Tumor Morphology and Microenvironment

Main interests

Our research is translational and focused on the study of tumor microenvironment in cancer progression and therapeutic responses. Our general goal is the use of the morphological pattern of human cancers (phenotype) as mirror of molecular alterations using different strategies from clinical-pathological features to cell culture approaches. We expect to improve cancer diagnosis and patients’ management as well as molecular stratification, prognosis and targeted therapy of gynecological cancers

morphological

Research Areas

HPV associated cancers: to study the effect of biological agents as initiators of carcinogenesis and tumor promotion, and to evaluate the role of extracellular matrix components and cell signaling molecules as new prognostic molecular markers and therapeutic targets.

Endometrial and Ovarian cancer: to explore molecular pathways associated with long survival and EMT features in the development of and therapy response with specially emphasizes in molecular pathways and endometrial carcinomas with EMT features.

Projects

- Build-up of precision medicine platform using patient-derived cell models for prediction of drug efficacy in ovarian cancer patients iNOVA4Health – UID/Multi/04462/2019, funded by FCT/MEC

- Build-up of precision medicine platform using patient-derived cell models for prediction of drug efficacy in ovarian cancer patients
iNOVA4Health supporting. Tracking Number: 34 PD/BD/128377/2017 (75 000€)
Principal investigator: Ana Félix and Inês Isidro

- DREAM-Dendrimer-based Report-Eradication Antineoplasic Machines. Projeto financiado pela FCT (PTDC/MEC-ONC/29327/2017; CQFM- IN and Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa) (225 000€)
Principal investigator: Vasco Bonifácio

- Long survival in patients with high-grade serous carcinoma of the ovary: a molecular and clinical study
AstraZeneca, Tracking Number: NCR-17-12893 (40 000€)
Principal investigator: Ana Félix

- "Infecção pelo Vírus Papiloma Humano e cancerigénese do colo do útero- factores biológicos na transformação e progressão neoplásicas" Fundação Calouste Gulbenkian

- “Saúde e Ambiente” in 2005

- "Cell and molecular alterations in ovarian cancer cells induced by vorinostat therapy, identification of biomarkers for therapy response", Departamento de Anatomia Patológica, FCM-CEDOC-UNL, financiado pelo CEDOC

- "Unravelling the role of JAK-STAT pathway inhibition in Solid Neoplasia and the impact of p53 mutational status", IPOLFG/CEDOC

- Ovarian cancer a suitable model to define metabolic profile as a tool to predict chemoresistance. CEDOC/IPOLFG/IBET

- Molecular mechanisms of cell migration and invasion: developing a new strategy to impair tumor progression, CEDOC/IPOLFG

- Biomarkers and new therapeutic targets in cervical invasive carcinoma - 2014 Terry Fox, financiado pela Liga Portuguesa Contra o Cancro

Publications

Ferreira J, Félix A. Carcinosarcoma (MMMT). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/uterusmmmt0.html. Accessed July 27th, 2020

Medeiros-Fonseca B, et al. HPV16 induces penile intraepithelial neoplasia and squamous cell carcinoma in transgenic mice: first mouse model for HPV-related penile cancer. J Pathol. 2020. 251, 4, 411-419. https://doi.org/10.1002/path.5475

Gil da Costa RM, Neto T, Estêvão D, Moutinho M, Félix A, Medeiros R, Lopes C, Bastos MMSM, Oliveira PA. Ptaquiloside from bracken (Pteridium spp.) promotes oral carcinogenesis initiated by HPV16 in transgenic mice. Food Funct. 2020. 11(4):3298-3305. doi: 10.1039/d0fo00207k

André S, Nunes SP, Silva F, Henrique R, Félix F, Jerónimo C. Analysis of Epigenetic Alterations in Homologous Recombination DNA Repair Genes in Male Breast Cancer. Int J Mol Sci. 2020. 21, 8, 2715.

Bargão Santos P, Lobo J, Félix A, Silva F, Manso RT, Costa JO, Lourenço B, Sequeira JP, Jerónimo C, Patel HHR, Henrique R. The inflammation-related biomarker CXCR7 independently predicts patient outcome after radical prostatectomy. Urol Oncol. 2020 Oct;38(10):794.e17-794.e27. doi: 10.1016/j.urolonc.2020.03.004. Epub 2020 Apr 9.

