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Energetic regulation of coordinated leader-follower dynamics during collective invasion of breast cancer cells.
Zhang J, Goliwas KF, Wang W, Taufalele PV, Bordeleau F, Reinhart-King CA
(2019) Proc Natl Acad Sci U S A 116: 7867-7872
MeSH Terms: Adenosine Diphosphate, Adenosine Triphosphate, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Energy Metabolism, Female, Glucose, Humans, Intracellular Space, Neoplasm Invasiveness
Show Abstract · Added April 10, 2019
The ability of primary tumor cells to invade into adjacent tissues, followed by the formation of local or distant metastasis, is a lethal hallmark of cancer. Recently, locomoting clusters of tumor cells have been identified in numerous cancers and associated with increased invasiveness and metastatic potential. However, how the collective behaviors of cancer cells are coordinated and their contribution to cancer invasion remain unclear. Here we show that collective invasion of breast cancer cells is regulated by the energetic statuses of leader and follower cells. Using a combination of in vitro spheroid and ex vivo organoid invasion models, we found that cancer cells dynamically rearrange leader and follower positions during collective invasion. Cancer cells invade cooperatively in denser collagen matrices by accelerating leader-follower switching thus decreasing leader cell lifetime. Leader cells exhibit higher glucose uptake than follower cells. Moreover, their energy levels, as revealed by the intracellular ATP/ADP ratio, must exceed a threshold to invade. Forward invasion of the leader cell gradually depletes its available energy, eventually leading to leader-follower transition. Our computational model based on intracellular energy homeostasis successfully recapitulated the dependence of leader cell lifetime on collagen density. Experiments further supported model predictions that decreasing the cellular energy level by glucose starvation decreases leader cell lifetime whereas increasing the cellular energy level by AMP-activated kinase (AMPK) activation does the opposite. These findings highlight coordinated invasion and its metabolic regulation as potential therapeutic targets of cancer.
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11 MeSH Terms
Modulation of cell adhesion and migration through regulation of the immunoglobulin superfamily member ALCAM/CD166.
von Lersner A, Droesen L, Zijlstra A
(2019) Clin Exp Metastasis 36: 87-95
MeSH Terms: Activated-Leukocyte Cell Adhesion Molecule, Animals, Cell Adhesion, Cell Movement, Gene Expression Regulation, Neoplastic, Humans, Neoplasm Invasiveness, Neoplasms
Show Abstract · Added April 10, 2019
In epithelial-derived cancers, altered regulation of cell-cell adhesion facilitates the disruption of tissue cohesion that is central to the progression to malignant disease. Although numerous intercellular adhesion molecules participate in epithelial adhesion, the immunoglobulin superfamily (IgSF) member activated leukocyte cell adhesion molecule (ALCAM), has emerged from multiple independent studies as a central contributor to tumor progression. ALCAM is an archetypal member of the IgSF with conventional organization of five Ig-like domains involved in homo- and heterotypic adhesions. Like many IgSF members, ALCAM is broadly expressed and involved in cellular adhesion across many cellular processes. While the redundancy of intercellular adhesion molecules (CAMs) could diminish the impact of any single CAM, consistent correlation between ALCAM expression and patient outcome for multiple cancers underscores its role in tumor progression. Unlike most oncogenes and tumor suppressors, ALCAM is neither mutated nor amplified or deleted. Experimental disruption of ALCAM-mediated adhesions implies that this IgSF member contributes to tumor progression through dynamic turnover of the protein at the cell surface. Since ALCAM is not frequently altered at the gene level, it appears to promote malignant behavior through regulation of its availability rather than its specific activity. These observations help explain its heterogeneous expression within malignant disease and the drastic changes in protein levels across tumor progression. To reveal how ALCAM contributes to tumor progression, we review regulation of its gene expression, alternative splicing, targeted proteolysis, binding partners, and surface shedding within the context of cancer. Studying ALCAM regulation has led to a novel understanding of the fine-tuning of cell adhesive state through the utilization of otherwise normal regulatory processes, which thereby enable tumor cell invasion and metastasis.
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8 MeSH Terms
Cumulative incidence of neck recurrence with increasing depth of invasion.
