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Ovarian cancer ascites fluid contains matrix proteins that can impact tumor growth via integrin receptor binding. In human ovarian tumor tissue arrays, we find that activation of the cytoplasmic focal adhesion (FAK) tyrosine kinase parallels increased tumor stage, β5 integrin, and osteopontin matrix staining. Elevated osteopontin, β5 integrin, and FAK mRNA levels are associated with decreased serous ovarian cancer patient survival. FAK remains active within ovarian cancer cells grown as spheroids, and anchorage-independent growth analyses of seven ovarian carcinoma cell lines identified sensitive (HEY, OVCAR8) and resistant (SKOV3-IP, OVCAR10) cells to 0.1 μmol/L FAK inhibitor (VS-4718, formerly PND-1186) treatment. VS-4718 promoted HEY and OVCAR8 G0–G1 cell-cycle arrest followed by cell death, whereas growth of SKOV3-IP and OVCAR10 cells was resistant to 1.0 μmol/L VS-4718. In HEY cells, genetic or pharmacological FAK inhibition prevented tumor growth in mice with corresponding reductions in β5 integrin and osteopontin expression. β5 knockdown reduced HEY cell growth in soft agar, tumor growth in mice, and both FAK Y397 phosphorylation and osteopontin expression in spheroids. FAK inhibitor–resistant (SKOV3-IP, OVCAR10) cells exhibited anchorage-independent Akt S473 phosphorylation, and expression of membrane-targeted and active Akt in sensitive cells (HEY, OVCAR8) increased growth but did not create a FAK inhibitor–resistant phenotype. These results link osteopontin, β5 integrin, and FAK in promoting ovarian tumor progression. β5 integrin expression may serve as a biomarker for serous ovarian carcinoma cells that possess active FAK signaling. Mol Cancer Ther; 13(8); 2050–61. ©2014 AACR.

PDF file - 44K, Antibodies, DNA plasmids, and probe sets used in this study.

PDF file - 138K, Integrin surface expression in HEY beta5 integrin knockdown cells.

PDF file - 66K, qPCR verification of beta5 transcripts.

PDF file - 315K, Cell survival and cell cycle progression analyses of VS-4718 FAK inhibitor sensitive (HEY and OVCAR8) and resistant (OVCAR10 and SKOV3-IP) cells.

PDF file - 112K, Pharmacological FAK inhibition decreases beta5 integrin and osteopontin (OPN) levels in ID8-IP cells in vivo.

PDF file - 894K, FAK and pY397 FAK immunostaining of human tissue array.

PDF file - 70K, Background information on the breast and ovarian carcinoma cell lines used in this study.

PDF file - 59K

Supplementary Table 1, Figures 1-5 from Epidermal Growth Factor Receptor/β-Catenin/T-Cell Factor 4/Matrix Metalloproteinase 1: A New Pathway for Regulating Keratinocyte Invasiveness after UVA Irradiation

Previous studies have established that UV irradiation results in epidermal growth factor receptor (EGFR) activation in keratinocytes. However, the signaling pathways and cellular effects related to this process remain incompletely elucidated. Herein, we describe for the first time that UVA-mediated EGFR activation results in β-catenin tyrosine phosphorylation at the Y654 residue responsible for the dissociation of E-cadherin/α-catenin/β-catenin complexes. Moreover, UVA induces an EGFR-dependent, but Wnt-independent, β-catenin relocalization from the membrane to the nucleus followed by its association with T-cell factor 4 (TCF4). This newly formed β-catenin/TCF4 complex binds to a specific site on matrix metalloproteinase 1 (MMP1) promoter and governs MMP1 gene and protein expression, as well as cell migration in collagen and gelatin. Altogether, these results suggest that UVA stimulates keratinocyte invasiveness through two coordinated EGFR-dependent processes: loss of cell-to-cell contact due to β-catenin/E-cadherin/α-catenin dissociation and increased cell migration through extracellular matrix component degradation due to β-catenin/TCF4–dependent MMP1 regulation. These events may represent an important step in epidermis repair following UVA injury and their abnormal regulation could contribute to photoaging and photocarcinogenesis. [Cancer Res 2009;69(8):3291–9]