Mestre VF, Medeiros-Fonseca B, Estêvão D, Casaca F, Silva S, Félix A, Silva F, Colaço B, Seixas F, Bastos MM, Lopes C, Medeiros R, Oliveira PA, Gil da Costa RM. HPV16 is sufficient to induce squamous cell carcinoma specifically in the tongue base in transgenic mice. J Pathol. 2020 May;251(1):4-11. doi: 10.1002/path.5387. Epub 2020 Mar 10.

Esteves G, Ferreira J, Afonso R, Martins C, Zagalo C, Félix A. HDAC Overexpression in a NUT Midline Carcinoma of the Parotid Gland with Exceptional Survival: A Case Report. Head Neck Pathol. 2020 Jan 27. doi: 10.1007/s12105-020-01130-6. Epub ahead of print.

Esteves GF, Félix A. Dermal nerve sheath myxoma. PathologyOutlines.com website http://www.pathologyoutlines.com/topic/softtissuenervesheathmyxoma.html. Accessed January 9th, 2020

Santos PB, Patel H, Henrique R, Félix A. Can epigenetic and inflammatory biomarkers identify clinically aggressive prostate cancer? World J Clin Oncol. 2020 Feb 24;11(2):43-52. doi: 10.5306/wjco.v11.i2.43.

Bennett JA, Ritterhouse LL, Furtado LV, Lastra RR, Pesci A, Newell JM, Burandt E, Kooreman L, Van de Vijver K, Krausz T, Felix A, Zannoni GF, Young RH, Oliva E. Female adnexal tumors of probable Wolffian origin: morphological, immunohistochemical, and molecular analysis of 15 cases. Mod Pathol. 2020 Apr;33(4):734-747. doi: 10.1038/s41379-019-0375-9. Epub 2019 Oct 7.

Lérias S, Esteves S, Silva F, Cunha M, Cochicho D, Martins L, Félix A. CD274 (PD-L1), CDKN2A (p16), TP53, and EGFR immunohistochemical profile in primary, recurrent and metastatic vulvar cancer. Mod Pathol. 2020 May;33(5):893-904. doi: 10.1038/s41379-019-0429-z. Epub 2019 Dec 16.

Cotzia P, Benayed R, Mullaney K, Oliva E, Felix A, Ferreira J, Soslow RA, Antonescu CR, Ladanyi M, Chiang S. Undifferentiated Uterine Sarcomas Represent Under-Recognized High-grade Endometrial Stromal Sarcomas. Am J Surg Pathol. 2019 May;43(5):662-669. doi: 10.1097/PAS.0000000000001215

Casalou C, Faustino A, Silva F, Ferreira IC, Vaqueirinho D, Ferreira A, Castanheira P, Barona T, Ramalho JS, Serpa J*, Félix A*, Barral DC. Arl13b Regulates Breast Cancer Cell Migration and Invasion by Controlling Integrin-Mediated Signaling, Cancers 2019, Sep 29;11(10). pii: E1461. doi: 10.3390/cancers11101461. *Equal contribution

Gouveia-Fernandes S, Carvalho T, Domingues G, Bordeira-Carriço R, Dias S, Serpa J. (2017) Colorectal Cancer Aggressiveness is Related to Fibronectin Over Expression, Driving the Activation of SDF-1:CXCR4 Axis. Int J Cancer Clin Res 2016, 3:072

Lopes-Coelho F, André S, Félix A, Serpa J. (2017) Breast cancer metabolic cross-talk: Fibroblasts are hubs and breast cancer cells are gatherers of lipids. Mol Cell Endocrinol. 2017 Jan 21. pii: S0303-7207(17)30044-8. doi: 10.1016/j.mce.2017.01.031. [Epub ahead of print]