Shinn JR, Wood CB, Colazo JM, Harrell FE, Rohde SL, Mannion K
(2018) Oral Oncol 87: 36-42
MeSH Terms: Aged, Female, Follow-Up Studies, Glossectomy, Humans, Incidence, Lymph Nodes, Lymphatic Metastasis, Male, Middle Aged, Neck, Neoplasm Invasiveness, Neoplasm Recurrence, Local, Neoplasm Staging, Retrospective Studies, Tongue, Tongue Neoplasms, Treatment Outcome
Show Abstract · Added November 7, 2019
OBJECTIVE - To determine if there is a critical depth of invasion that predicts micrometastasis in early oral tongue cancer.
METHODS - Retrospective series identifying patients undergoing primary surgical resection of T1 or T2 oral tongue cancer who elected against neck treatment between 2000 and 2015. Cox proportional-hazard model compared the relative hazard and cumulative incidence of recurrence to depth of invasion. The model used a 2 parameter quadratic effect for depth that was chosen based on Akaike's information criterion.
RESULTS - Ninety-three patients were identified with T1 or T2 oral tongue squamous cell carcinoma and clinically N0 neck undergoing glossectomy without elective neck treatment. 61% were male and median age was 60 years. Median follow up was 45 months, and 76 patients had at least two years of follow up. Thirty-six of 76 patients recurred (47.4%), with 15 recurring in the oral cavity (19.7%) and 21 developing nodal metastasis (27.6%). Cox proportional-hazards quadratic polynomial showed increasing hazard of recurrence with depth of invasion and the cumulative incidence increased sharply within the range of data from 2 to 6 mm depth of invasion.
CONCLUSIONS - Depth of invasion is significantly associated with nodal metastasis and has been added to the 8th AJCC staging guidelines. Variable depths of invasion have been associated with regional metastasis; however, there is likely not a critical depth that predicts neck recurrence due to progressive hazards and cumulative risk of occult metastasis. The risk of regional metastasis is likely much greater than previously believed and increases progressively with increasing depth.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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18 MeSH Terms
Emerin Deregulation Links Nuclear Shape Instability to Metastatic Potential.
Reis-Sobreiro M, Chen JF, Novitskaya T, You S, Morley S, Steadman K, Gill NK, Eskaros A, Rotinen M, Chu CY, Chung LWK, Tanaka H, Yang W, Knudsen BS, Tseng HR, Rowat AC, Posadas EM, Zijlstra A, Di Vizio D, Freeman MR
(2018) Cancer Res 78: 6086-6097
MeSH Terms: Animals, Apoptosis, Biomarkers, Tumor, Cell Line, Tumor, Cell Movement, Cell Nucleus, Disease Progression, Gene Expression Regulation, Neoplastic, Humans, Male, Membrane Proteins, Mice, Mice, SCID, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplastic Cells, Circulating, Nuclear Envelope, Nuclear Proteins, Prostatic Neoplasms
Show Abstract · Added April 10, 2019
Abnormalities in nuclear shape are a well-known feature of cancer, but their contribution to malignant progression remains poorly understood. Here, we show that depletion of the cytoskeletal regulator, Diaphanous-related formin 3 (DIAPH3), or the nuclear membrane-associated proteins, lamin A/C, in prostate and breast cancer cells, induces nuclear shape instability, with a corresponding gain in malignant properties, including secretion of extracellular vesicles that contain genomic material. This transformation is characterized by a reduction and/or mislocalization of the inner nuclear membrane protein, emerin. Consistent with this, depletion of emerin evokes nuclear shape instability and promotes metastasis. By visualizing emerin localization, evidence for nuclear shape instability was observed in cultured tumor cells, in experimental models of prostate cancer, in human prostate cancer tissues, and in circulating tumor cells from patients with metastatic disease. Quantitation of emerin mislocalization discriminated cancer from benign tissue and correlated with disease progression in a prostate cancer cohort. Taken together, these results identify emerin as a mediator of nuclear shape stability in cancer and show that destabilization of emerin can promote metastasis. This study identifies a novel mechanism integrating the control of nuclear structure with the metastatic phenotype, and our inclusion of two types of human specimens (cancer tissues and circulating tumor cells) demonstrates direct relevance to human cancer. http://cancerres.aacrjournals.org/content/canres/78/21/6086/F1.large.jpg .