Background Real-world knowledge of the burden of hidradenitis suppurativa (HS) on patients remains limited. Objectives To measure the impact of adalimumab on moderate-to-severe HS patients’ health-related quality of life (HRQoL) and work productivity. Methods In 23 Canadian centres, 138 adults with moderate-to-severe HS requiring a change in ongoing therapy were treated with adalimumab for up to 52 weeks as per the physician’s practice. Patient-reported outcome measures (PROMs) were obtained at baseline, weeks 24 and 52 to measure overall HRQoL, HS severity, levels of anxiety and depression, impact and symptoms of HS, work productivity and activity impairment. A post-hoc analysis further explored the PROMs by abscess and inflammatory nodule (AN) count at baseline (≤5, low; 6–10, medium; ≥11, high). Results From baseline to weeks 24 and 52, all PRO overall scores improved significantly ( P ≤ .0023). The number of patients reporting “good disease control” and “complete disease control” increased from 9.7% to 66.4% over 52 weeks. The score in Health Utility Index Mark 3 (HUI3) pain attribute meaningfully decreased over 52 weeks (mean difference ≥.05). The HS symptoms skin “tenderness” and “itchiness” improved the most. Work productivity loss and activity impairment improved by approximately 20% over 52 weeks. Disease burden improved more in 24 week responders with low and medium AN counts at baseline than in those with high AN count or in 24 week nonresponders. Conclusion At week 24 and maintained at week 52 in a real-world setting, adalimumab meaningfully improved HRQoL, work productivity, and activity impairment in moderate-to-severe HS patients.

Research Letter There are few data on long-term effects and quality of life impact of peanut OIT. PPOIT was shown to induce 8-week sustained unresponsiveness that persists to 3-years post-treatment after ad libitum peanut ingestion. PPOIT provides lasting benefits for children with peanut allergy, with long-lasting improvement in health-related quality of life.

Additional file 1: Fig. S1. Amplicon products at 1% agarose with the DNA marker (1 Kb plus ladder, Invitrogen). Amplicons showed the good quality of single and intense band for each sample with 400–600 bp size target, were purified using Exosap IT to remove the unnecessary smears and other possible inhibitors.

Importance: Surgery is a mainstay in the management of hidradenitis suppurativa (HS). Adalimumab is the first drug approved for HS. Objective: To investigate the efficacy and safety of adalimumab in combination with wide-excision surgery followed by secondary intention healing. Design, Setting, and Participants: The Safety and Efficacy of Adalimumab for Hidradenitis Suppurativa Peri-Surgically (SHARPS) trial was a phase 4, randomized, double-blind, placebo-controlled study of adalimumab in conjunction with surgery. Patients were enrolled in 45 sites across 20 countries from July 18, 2016, to February 2, 2019, with the last patient visit on October 16, 2019. Eligible patients (aged 18-65 years) had moderate to severe HS that required radical surgery in an axillary or inguinal region and had 2 other anatomical regions affected, with 1 or more regions at Hurley stage II or III. Analysis was conducted in November 2019. Interventions: Patients were randomized 1:1 to receive continuous adalimumab, 40 mg, or placebo during presurgery (12 weeks), perioperative (2 weeks), and postoperative (10 weeks) periods. Main Outcomes and Measures: The primary end point was the proportion of patients achieving HS clinical response across all body regions at week 12. Results: Overall, 103 patients were randomized to adalimumab and 103 to matching placebo. Among all patients, 51% (n = 106) were women, 94% (n = 193) were White, and the mean (SD) age was 37.6 (11.3) years. At week 12, significantly more patients receiving adalimumab (49 of 103 [48%]) vs placebo (35 of 103 [34%]; P =.049) achieved HS clinical response across all body regions (treatment difference, 14% [95% CI, 0%-27%]). Treatment-emergent adverse events were reported in 74 of 103 patients (72%) and 69 of 103 patients (67%) in the adalimumab and placebo groups, respectively. No increased risk of postoperative wound infection, complication, or hemorrhage was observed with adalimumab vs placebo. Two deaths occurred in the adalimumab group; neither was considered as having a reasonable possibility of relationship to study drug. Conclusions and Relevance: Adalimumab was efficacious in conjunction with wide-excision surgery followed by secondary intention healing, with no need to interrupt treatment prior to surgery. These data support further investigation of adalimumab as an adjuvant therapy to surgery in patients with moderate to severe HS. Trial Registration: ClinicalTrials.gov Identifier: NCT02808975.

