Interrogating the precancerous evolution of pathway dysfunction in lung squamous cell carcinoma using XTABLE.

Lung squamous cell carcinoma (LUSC) is a type of lung cancer with a dismal prognosis that lacks adequate therapies and actionable targets. This disease is characterized by a sequence of low- and high-grade preinvasive stages with increasing probability of malignant progression. Increasing our knowledge about the biology of these premalignant lesions (PMLs) is necessary to design new methods of early detection and prevention, and to identify the molecular processes that are key for malignant progression. To facilitate this research, we have designed XTABLE (Exploring Transcriptomes of Bronchial Lesions), an open-source application that integrates the most extensive transcriptomic databases of PMLs published so far. With this tool, users can stratify samples using multiple parameters and interrogate PML biology in multiple manners, such as two- and multiple-group comparisons, interrogation of genes of interests, and transcriptional signatures. Using XTABLE, we have carried out a comparative study of the potential role of chromosomal instability scores as biomarkers of PML progression and mapped the onset of the most relevant LUSC pathways to the sequence of LUSC developmental stages. XTABLE will critically facilitate new research for the identification of early detection biomarkers and acquire a better understanding of the LUSC precancerous stages.

Lung squamous cell carcinoma is the second most common lung cancer. However, very little is known about how normal tissues in the lung develop in to these tumours. Like many cancers, this transformation comprises of an intermediate phase where healthy cells begin to form lesions that may (or may not) progress in to tumours. Understanding the biology of these lesions in lung squamous cell carcinoma may help clinicians detect them before they become cancerous. Knowing which genes are switched on and off during this intermediary phase can provide clues as to how these lesions form. There are already some publicly available transcriptional datasets showing the activity of tens of thousands of genes in pre-cancerous lesions extracted from patients with lung squamous cell carcinoma. But not every laboratory has the bioinformatic tools and skills required to interrogate these extensive databases. To address this, Roberts et al. built an open-source platform called XTABLE (short for Exploring Transcriptomes of Bronchial Lesions) which can analyse transcriptional datasets in multiple ways depending on the needs of the user. For instance, the tool can stratify the data into groups based on different parameters, such as the lesions potential to progress in to cancer, to see how the genes of the groups compare. It can also analyse the activity of individual genes and sets of genes involved in the same biological processes. Using XTABLE, Roberts et al. showed that a biological process linked to lung squamous cell carcinoma is also involved in the formation of pre-cancerous lesions. This suggests that molecules and genes associated with this process could potentially help scientists design prevention strategies. XTABLE will help researchers to better understand the biology of pre-cancerous lesions and how they develop in to tumours. Moreover, it will make it easier for scientists to validate their hypotheses using data collected from patients. The tool could also be useful for scientists interested in other types of lung cancers that share a similar biology.

High Flow Nasal Cannula Therapy in the Emergency Department: Main Benefits in Adults, Pediatric Population and against COVID-19: A Narrative Review.

This review aims to summarize the literature's main results about high flow nasal cannula therapy (HFNC) HFNC benefits in the Emergency Department (ED) in adults and pediatrics, including new Coronavirus Disease (COVID-19). HFNC has recently been established as the usual treatment in the ED to provide oxygen support. Its use has been generalized due to its advantages over traditional oxygen therapy devices, including decreased nasopharyngeal resistance, washing out of the nasopharyngeal dead space, generation of positive pressure, increasing alveolar recruitment, easy adaptation due to the humidification of the airways, increased fraction of inspired oxygen and improved mucociliary clearance. A wide range of pathologies has been studied to evaluate the potential benefits of HFNC; some examples are heart failure, pneumonia, chronic pulmonary obstructive disease, asthma, and bronchiolitis. The regular use of this oxygen treatment is not established yet due to the literature's controversial results. However, several authors suggest that it could be useful in several pathologies that generate acute respiratory failure. Consequently, the COVID-19 irruption has generated the question of HFNC as a safety and effective treatment. Our results suggested that HFNC seems to be a useful tool in the ED, especially in patients affected by acute hypoxemic respiratory failure, acute heart failure, pneumonia, bronchiolitis, asthma and acute respiratory distress syndrome in patients affected by COVID-19. Its benefits in hypercapnic respiratory failure are more discussed, being only observed benefits in patients with mild-moderate disease. These results are based in clinical as well as cost-effectiveness outcomes. Future studies with largest populations are required to confirm these results as well as establish a practical guideline to use this device.