©2018 American Association for Cancer Research.
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19 MeSH Terms
Quantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis.
Stoletov K, Willetts L, Paproski RJ, Bond DJ, Raha S, Jovel J, Adam B, Robertson AE, Wong F, Woolner E, Sosnowski DL, Bismar TA, Wong GK, Zijlstra A, Lewis JD
(2018) Nat Commun 9: 2343
MeSH Terms: Animals, Cell Line, Tumor, Cell Movement, Chick Embryo, Collagen, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, Nude, Mice, SCID, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Transplantation, Phenotype, Prostatic Neoplasms, RNA Interference, RNA, Small Interfering
Show Abstract · Added April 10, 2019
Metastasis is the most lethal aspect of cancer, yet current therapeutic strategies do not target its key rate-limiting steps. We have previously shown that the entry of cancer cells into the blood stream, or intravasation, is highly dependent upon in vivo cancer cell motility, making it an attractive therapeutic target. To systemically identify genes required for tumor cell motility in an in vivo tumor microenvironment, we established a novel quantitative in vivo screening platform based on intravital imaging of human cancer metastasis in ex ovo avian embryos. Utilizing this platform to screen a genome-wide shRNA library, we identified a panel of novel genes whose function is required for productive cancer cell motility in vivo, and whose expression is closely associated with metastatic risk in human cancers. The RNAi-mediated inhibition of these gene targets resulted in a nearly total (>99.5%) block of spontaneous cancer metastasis in vivo.
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ERα-Mediated Nuclear Sequestration of RSK2 Is Required for ER Breast Cancer Tumorigenesis.
Ludwik KA, McDonald OG, Brenin DR, Lannigan DA
(2018) Cancer Res 78: 2014-2025
MeSH Terms: Animals, Breast Neoplasms, Carcinogenesis, Cell Nucleus, Estrogen Receptor alpha, Female, Humans, MCF-7 Cells, Mice, Mice, Inbred C57BL, Neoplasm Invasiveness, Ribosomal Protein S6 Kinases, 90-kDa
Show Abstract · Added July 20, 2018
Although ribosomal protein S6 kinase A3 (RSK2) activation status positively correlates with patient responses to antiestrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple and models of estrogen receptor-positive (ER) breast cancer, we report that ERα sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERα through its N terminus to activate a proneoplastic transcriptional network critical to the ER lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERα status. ER tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high-grade ductal carcinoma Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Antiestrogens disrupted the interaction between RSK2 and ERα, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERα-mediated transcriptional programs, tumorigenesis, and divergent patient responses to antiestrogen therapies. Nuclear accumulation of active RSK drives a protumorigenic transcriptional program and renders ER breast cancer susceptible to endocrine-based therapies. .
©2018 American Association for Cancer Research.
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12 MeSH Terms
Nodal Disease in Rectal Cancer Patients With Complete Tumor Response After Neoadjuvant Chemoradiation: Danger Below Calm Waters.
Baucom RB, Maguire LH, Kavalukas SL, Geiger TM, Ford MM, Muldoon RL, Hopkins MB, Hawkins AT
(2017) Dis Colon Rectum 60: 1260-1266
MeSH Terms: Adenocarcinoma, Case-Control Studies, Chemoradiotherapy, Combined Modality Therapy, Female, Humans, Lymphatic Metastasis, Male, Middle Aged, Neoadjuvant Therapy, Neoplasm Invasiveness, Neoplasm Staging, Neoplasm, Residual, Rectal Neoplasms, Retrospective Studies, Risk Factors, Survival Rate, Treatment Outcome, United States
Show Abstract · Added December 14, 2017
BACKGROUND - A subset of patients with rectal cancer who undergo neoadjuvant chemoradiation therapy will develop a complete pathologic tumor response. Complete nodal response is not universal in these patients and is difficult to assess clinically. Quantifying the risk of nodal disease would allow for targeted therapy with either radical resection or "watchful waiting."
OBJECTIVE - This study aimed to identify risk factors for residual nodal disease in ypT0 rectal adenocarcinoma.