OBJECTIVE The first objective was to identify a method for early prediction of independent outdoor functional walking 1 yr after a traumatic spinal cord injury using the motor and sensory function derived from the International Standards for Neurological Classification of Spinal Cord Injury assessment during acute care. Then, the second objective was to develop a clinically relevant prediction rule that would be accurate, easy to use, and quickly calculated in clinical setting. DESIGN A prospective cohort of 159 traumatic spinal cord injury patients was analyzed. Bivariate correlations were used to determine the assessment method of motor strength and sensory function as well as the specific dermatomes and myotomes best associated with independent outdoor functional walking 1 yr after injury. An easy-to-use clinical prediction rule was produced using a multivariable linear regression model. RESULTS The highest motor strength for a given myotome (L3 and L5) and preserved light touch sensation (dermatome S1) were the best predictors of the outcome. The proposed prediction rule displayed a sensitivity of 84.21%, a specificity of 85.54%, and a global accuracy of 84.91% for classification. CONCLUSIONS After an acute traumatic spinal cord injury, accurately predicting the ability to walk is challenging. The proposed clinical prediction rule aims to enhance previous work by identifying traumatic spinal cord injury patients who will reach a mobility level that fosters social participation and quality of life in the chronic period after the injury. TO CLAIM CME CREDITS Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME. CME OBJECTIVES Upon completion of this article, the reader should be able to: (1) Revise the different motor and sensory function assessment methods used for prognostication of walking after an acute traumatic spinal cord injury; (2) Identify clinical factors that are significantly associated with functional walking 1 yr after a traumatic spinal cord injury; and (3) Accurately estimate the likelihood of reaching independent outdoor functional walking in the chronic phase after an acute traumatic spinal cord injury. LEVEL Advanced. ACCREDITATION The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Pancreatic ductal adenocarcinoma (PDAC) aggressiveness results from its high metastatic and chemoresistance potential. Pancreatic cancer cells are immersed in an exuberant tumor microenvironment (or stroma), which represents up to 80% of PDAC tumor volume, and is hijacked by cancer cells for their own survival and metastasis. Additionally, PDAC tumors are heterogeneous, e.g. transcriptomic (RNAseq) analyses of human PDAC tumors have allowed patients to be stratified into two tumor subgroups (basal and classical) with different prognoses. Therefore, we aimed to understand which tumor-stroma crosstalks are critical for PDAC aggressiveness in the context of its heterogeneity, and how they can be pharmacologically targeted, to then propose more effective personalized therapeutic strategies. By performing bioinformatical analysis on RNAseq data from PDX (Patient Derived Xenograft), a hybrid tumor model from which human-derived tumor cell sequences are distinguishable from murine-derived stromal cell sequences, we searched for different stromal behaviors linked to the tumor aggressiveness, to be then validated in published PDAC patient databases. According to NMF (Non-negative matrix factorization) and GSEA (Gene Set Enrichment Analyses), we identified two components, which classify the samples according to a stromal gradient. Interestingly, these components are characterized by distinct functional signatures of aggressiveness and they are highly prognostic (correlated with survival). In addition, these components stratify patients independently on the described molecular tumor (basal or classical) classification. Importantly, we validated those results on other PDAC published databases. Moreover, ligand-receptor bioinformatics analyses identified novel players of the TGFβ superfamily in the most aggressive stromal component. Indeed, we have highlighted the involvement of the ligand activin a member of this large superfamily. Using in situ hybridization coupled with immunofluorescence, we were able to demonstrate that activin is only expressed by stromal cells, and more specifically by cancer associated fibroblasts (CAF), with however a strong heterogeneity (inter and intra-tumor). In vitro, activin strongly increases the migratory capacity of fibroblasts but also of specific cancer cells, this effect being effectively blocked pharmacologically with an activin receptor-targeting drug that is now tested in a pre-clinical PDAC murine model. Therapeutic targeting of the stroma must take into account its functional heterogeneity. We have identified in specific aggressive PDAC tumors novel stromal players involved in the tumor-stroma symbiosis, and which presumably play a critical role in CAFs and cancer cells migration and invasion. Our work should enable to delineate which stroma-targeting drug to co-deliver, in addition to chemotherapies, in stratified patients, to improve PDAC prognosis. Citation Format: Alexia Brunel, Jérôme Raffenne, Remy Nicolle, Ilse Rooman, Elisa Espinet, Marjorie Fanjul, Aurélie Perraud, Muriel Mathonnet, Sophie Vasseur, Nelson Dusetti, Yvan Martineau, Christine Jean, Corinne Bousquet. Bioinformatical identification of cancer-associated-fibroblasts with tumor cells pro-migratory crosstalks depending on activin [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C034.

