first with conventional white light imaging and then with CHROMA enhancement. We quantified the number of tumors seen with white light and any additional tumors seen with CHROMA and correlated with pathologic results. Results: A total of 165 tumors were viewed in 47 patients; of these, 25 were only seen using CHROMA. Use of CHROMA yielded additional tumors not appreciated on white light in 14 of 39 patients with underlying malignancy, for an additional detection rate (ADR) of 36% (95% confidence interval, 21%-53%). CHROMA improved detection of tumors in the setting of both low-grade (LG) and high-grade (HG) disease with equal efficacy (ADR 43% in LG and 44% in HG, p = 0.98, Barnard exact test). Conclusions: Cystoscopy with CHROMA contrast enhancement facilitates detection of bladder tumors that are not readily appreciated using conventional white light cystoscopy. The technology integrates seamlessly with current practice and can serve as an adjunct to other novel technologies.

Metastasis-directed radiation therapy after radical cystectomy for bladder cancer.

PURPOSE: Metastasis-directed radiation therapy (MDRT) may improve oncologic and quality of life outcomes in patients with metastatic cancer, but data on its use in metastatic bladder cancer is severely limited. We sought to review our institutional experience with MDRT in patients with metastatic bladder cancer following radical cystectomy. MATERIALS AND METHODS: We reviewed records of patients who underwent radical cystectomy and subsequent MDRT at our institution between 2009 and 2020. Baseline demographic and clinical/pathologic factors were collected, as were details of treatment including systemic therapy and MDRT. Cases were categorized by treatment intent as consolidative (intended to prolong survival) and palliative (intended only to relieve symptoms). Response to treatment, survival, and toxicity outcomes were reviewed. RESULTS: A total of 52 patients underwent MDRT following radical cystectomy. MDRT was categorized as consolidative in 40% of cases and palliative in 60%. Toxicity (CTCAE Grade ≥ 2) was reported in 15% of patients, none of which exceeded Grade 3. Most patients undergoing consolidative MDRT were treated with SBRT techniques (76%) and a majority (67%) received concurrent treatment with an immuno-oncology agent. Among patients treated with consolidative intent, 2-year progression-free and overall survival were 19% and 60%, respectively. CONCLUSION: MDRT is safe and well-tolerated by a majority of patients. A majority of patients treated with consolidative intent survived ≥ 2 years from treatment.

TCF7L1 promotes skin tumorigenesis independently of ß-catenin through induction of LCN2.

The transcription factor TCF7L1 is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in skin tumorigenesis has not yet been defined. Here we document TCF7L1 upregulation in skin squamous cell carcinoma (SCC) and demonstrate that TCF7L1 overexpression increases tumor incidence, tumor multiplicity, and malignant progression in the chemically induced mouse model of skin SCC. Additionally, we show that downregulation of TCF7L1 and its paralogue TCF7L2 reduces tumor growth in a xenograft model of human skin SCC. Using separation-of-function mutants, we show that TCF7L1 promotes tumor growth, enhances cell migration, and overrides oncogenic RAS-induced senescence independently of its interaction with ß-catenin. Through transcriptome profiling and combined gain- and loss-of-function studies, we identified LCN2 as a major downstream effector of TCF7L1 that drives tumor growth. Our findings establish a tumor-promoting role for TCF7L1 in skin and elucidate the mechanisms underlying its tumorigenic capacity.