DESIGN - This is a retrospective case control study.
SETTINGS - The National Cancer Database 2006 to 2014 was used to identify patients for this study.
PATIENTS - Patients with stage II/III rectal adenocarcinoma who completed chemoradiation therapy followed by resection and who had ypT0 tumors were included. Patients with metastatic disease and <2 lymph nodes evaluated were excluded. Patients were divided into 2 groups: node positive and node negative.
MAIN OUTCOME MEASURES - The main outcome was nodal disease. The secondary outcome was overall survival.
RESULTS - A total of 42,257 patients with stage II/III rectal cancer underwent chemoradiation therapy and radical resection; 4170 (9.9%) patients had ypT0 tumors and 395 (9.5%) were node positive. Of patients with clinically node-negative disease (ie, pretreatment imaging), 6.2% were node positive after chemoradiation therapy and resection. In multivariable analysis, factors predictive of nodal disease included increasing (pretreatment) clinical N-stage, high tumor grade (3/4), perineural invasion, and lymphovascular invasion. Higher clinical T-stage was inversely associated with residual nodal disease. Overall 5-year survival was significantly different between patients with ypN0, ypN1, and ypN2 disease (87.4%, 82.2%, and 62.5%, p = 0.002).
LIMITATIONS - This study was limited by the lack of clinical detail in the database and the inability to assess recurrence.
CONCLUSIONS - Ten percent of patients with ypT0 tumors had positive nodes after chemoradiation therapy and resection. Factors associated with residual nodal disease included clinical nodal disease at diagnosis and poor histologic features. Patients with any of these features should consider radical resection regardless of tumor response. Others could be suitable for "watchful waiting" strategies. See Video Abstract at http://links.lww.com/DCR/A458.
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19 MeSH Terms
Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin.
Erdogan B, Ao M, White LM, Means AL, Brewer BM, Yang L, Washington MK, Shi C, Franco OE, Weaver AM, Hayward SW, Li D, Webb DJ
(2017) J Cell Biol 216: 3799-3816
MeSH Terms: Cancer-Associated Fibroblasts, Cell Communication, Cell Line, Tumor, Cell Movement, Coculture Techniques, Extracellular Matrix, Fibronectins, Humans, Integrin alpha5beta1, Male, Mechanotransduction, Cellular, Neoplasm Invasiveness, Nonmuscle Myosin Type IIA, Prostatic Neoplasms, RNA Interference, Receptor, Platelet-Derived Growth Factor alpha, Time Factors, Transfection, Tumor Cells, Cultured, Tumor Microenvironment
Show Abstract · Added March 14, 2018
Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are poorly understood. In this study, we show that fibronectin (Fn) assembled by CAFs mediates CAF-cancer cell association and directional migration. Compared with normal fibroblasts, CAFs produce an Fn-rich extracellular matrix with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing nonmuscle myosin II- and platelet-derived growth factor receptor α-mediated contractility and traction forces, which are transduced to Fn through α5β1 integrin. We further show that prostate cancer cells use αv integrin to migrate efficiently and directionally on CAF-derived matrices. We demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.
© 2017 Erdogan et al.
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20 MeSH Terms
Gallbladder Cancer Presenting with Jaundice: Uniformly Fatal or Still Potentially Curable?
Tran TB, Norton JA, Ethun CG, Pawlik TM, Buettner S, Schmidt C, Beal EW, Hawkins WG, Fields RC, Krasnick BA, Weber SM, Salem A, Martin RCG, Scoggins CR, Shen P, Mogal HD, Idrees K, Isom CA, Hatzaras I, Shenoy R, Maithel SK, Poultsides GA
(2017) J Gastrointest Surg 21: 1245-1253
MeSH Terms: Aged, Bilirubin, Blood Vessels, CA-19-9 Antigen, Drainage, Female, Gallbladder Neoplasms, Humans, Jaundice, Obstructive, Lymphatic Vessels, Male, Middle Aged, Neoplasm Invasiveness, Postoperative Complications, Reoperation, Survival Rate, United States
Show Abstract · Added April 10, 2018
BACKGROUND - Jaundice as a presenting symptom of gallbladder cancer has traditionally been considered to be a sign of advanced disease, inoperability, and poor outcome. However, recent studies have demonstrated that a small subset of these patients can undergo resection with curative intent.