Simple Summary Stroma modifications observed in solid cancer are now recognized as critical events for cancer progression and as potential therapeutic or diagnostic targets. The recent appreciation of multiple but complex roles of the extracellular matrix (ECM) in cancer, and of the cancer-associated fibroblast (CAF) diversity, has revolutionized the field and raised innovative but challenging questions. In this review, we summarize the latest knowledge regarding the role of the ECM in cancer progression, discuss the potential use of such stromal pro-tumoral modifications as therapeutic or diagnostic targets, and, finally, discuss benefits, disappointments, or even failures, of recently reported stroma-targeting strategies. Abstract Solid cancer progression is dictated by neoplastic cell features and pro-tumoral crosstalks with their microenvironment. Stroma modifications, such as fibroblast activation into cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling, are now recognized as critical events for cancer progression and as potential therapeutic or diagnostic targets. The recent appreciation of the key, complex and multiple roles of the ECM in cancer and of the CAF diversity, has revolutionized the field and raised innovative but challenging questions. Here, we rapidly present CAF heterogeneity in link with their specific ECM remodeling features observed in cancer, before developing each of the impacts of such ECM modifications on tumor progression (survival, angiogenesis, pre-metastatic niche, chemoresistance, etc.), and on patient prognosis. Finally, based on preclinical studies and recent results obtained from clinical trials, we highlight key mechanisms or proteins that are, or may be, used as potential therapeutic or diagnostic targets, and we report and discuss benefits, disappointments, or even failures, of recently reported stroma-targeting strategies.

Cancer‐associated fibroblasts (CAFs) are considered the most abundant type of stromal cells in pancreatic ductal adenocarcinoma (PDAC), playing a critical role in tumour progression and chemoresistance; however, a druggable target on CAFs has not yet been identified. Here we report that focal adhesion kinase (FAK) activity (evaluated based on 397 tyrosine phosphorylation level) in CAFs is highly increased compared to its activity in fibroblasts from healthy pancreas. Fibroblastic FAK activity is an independent prognostic marker for disease‐free and overall survival of PDAC patients (cohort of 120 PDAC samples). Genetic inactivation of FAK within fibroblasts (FAK kinase‐dead, KD) reduces fibrosis and immunosuppressive cell number within primary tumours and dramatically decreases tumour spread. FAK pharmacologic or genetic inactivation reduces fibroblast migration/invasion, decreases extracellular matrix (ECM) expression and deposition by CAFs, modifies ECM track generation and negatively impacts M2 macrophage polarization and migration. Thus, FAK activity within CAFs appears as an independent PDAC prognostic marker and a druggable driver of tumour cell invasion., Understanding how cancer‐associated fibroblasts (CAFs) promote PDAC progression is of major interest given the poor prognosis of patients. This study identifies a druggable key regulator of CAF‐induced tumour cell metastasis and a prognostic factor: the protein Focal Adhesion Kinase (FAK).

The MNK1 protein kinase is directly activated by the MAPK pathway and is specifically expressed in pancreatic acinar cells. Both the MNK1 kinase and the MAPK pathway are required for response to pancreatitis, suggesting that their pharmacological targeting would be of therapeutic interest. Because the mRNA cap-binding protein and translation initiation factor eIF4E is the major known MNK1 substrate, one could anticipate that the protective function of MNK1 in pancreatitis is mediated by eIF4E phosphorylation.Acute pancreatitis was induced by the intraperitoneal administration of cerulein in wild-type mice and in transgenic mice carrying two non-phosphorylatable Eif4e alleles. The expression and phosphorylation of proteins of the MNK1-eIF4E pathway was visualized by western-blotting. The severity of pancreatitis was monitored by the measure of serum amylase levels and by histopathology and immunohistochemistry using apoptosis and immune infiltrate markers.Despite a strong induction in MNK1 kinase activity in both wild-type and transgenic mice, precluding eIF4E phosphorylation has no impact on the severity of acute pancreatitis. Serum amylase is equally induced in both mouse genotypes and neither acinar cell apoptosis nor immune infiltrate is exacerbated.eIF4E phosphorylation is not required for response to pancreatitis indicating that the acinar-cell-specific MNK1 kinase acts in acute pancreatitis via another substrate.

