Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers

Pearce, Oliver M.T.; Delaine-Smith, Robin; Maniati, Eleni; Nichols, Sam; Wang, Jun; Böhm, Steffen; Rajeeve, Vinothini; Ullah, Dayem; Chakravarty, Probir; Jones, Roanne R.; Montfort, Anne; Dowe, Tom; Gribben, John G.; Jones, J. Louise; Kocher, Hemant M.; Serody, Jonathan S.; Vincent, Benjamin G.; Connelly, John T.; Brenton, James D.; Chelala, Claude; Cutillas, Pedro R.; Lockley, Michelle; Bessant, Conrad; Knight, Martin M.; Balkwill, Frances R.

doi:10.1158/2159-8290.cd-17-0284

Cited by 271 publications

(339 citation statements)

References 65 publications

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“…In addition, CAFs protect tumor cells from CTL attack by remodeling the ECM . There are strong correlations between the chemoattractant IL‐16 and the density of CD3 + , CD45RO + , and CD8 + cells.…”

Section: Regulation Of Tumor Immune Response By Cancer‐associated Fibmentioning

confidence: 99%

“…Even after high-dose irradiation, CAFs maintain their powerful immunosuppressive effect over activated T cells [44]. In addition, CAFs protect tumor cells from CTL attack by remodeling the ECM [45,46]. There are strong correlations between the chemoattractant IL-16 and the density of CD3 + , CD45RO + , and CD8 + cells.…”

Section: Regulation Of Tumor Immune Response By Cancer-associated Fibmentioning

confidence: 99%

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The influence of microenvironment on tumor immunotherapy

Zhang

Shi

et al. 2019

The FEBS Journal

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Tumor immunotherapy has achieved remarkable efficacy, with immune‐checkpoint inhibitors as especially promising candidates for cancer therapy. However, some issues caused by immunotherapy have raised attention, such as limited efficacy for some patients, narrow antineoplastic spectrum, and adverse reactions, suggesting that using regulators of tumor immune response may prove to be more complicated than anticipated. Current evidence indicates that different factors collectively constituting the unique tumor microenvironment promote immune tolerance, and these include the expression of co‐inhibitory molecules, the secretion of lactate, and competition for nutrients between tumor cells and immune cells. Furthermore, cancer‐associated fibroblasts, the main cellular components of solid tumors, promote immunosuppression through inhibition of T cell function and extracellular matrix remodeling. Here, we summarize the research advances in tumor immunotherapy and the latest insights into the influence of microenvironment on tumor immunotherapy.

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Section: Regulation Of Tumor Immune Response By Cancer‐associated Fibmentioning

confidence: 99%

Section: Regulation Of Tumor Immune Response By Cancer-associated Fibmentioning

confidence: 99%

The influence of microenvironment on tumor immunotherapy

Zhang

Shi

et al. 2019

The FEBS Journal

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“…A comprehensive profile of the ovarian cancer matrisome has been obtained in clinical biopsies by measuring and integrating multiple components, including gene expression, proteomics, cytokine and chemokine levels, cellularity, and extracellular matrix organization. An expression pattern for 22 matrisome genes distinguished patients with a shorter overall survival in high‐grade serous ovarian cancer (HGSOC) and 12 other primary solid cancers, suggesting that there may be a common matrix response to human cancer . Networks of cytokines and chemokines appear to regulate the influx of leukocytes into ovarian cancer metastases, and an index of matrisome proteins correlates with infiltration of CD4+ and FOXP3+ T cells.…”

Section: How Does the Microenvironment Influence Cancer Growth And Rementioning

confidence: 99%

“…An expression pattern for 22 matrisome genes distinguished patients with a shorter overall survival in high-grade serous ovarian cancer (HGSOC) and 12 other primary solid cancers, suggesting that there may be a common matrix response to human cancer. 11 Networks of cytokines and chemokines appear to regulate the influx of leukocytes into ovarian cancer metastases, and an index of matrisome proteins correlates with infiltration of CD4+ and FOXP3+ T cells.…”

Section: How Does the Microenvironment Influence Cancer Growth And Rementioning

confidence: 99%

Critical questions in ovarian cancer research and treatment: Report of an American Association for Cancer Research Special Conference

Bast

Matulonis

Sood

et al. 2019

Cancer

Self Cite

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Substantial progress has been made in understanding ovarian cancer at the molecular and cellular level. Significant improvement in 5‐year survival has been achieved through cytoreductive surgery, combination platinum‐based chemotherapy, and more effective treatment of recurrent cancer, and there are now more than 280,000 ovarian cancer survivors in the United States. Despite these advances, long‐term survival in late‐stage disease has improved little over the last 4 decades. Poor outcomes relate, in part, to late stage at initial diagnosis, intrinsic drug resistance, and the persistence of dormant drug‐resistant cancer cells after primary surgery and chemotherapy. Our ability to accelerate progress in the clinic will depend on the ability to answer several critical questions regarding this disease. To assess current answers, an American Association for Cancer Research Special Conference on “Critical Questions in Ovarian Cancer Research and Treatment” was held in Pittsburgh, Pennsylvania, on October 1‐3, 2017. Although clinical, translational, and basic investigators conducted much of the discussion, advocates participated in the meeting, and many presentations were directly relevant to patient care, including treatment with poly adenosine diphosphate ribose polymerase (PARP) inhibitors, attempts to improve immunotherapy by overcoming the immune suppressive effects of the microenvironment, and a better understanding of the heterogeneity of the disease.

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“…HGSOC tumors with PTK2 gains exhibit elevated FAK expression and FAK Y397 phosphorylation (Cancer Genome Atlas Research, 2011, Zhang, Liu et al, 2016. Metastatic HGSOC tumor micro-environments are enriched with matrix proteins that are activators of FAK (Pearce, Delaine-Smith et al, 2018). While FAK knockdown and FAK inhibitor studies support an important role in promoting invasive tumor growth (Tancioni, Uryu et al, 2014, Ward, Tancioni et al, 2013, the targets downstream of FAK are varied and may be tumor or stroma context-dependent (Haemmerle, Bottsford-Miller et al, 2016.…”

Section: Introductionmentioning

confidence: 99%

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

Osterman¹,

Ozmadenci²,

Kleinschmidt³

et al. 2019

Preprint

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= 175 words 7 Figures and 2 Tables AbstractGene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-b-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encoding KRAS, MYC and FAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neoadjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosis in vitro and in vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/b-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer. Running title (40 characters including spaces): FAK dependent signaling in ovarian cancerKeywords (5): b-catenin, FAK, Myc, ovarian cancer, platinum chemotherapy 3 Graphical Summary Key Points• High grade serous ovarian carcinoma tumors contain PTK2 (FAK) 8q24.3 gains associated with prognostic differences.• KMF, a new murine ovarian cancer model with K-Ras, Myc, and FAK gene gains and intrinsic platinum resistance.• FAK activation in tumors surviving platinum chemotherapy promotes cancer stem cell survival.• FAK facilitates a b-catenin-Myc signaling axis controlling gene expression supporting platinum resistance.• FAK activity is essential for KMF tumor growth and is a targetable cellular adaptation of platinum resistance. We thank our colleagues for helpful discussion and comments. We thank R. Winters (FCCC BRF manager) and D. Flieder (FCCC Pathology) for identifying, reviewing the cases, and for procuring patient tumor samples used in this study.

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Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers

Cited by 271 publications

References 65 publications

The influence of microenvironment on tumor immunotherapy

The influence of microenvironment on tumor immunotherapy

Critical questions in ovarian cancer research and treatment: Report of an American Association for Cancer Research Special Conference

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

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