Concordance between Ki-67 index in invasive breast cancer and molecular signatures: EndoPredict and MammaPrint.

Identifying patients with hormone receptor-positive (HR+) early invasive breast cancer (EIBC) who benefit from adjuvant chemotherapy has improved with molecular signature tests. However, due to high cost and limited availability, alternative tests are used. The present study sought to evaluate the performance of the proliferation marker Ki-67 to identify these patients and explore its association with molecular signatures and risk stratification markers. From the San José TecSalud Hospital in Monterrey México, patients with HR+ EIBC as tested with EndoPredict or MammaPrint and Ki-67 index were identified. They were categorized into two groups: Group 1 (June 2016-August 2018) was evaluated using EndoPredict and Group 2 (June 2016-August 2018) with MammaPrint. A ≥20% Ki67 index cutoff was utilized to identify highly proliferative EIBC and an area under the receiver-operating characteristic curve and κ concordance were utilized to evaluate the performance of Ki-67 index compared to molecular signature tests. In the EndoPredict group, 54/96 patients were considered high-risk based on their EPclin score, while 57/96 patients had Ki-67 index ≥20%. However, there was no significant overall concordance between them (59.37%, κ=0.168, P=0.09), while the given risk of distant recurrence given in percentage by EPclin had a positive association with the Ki67 index (P=0.04). In the MammaPrint group, 21/70 patients were considered high-risk and 36/70 patients presented with a Ki-67 index ≥20% with a significant overall concordance (67.14%, κ=0.35, P<0.001). In addition, high Ki-67 index was associated with the Nottingham histological grade in both groups. In conclusion, there was a concordance between Ki-67 and MammaPrint risk stratification of HR+ EIBC and no concordance with the EndoPredict molecular signature, but a positive association with the given percentage of recurrence and the median Ki-67 index as the cutoff at our center. Cost-effectiveness analyses of these tests in developing countries are required; until then, the use of Ki-67 appears reasonable to aid clinical decisions, together with the other established clinicopathological variables.

Molecular, Histological, and Clinical Characteristics of Oligodendrogliomas: A Multi-Institutional Retrospective Study.

BACKGROUND: Reports suggest that phosphatidylinositol 3-kinase pathway alterations confer increased risk of progression and poor prognosis in oligodendroglioma, IDH-mutant, and 1p/19q-codeleted molecular oligodendrogliomas (mODG). However, factors that affect prognosis in mODG have not been thoroughly studied. In addition, the benefits of adjuvant radiation and temozolomide (TMZ) in mODGs remain to be determined. OBJECTIVE: To evaluate the role of PIK3CA mutations in mODGs. METHODS: One hundred seven mODGs (2008-2019) diagnosed at 2 institutions were included. A retrospective review of clinical characteristics, molecular alterations, treatments, and outcomes was performed. RESULTS: The median age was 37 years, and 61 patients (57%) were male. There were 64 (60%) World Health Organization (WHO) grade 2 and 43 (40%) WHO grade 3 tumors. Eighty-two patients (77%) were stratified as high risk (age 40 years or older and/or subtotal resection per Radiation Treatment Oncology Group-9802). Gross-total resection was achieved in 47 patients (45%). Treatment strategies included observation (n = 15), TMZ (n = 11), radiation (n = 13), radiation/TMZ (n = 62), and others (n = 6). Our results show a benefit of TMZ vs observation in progression-free survival (PFS). No difference in PFS or overall survival (OS) was observed between radiation and radiation/TMZ. PIK3CA mutations were detected in 15 (14%) mODG, and shorter OS was observed in PIK3CA-mutant compared with PIK3CA wild-type mODGs (10.7 years vs 15.1 years, P = .009). WHO grade 3 tumors showed a shorter PFS, but no significant difference in OS was observed between WHO grades. CONCLUSION: Our findings suggest that mODGs harboring PIK3CA mutations have worse OS. Except for an advantage in PFS with TMZ treatment, adjuvant TMZ, radiation, or a combination of the two showed no significant improvement in OS.