Background & Aims Cancer-associated fibroblasts (CAFs) from pancreatic adenocarcinoma (PDA) present high protein synthesis rates. CAFs express the G-protein–coupled somatostatin receptor sst1. The sst1 agonist SOM230 blocks CAF protumoral features in vitro and in immunocompromised mice. We have explored here the therapeutic potential of SOM230, and underlying mechanisms, in immunocompetent models of murine PDA mimicking the heavy fibrotic and immunosuppressive stroma observed in patient tumors. Methods Large-scale mass spectrometry analyses were performed on media conditioned from 9 patient PDA-derived CAF primary cultures. Spontaneous transgenic and experimental (orthotopic co-graft of tumor cells plus CAFs) PDA-bearing mice were longitudinally ultrasound-monitored for tumor and metastatic progression. Histopathology and flow cytometry analyses were performed on primary tumors and metastases. Stromal signatures were functionally validated through bioinformatics using several published, and 1 original, PDA database. Results Proteomics on the CAF secretome showed that SOM230 controls stromal activities including inflammatory responses. Among the identified secreted proteins, we validated that colony-stimulating factor 1 (CSF-1) (a macrophage growth factor) was reduced by SOM230 in the tumor and plasma of PDA-harboring mice, alongside intratumor stromal normalization (reduced CAF and macrophage activities), and dramatic metastasis reduction. In transgenic mice, these SOM230 benefits alleviate the chemotherapy-induced (gemcitabine) immunosuppressive stroma reshaping. Mechanistically, SOM230 acts in vivo on CAFs through sst1 to disrupt prometastatic CAF production of CSF-1 and cross-talk with macrophages. We found that in patients, stromal CSF-1 was associated with aggressive PDA forms. Conclusions We propose SOM230 as an antimetastatic therapy in PDA for its capacity to remodel the fibrotic and immunosuppressive myeloid stroma. This pharmacotherapy should benefit PDA patients treated with chemotherapies., Graphical abstract

Molecular profiling of Pancreatic Ductal Adenocarcinoma (PDA), based on transcriptomic analyses, identifies two main prognostic subtypes (basal-like and classical), but does not allow personalized first-line treatment. To date, tumors have not been profiled based on protein synthesis rates, yet the step of mRNA translation is highly dysregulated in both PDA cancer cells and their microenvironment. We aim at assessing whether quantification of mRNA translation could provide a distinct perspective on PDA and identify novel tumor subtypes. Using a collection of twenty-seven pancreatic Patient-Derived Xenografts (PDX), we performed transcriptome-wide analysis of translated mRNA (translatome). Unsupervised bioinformatics analysis allowed PDA tumors classification according to mRNA translation rate. PDX-derived cancer cells as well as common PDA cell lines were used to functionally characterize newly identified subtype. Independent component analysis revealed a new tumor subtype harboring a low protein synthesis rate, but associated with a robust translation of mRNAs encoding effectors of the integrated stress response (ISR), including the transcription factor ATF4. Functional characterization of the “ISR-activated” human cancer cells revealed a high resistance to drugs, low autophagic capacities, and importantly, metabolic impairments in the serine synthesis and transsulfuration pathways. Therefore, the drug-resistant cancer cell phenotype showing auxotrophy to both serine and cysteine may be amenable to targeted therapy. Overall, our study highlights profiling of mRNA translation in cancer as an underexplored avenue for identification of previously unrecognized subtypes together with potential treatments. Citation Format: Sauyeun Shin, Remy Nicolle, Mehdi Liauzun, Jacobo Solorzano, Alexia Brunel, Christine Jean, Remi Samain, Jerôme Raffenne, Cindy Neuzillet, Carine Joffre, Stephane Rocci, Juan Iovanna, Nelson Dusetti, Ola Larsson, Stephane Pyronnet, Corinne Bousquet, Yvan Martineau. Classification based on efficiency of mRNA translation reveals a metabolically-dependent subtype of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-088.