METHODS - Patients with gallbladder cancer managed surgically from 2000 to 2014 in 10 US academic institutions were stratified based on the presence of jaundice at presentation (defined as bilirubin ≥4 mg/ml or requiring preoperative biliary drainage). Perioperative morbidity, mortality, and overall survival were compared between jaundiced and non-jaundiced patients.
RESULTS - Of 400 gallbladder cancer patients with available preoperative data, 108 (27%) presented with jaundice while 292 (73%) did not. The fraction of patients who eventually underwent curative-intent resection was much lower in the presence of jaundice (n = 33, 30%) than not (n = 218, 75%; P < 0.001). Jaundiced patients experienced higher perioperative morbidity (69 vs. 38%; P = 0.002), including a much higher need for reoperation (12 vs. 1%; P = 0.003). However, 90-day mortality (6.5 vs. 3.6%; P = 0.35) was not significantly higher. Overall survival after resection was worse in jaundiced patients (median 14 vs. 32 months; P < 0.001). Further subgroup analysis within the jaundiced patients revealed a more favorable survival after resection in the presence of low CA19-9 < 50 (median 40 vs. 12 months; P = 0.003) and in the absence of lymphovascular invasion (40 vs. 14 months; P = 0.014).
CONCLUSION - Jaundice is a powerful preoperative clinical sign of inoperability and poor outcome among gallbladder cancer patients. However, some of these patients may still achieve long-term survival after resection, especially when preoperative CA19-9 levels are low and no lymphovascular invasion is noted pathologically.
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Matrix stiffening promotes a tumor vasculature phenotype.
Bordeleau F, Mason BN, Lollis EM, Mazzola M, Zanotelli MR, Somasegar S, Califano JP, Montague C, LaValley DJ, Huynh J, Mencia-Trinchant N, Negrón Abril YL, Hassane DC, Bonassar LJ, Butcher JT, Weiss RS, Reinhart-King CA
(2017) Proc Natl Acad Sci U S A 114: 492-497
MeSH Terms: Animals, Biomechanical Phenomena, Cattle, Cells, Cultured, Chick Embryo, Collagen, Extracellular Matrix, Female, Human Umbilical Vein Endothelial Cells, Humans, Mammary Neoplasms, Experimental, Matrix Metalloproteinases, Mice, Microvessels, Neoplasm Invasiveness, Neovascularization, Pathologic, Phenotype, Tumor Microenvironment, Vascular Stiffness
Show Abstract · Added April 10, 2019
Tumor microvasculature tends to be malformed, more permeable, and more tortuous than vessels in healthy tissue, effects that have been largely attributed to up-regulated VEGF expression. However, tumor tissue tends to stiffen during solid tumor progression, and tissue stiffness is known to alter cell behaviors including proliferation, migration, and cell-cell adhesion, which are all requisite for angiogenesis. Using in vitro, in vivo, and ex ovo models, we investigated the effects of matrix stiffness on vessel growth and integrity during angiogenesis. Our data indicate that angiogenic outgrowth, invasion, and neovessel branching increase with matrix cross-linking. These effects are caused by increased matrix stiffness independent of matrix density, because increased matrix density results in decreased angiogenesis. Notably, matrix stiffness up-regulates matrix metalloproteinase (MMP) activity, and inhibiting MMPs significantly reduces angiogenic outgrowth in stiffer cross-linked gels. To investigate the functional significance of altered endothelial cell behavior in response to matrix stiffness, we measured endothelial cell barrier function on substrates mimicking the stiffness of healthy and tumor tissue. Our data indicate that barrier function is impaired and the localization of vascular endothelial cadherin is altered as function of matrix stiffness. These results demonstrate that matrix stiffness, separately from matrix density, can alter vascular growth and integrity, mimicking the changes that exist in tumor vasculature. These data suggest that therapeutically targeting tumor stiffness or the endothelial cell response to tumor stiffening may help restore vessel structure, minimize metastasis, and aid in drug delivery.
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