Antizyme Inhibitor 2-Deficient Mice Exhibit Altered Brain Polyamine Levels and Reduced Locomotor Activity.

BACKGROUND: Alterations in the neural polyamine system are known to be associated with different brain pathological conditions. In addition, the regulation of enzymes involved in polyamine metabolism such as ornithine decarboxylase (ODC), antizymes (AZs), and antizyme inhibitors (AZINs) is critical during brain development. However, while most studies focus on ODC and AZs, less is known about AZIN expression and function in the brain. Thus, our aim was to analyze the expression pattern of AZIN2 during postnatal development, its brain distribution, and its possible implication in phenotypical alterations. METHODS: The expression pattern of Azin2 and other genes related to polyamine metabolism was analyzed by RT-qPCR. ß-D-galactosidase staining was used to determine the anatomical distribution of AZIN2 in a Azin2 knockout model containing the ßGeo marker. Brain polyamine content was determined by HPLC. The Rota-Rod and Pole functional tests were used to evaluate motor skills in Azin2-lacking mice. RESULTS: Our results showed that expression of genes codifying for AZs and AZINs showed a similar increasing pattern over time that coincided with a decrease in ODC activity and putrescine levels. The analysis of AZIN2 distribution demonstrated that it is strongly expressed in the cerebellum and distributed along the neuron body and dendrites. The ablation of Azin2 showed a decrease in putrescine levels and is related to reduced motor skills. CONCLUSIONS: Our study revealed that AZIN2 expression in the brain is particularly limited to the cerebellum. In addition, the ablation of Azin2 leads to a reduction in putrescine that relates to alterations in motor function, suggesting the role of AZIN2 in the functioning of dopaminergic neurons.

Hormone exposure and its suppressive effect on risk of high-grade gliomas among patients with breast cancer.

BACKGROUND: Prior reports demonstrate the expression of estrogen and progesterone receptors in high-grade gliomas (HGGs), but the relationship between hormone receptor-positive disease and risk of HHGs in patients with breast cancer (BC) remains uncharacterized. METHODS: Using the SEER 18 registries (2000-2017), we examined the temporal trend of the incidence of HGGs and BC. The standardized incidence ratio was calculated to assess the risk of subsequent HGG in BC patients. RESULTS: During the study period, the incidence of BC and HGGs remained comparable for men and women. Among 976,134 patients with BC, we found a decreased incidence of HGGs in females, but not in males. Female BC patients with hormone receptor-positive disease were at a lower risk of developing glioblastoma and anaplastic astrocytoma. CONCLUSION: Our study findings allude to the protective role of hormone exposure in the development of HGGs, which may lead to the development of therapies targeting hormonal pathways.

Metastatic colorectal micropapillary carcinoma presenting as lymphangitic lung carcinomatosis.

Pulmonary lymphangitic carcinomatosis denotes the infiltration of tumor cells into the lung parenchymal lymphatic channels. Breast, lung, stomach, and colon adenocarcinoma are the most common origin of this invasion pattern. The micropapillary variant of colorectal adenocarcinoma has a high rate of lymph node metastases and poor overall survival. A 49 year-old man with a 6 months history of persistent cough and a relevant occupational chemical exposure had a computed tomography that showed bilateral interstitial lung infiltrates. The lung biopsy demonstrated a micropapillary adenocarcinoma with diffusely obstruction of the lung parenchymal lymphatics. The immunohistochemistry confirmed a colorectal origin. The colonoscopy evidenced a mass with identical morphology. Colorectal micropapillary carcinoma with metastatic lung lymphangitic carcinomatosis can occur, as a persistent cough, as presenting symptom in extraordinarily rare cases. To the best of our knowledge, this is the first case of an alive patient with colorectal metastatic micropapillary carcinoma presenting with lymphangitic lung carcinomatosis.

Differences in Genomic Alterations Between Brain Metastases and Primary Tumors.