Molecular profiling of Pancreatic Ductal Adenocarcinoma (PDA), based on transcriptomic analyses, identifies two main prognostic subtypes (basal-like and classical), but does not allow personalized first-line treatment. To date, tumors have not been profiled based on protein synthesis rates, yet the step of mRNA translation is highly deregulated in both PDA cancer cells and their microenvironment. Using a collection of twenty-seven pancreatic Patient-Derived Xenografts (PDX), we performed genome-wide analysis of translated mRNA (translatome). Unsupervised bioinformatics analysis revealed a new tumor subtype harboring a low protein synthesis rate, but associated with a robust translation of mRNAs encoding effectors of the integrated stress response (ISR), including the transcription factor ATF4. Functional characterization of the “ISR-activated” human cancer cells revealed a high resistance to drugs, low autophagic capacities, and importantly, metabolic impairments in the serine synthesis and transsulfuration pathways. Overall, our study highlights the strength of translatomic profiling on PDA, which here revealed an unforeseen drug-resistant cancer cell phenotype, whose auxotrophy to both serine and cysteine may be amenable to targeted therapy.

Pancreatic ductal adenocarcinoma (PDAC) relies on hyperactivated protein synthesis. Consistently, human and mouse PDAC lose expression of the translational repressor and mTOR target 4E-BP1. Using genome-wide polysome profiling, we here explore mRNAs whose translational efficiencies depend on the mTOR/4E-BP1 axis in pancreatic cancer cells. We identified a functional enrichment for mRNAs encoding DNA replication and repair proteins, including RRM2 and CDC6. Consequently, 4E-BP1 depletion favors DNA repair and renders DNA replication insensitive to mTOR inhibitors, in correlation with a sustained protein expression of CDC6 and RRM2, which is inversely correlated with 4E-BP1 expression in PDAC patient samples. DNA damage and pancreatic lesions induced by an experimental pancreatitis model uncover that 4E-BP1/2-deleted mice display an increased acinar cell proliferation and a better recovery than WT animals. Targeting translation, independently of 4E-BP1 status, using eIF4A RNA helicase inhibitors (silvestrol derivatives) selectively modulates translation and limits CDC6 expression and DNA replication, leading to reduced PDAC tumor growth. In summary, 4E-BP1 expression loss during PDAC development induces selective changes in translation of mRNA encoding DNA replication and repair protein. Importantly, targeting protein synthesis by eIF4A inhibitors circumvents PDAC resistance to mTOR inhibition.

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance., eLife digest Ovarian cancer is one of the deadliest types of cancer in women. There are two main reasons for the aggressiveness of this cancer. First, ovarian cancer cells can spread to other parts of a woman’s body before she has been diagnosed, where the cells grow as tiny clumps or spheres of tumor cells, also called tumorspheres. Second, in the majority of patients, some ovarian cancer cells will develop resistance to the chemotherapy used. It is not clear exactly how these tumor cells become resistant to therapy. One way in which cells could do this is by gaining extra copies of genes that remove toxic substances or repair DNA, which help them withstand the therapy. Here, Osterman, Ozmadenci, Keinschmidt, Taylor, Barrie, Jiang, Bean, Sulzmaier et al. set up a new experimental method to study how some ovarian cancer cells resist chemotherapy. Comparing ovarian cancer cells from mice at early and late stages of the disease showed that the later-stage, more aggressive cells had more genetic changes. One of these changes affected the gene for a protein called FAK, which was found to have more copies than normal. The FAK protein is an enzyme that helps cancer cells move around. In cells from mice with late-stage cancer, FAK was over-active and present at high levels. When these cells grew as tumorspheres, the tumors were more resistant to chemotherapy than their early-stage counterparts. In patients who have received chemotherapy, surviving tumor cells also exhibit high levels of FAK activity. Human ovarian cancer cells that are resistant to chemotherapy can be grown into tumors in mice, where they retain their resistance to chemotherapy. However, if chemotherapy is combined with a drug that targets the FAK enzyme, the tumors shrink. This experiment highlights a possible weak spot of these tumor cells. To understand how FAK makes ovarian cancer cells resistant to chemotherapy, Osterman et al. deleted the gene for FAK from the cells and then looked at how this changed the levels of activation of different genes. They found that, in addition to its effects on cell movement, FAK also activated a group of genes that increase resistance to chemotherapy and repair damaged DNA. This better understanding of how ovarian cancer cells resist chemotherapy could lead to new therapies. In particular, there is now a clinical trial for women with chemo-resistant ovarian cancer in which standard chemotherapy is combined with an inhibitor of the FAK protein.