BACKGROUND: Brain metastases (BMs) occur in ∼1/3 of cancer patients and are associated with poor prognosis. Genomic alterations contribute to BM development; however, mutations that predispose and promote BM development are poorly understood. OBJECTIVE: To identify differences in genomic alterations between BM and primary tumors. METHODS: A retrospective cohort of 144 BM patients were tested for genomic alterations (85 lung, 21 breast, 14 melanoma, 4 renal, 4 colon, 3 prostate, 4 others, and 9 unknown carcinomas) by a next-generation sequencing assay interrogating 315 genes. The differences in genomic alterations between BM and primary tumors from COSMIC and TCGA were evaluated by chi-square or Fisher's exact test. Overall survival curves were plotted using the Kaplan-Meier method. RESULTS: The comparison of BM and primary tumors revealed genes that were mutated in BM with increased frequency: TP53, ATR, and APC (lung adenocarcinoma); ARID1A and FGF10 (lung small-cell); PIK3CG, NOTCH3, and TET2 (lung squamous); ERBB2, BRCA2, and AXL1 (breast carcinoma); CDKN2A/B, PTEN, RUNX1T1, AXL, and FLT4 (melanoma); and ATM, AR, CDKN2A/B, TERT, and TSC1 (renal clear-cell carcinoma). Moreover, our results indicate that lung adenocarcinoma BM patients with CREBBP, GPR124, or SPTA1 mutations have a worse prognosis. Similarly, ERBB2, CDK12, or TP53 mutations are associated with worse prognosis in breast cancer BM patients. CONCLUSION: The present study demonstrates significant differences in the frequency of mutations between primary tumors and BM and identifies targetable alterations and genes that correlate with prognosis. Identifying the genomic alterations that are enriched in metastatic central nervous system tumors could help our understanding of BM development and improve patient management.

Immunotyping of tumor-infiltrating lymphocytes in triple-negative breast cancer and genetic characterization.

Tumor-infiltrating lymphocytes (TILs) reflect the host immune response against cancer cells. Immunomodulators have been recently suggested as a novel therapeutic strategy against triple-negative breast cancer (TNBC). However, the TIL profile in TNBC has not been thoroughly investigated. In the present study, the percentage, immunophenotype and genetic profiles of TILs in pre-surgical tumor samples of patients with TNBC were evaluated prior to neoadjuvant chemotherapy (NAC). Patients diagnosed with breast cancer at Hospital San José TecSalud were consecutively and prospectively enrolled in the present study between August 2011 and August 2015. The pathological response to NAC was evaluated using the de Miller-Payne and MD Anderson Cancer Center system. TIL percentage (low, intermediate, and high) was evaluated using special hematoxylin-eosin staining on the core needle biopsies. The immunophenotype of TILs was assessed by immunohistochemistry (IHC) for CD3+, CD4+ and CD8+. In addition, the gene expression profile of CD3, CD4, CD8, CD20, CD45, forkhead box P3, interleukin 6, programmed cell death 1 and CD274 molecule was assessed in all patients. A total of 26 samples from patients with TNBC prior to NAC were included in the present study. TILs were low in 30.7%, intermediate in 38.4% and elevated in 30.7% of tumors. CD3+ and CD4+ counts were associated with the pathological response to NAC (P=0.04). Finally, an overexpression pattern of CD3, CD4, CD8, CD45 and CD20 genes was observed in patients with a partial or complete pathological response. The present results demonstrated that TILs may predict the pathological response to NAC in patients with TNBC. Furthermore, a more accurate association was identified between the high expression levels of CD3, CD4, CD8, CD45 and CD20 genes and partial and complete pathological response, compared with the association between high expression and IHC alone.

A solitary presentation of panniculitis in a patient with a history of breast cancer.

INTRODUCTION: Panniculits presents as an inflammation of the subcutaneous adipose tissue of the skin. In breast, panniculitis is very rare and is usually a manifestation of underlying inflammatory conditions. The typical presentation is palpable tender nodules, which in cases of breast panniculitis, triggers an extensive work up to exclude a malignancy. Herein we present a case of septal and lobar panniculitis in a female with clinical history of invasive ductal carcinoma. PRESENTATION OF THE CASE: A 52-year old female with past medical history of invasive breast carcinoma 5 years prior to the presentation. The patient's chief complaint was a 1-year history of a subcutaneous nodular lesion on her left breast. A core biopsy of the firm nodule showed marked inflammation of the breast. A second skin biopsy showed an abundant chronic inflammatory infiltrate, with lymphocytic vasculitis and neuritis, suggestive of an underlying autoimmune process. DISCUSSION: Subcutaneous panniculitis with or without vasculitis is a rare condition when presenting in the breast. Panniculitis can mimic malignancy and thus, it is important to differentially diagnose it from breast carcinoma. Histologically, it is classified in lobular and septal lymphocytic panniculitis depending on specific diagnostic characteristics. CONCLUSION: Panniculitis of the breast is a rare condition that needs to be included in the differential diagnosis of subcutaneous breast masses. In all cases, but specifically in females with history of breast cancer, panniculitis still should be thought of as a possibility, and imaging as well as other diagnostic techniques can aid in making the correct diagnosis.

Pure mucinous breast carcinoma in a 25-year-old female, a case report.

INTRODUCTION: Mucinous carcinoma is a variant of invasive breast carcinomas representing 2% of them. These tumors frequently develop in postmenopausal females; it is a rare histological variant in young patients. CASE PRESENTATION: A 25-year-old female refers a slow growth mass of 2 years of evolution. Excisional biopsy reveals a pure mucinous carcinoma with positive hormone receptors and negative HER2. She was treated with hormone therapy and surgical resection. DISCUSSION: Mucinous carcinoma is a rare variant reported in young patients. Many series report that is frequently found in postmenopausal patients. We present a case of a pure mucinous carcinoma in a 25-year-old female with the importance of being a low-frequency malignancy in young patients. CONCLUSION: Due to its benign course, it is important to know that this lesion can also present in young patients. The importance underlies in the multidisciplinary management at the right time in a proper way.

Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities.

Chromosomal instability (CIN) is the result of ongoing changes in the number (aneuploidy) and structure of chromosomes. CIN is induced by chromosome missegregation in mitosis and leads to karyotypic diversity within the cancer cell population, thereby adding to intratumor heterogeneity. Regardless of the overall pro-oncogenic function of CIN, its onset is typically detrimental for cell fitness and thus tumors must develop CIN-tolerance mechanisms in order to propagate. There is overwhelming genetic and functional evidence linking mutations in the tumor suppressor TP53 with CIN-tolerance. However, the pathways leading to p53 activation following chromosome missegregation remain controversial. Recently, additional mechanisms have been identified in CIN-surveillance, resulting in a more complex network of pathways acting independently or in cooperation with p53. Tolerance might also be achieved by modifying aspects of the cancer cell physiology in order to attenuate CIN or by adaptation to the consequences of aneuploid karyotypes. In this review, we summarize the current knowledge about p53-dependent and -independent mechanisms of CIN-tolerance in cancer, the adaptations observed in CIN cells buffering CIN levels, its consequences for cellular homeostasis, and the potential of exploiting these adaptations in order to design new cancer therapies.

Generation of a disease-specific iPS cell line derived from a patient with Charcot-Marie-Tooth type 2K lacking functional GDAP1 gene.

Human CMT2-FiPS4F1 cell line was generated from fibroblasts of a patient with Charcot-Marie-Tooth disease harbouring the following mutations in the GDAP1 gene in heterozygosis: p.Q163X/p.T288NfsX3. This patient did not present mutations in the PM22, MPZ or GJB genes. Human reprogramming factors OCT3/4, KLF4, SOX2 and C-MYC were delivered using a non-integrative methodology that involves the use of Sendai virus.

BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer.

Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution.

APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability.

Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization. APC/C impairment caused adaptation to MPS1 inhibitors, revealing a likely resistance mechanism to therapies targeting the spindle assembly checkpoint. Finally, CRISPR-mediated introduction of cancer somatic mutations in the APC/C subunit cancer driver gene CDC27 reduces chromosome segregation errors, whereas reversal of an APC/C subunit nonsense mutation increases CIN. Subtle variations in mitotic duration, determined by APC/C activity, influence the extent of CIN, allowing cancer cells to dynamically optimize fitness during tumor evolution. SIGNIFICANCE: We report a mechanism whereby cancers balance the evolutionary advantages associated with CIN against the fitness costs caused by excessive genome instability, providing insight into the consequence of CDC27 APC/C subunit driver mutations in cancer. Lengthening of mitosis through APC/C modulation may be a common mechanism of resistance to cancer therapeutics that increase chromosome segregation errors. Cancer Discov; 7(2); 218-33. ©2017 AACR.See related commentary by Burkard and Weaver, p. 134This article is highlighted in the In This Issue feature, p. 115.

Dysfunctional mitochondrial fission impairs cell reprogramming.

We have recently shown that mitochondrial fission is induced early in reprogramming in a Drp1-dependent manner; however, the identity of the factors controlling Drp1 recruitment to mitochondria was unexplored. To investigate this, we used a panel of RNAi targeting factors involved in the regulation of mitochondrial dynamics and we observed that MiD51, Gdap1 and, to a lesser extent, Mff were found to play key roles in this process. Cells derived from Gdap1-null mice were used to further explore the role of this factor in cell reprogramming. Microarray data revealed a prominent down-regulation of cell cycle pathways in Gdap1-null cells early in reprogramming and cell cycle profiling uncovered a G2/M growth arrest in Gdap1-null cells undergoing reprogramming. High-Content analysis showed that this growth arrest was DNA damage-independent. We propose that lack of efficient mitochondrial fission impairs cell reprogramming by interfering with cell cycle progression in a DNA damage-independent manner.

Tissue-specific regulation of potassium homeostasis by high doses of cationic amino acids.

The administration of l-arginine hydrochloride has been used for testing pituitary secretion in humans, and as an experimental model for induction of acute pancreatitis in rats and mice. Whereas in the first case, the administration of the amino acid is associated with hiperkalemia, in the model of acute pancreatitis no data are available on possible changes in potassium homeostasis. The present study shows that the acute administration to mice of l-arginine hydrochloride or other cationic amino acids almost duplicate plasma potassium levels. This effect was associated to a marked decrease of tissue potassium in both pancreas and liver. No changes were found in other tissues. These changes cannot be ascribed to the large load of chloride ions, since similar effects were produced when l-ornithine aspartate was administered. The changes in potassium levels were dependent on the dose. The displacement of intracellular potassium from the liver and pancreas to the extracellular compartment appears to be dependent on the entry of the cationic amino acid, since the administration of an equivalent dose of alfa-difluoromethyl ornithine HCl (DFMO), a non physiological analog of l-ornithine, which is poorly taken by the tissues in comparison with the physiological cationic amino acids, did not produce any change in potassium levels in pancreas and liver. The analyses of the expression of cationic amino acid transporters (CAT) suggest that the CAT-2 transporter may be implicated in the potassium/cationic amino acid interchange in liver and pancreas. The possible physiological or pathological relevance of these findings is discussed.

Early ERK1/2 activation promotes DRP1-dependent mitochondrial fission necessary for cell reprogramming.

During the process of reprogramming to induced pluripotent stem (iPS) cells, somatic cells switch from oxidative to glycolytic metabolism, a transition associated with profound mitochondrial reorganization. Neither the importance of mitochondrial remodelling for cell reprogramming, nor the molecular mechanisms controlling this process are well understood. Here, we show that an early wave of mitochondrial fragmentation occurs upon expression of reprogramming factors. Reprogramming-induced mitochondrial fission is associated with a minor decrease in mitochondrial mass but not with mitophagy. The pro-fission factor Drp1 is phosphorylated early in reprogramming, and its knockdown and inhibition impairs both mitochondrial fragmentation and generation of iPS cell colonies. Drp1 phosphorylation depends on Erk activation in early reprogramming, which occurs, at least in part, due to downregulation of the MAP kinase phosphatase Dusp6. Taken together, our data indicate that mitochondrial fission controlled by an Erk-Drp1 axis constitutes an early and necessary step in the reprogramming process to pluripotency.