Alemany L, Cubilla A, Halec G, Kasamatsu E, Quirós B, Masferrer E, Tous S, Lloveras B, Hernández-Suarez G, Lonsdale R, Tinoco L, Alejo M, Alvarado-Cabrero I, Laco J, Guimerà N, Poblet E, Lombardi LE, Bergeron C, Clavero O, Shin HR, Ferrera A, Felix A, Germar J, Mandys V, Clavel C, Tzardi M, Pons LE, Wain V, Cruz E, Molina C, Mota JD, Jach R, Velasco J, Carrilho C, López-Revilla R, Goodman MT, Quint WG, Castellsagué X, Bravo I, Pawlita M, Muñoz N, Bosch FX, de Sanjosé S; HPV VVAP study group. Role of Human Papillomavirus in Penile Carcinomas Worldwide. Eur Urol. 2016 Jan 4. pii: S0302-2838(15)01215-4. doi: 10.1016/j.eururo.2015.12.007. [Epub ahead of print] PMID: 26762611

Silva LS, Goncalves LG, Silva F, Domingues G, Maximo V, Ferreira J, Lam EW, Dias S, Felix A, Serpa J. (2015) STAT3:FOXM1 and MCT1 drive uterine cervix carcinoma fitness to a lactate-rich microenvironment. Tumour Biol. 2015 Nov 12. [Epub ahead of print]

Lopes-Coelho F, Gouveia-Fernandes S, Gonçalves LG, Nunes C, Faustino I, Silva F, Félix A, Pereira SA, Serpa J. (2015) HNF1β drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC). Tumour Biol. [Epub ahead of print]

Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M, Farinha P, et al. MHC class IItransactivator CIITA is a recurrent gene fusion partner in lymphoid cancers.Nature. 2011 Mar 17;471(7338):377-81. Epub 2011 Mar 2. PubMed PMID: 21368758.

Steidl C, Farinha P, Gascoyne RD. Macrophages predict treatment outcome inHodgkin's lymphoma. Haematologica. 2011 Feb;96(2):186-9. PubMed PMID: 21282720; PubMed Central PMCID: PMC3031684.

Serpa J, Dias S. Metabolic cues from the microenvironment act as a major selective factor for cancer progression and metastases formation. Cell Cycle.2011 Jan 15;10(2):180-1. Epub 2011 Jan 15. PubMed PMID: 21239877.

Cavaco BM, Santos R, Félix A, Carvalho D, Lopes JM, Domingues R, Sirgado M,Rei N, Fonseca F, Santos JR, Sobrinho L, Leite V. Identification of de novogermline mutations in the HRPT2 gene in two apparently sporadic cases with challenging parathyroid tumor diagnoses. Endocr Pathol. 2011 Mar;22(1):44-52.PubMed PMID: 21360064.

Rodig SJ, Kutok JL, Paterson JC, Nitta H, Zhang W, Chapuy B, et al. The pre-B-cell receptor associated protein VpreB3 is a useful diagnostic marker for identifying c-MYC translocated lymphomas. Haematologica. 2010 Dec;95(12):2056-62. Epub 2010 Sep 7. PubMed PMID: 20823132; PubMed Central PMCID: PMC2995563.

Farinha P, Kyle AH, Minchinton AI, Connors JM, Karsan A, Gascoyne RD. Vascularization predicts overall survival and risk of transformation in follicular lymphoma. Haematologica. 2010 Dec;95(12):2157-60. Epub 2010 Aug 16. PubMed PMID: 20713461; PubMed Central PMCID: PMC2995576.

de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B,et al. Retrospective International Survey and HPV Time Trends Study Group. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010 Nov;11(11):1048-56. Epub 2010 Oct 15. PubMed PMID: 20952254.

Relander T, Johnson NA, Farinha P, Connors JM, Sehn LH, Gascoyne RD. Prognostic factors in follicular lymphoma. J Clin Oncol. 2010 Jun 10;28(17):2902-13. Epub 2010 Apr 12. Review. Erratum in: J Clin Oncol. 2010 Oct 20;28(30):4664. PubMed PMID: 20385990.

Steidl C, Telenius A, Shah SP, Farinha P, Barclay L, Boyle M, et al. Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood. 2010 Jul 22;116(3):418-27. Epub 2010 Mar 25. PubMed PMID: 20339089.

Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med. 2010 Mar 11;362(10):875-85. PubMed PMID: 20220182; PubMed Central PMCID: PMC2897174.

Evens AM, Sehn LH, Farinha P, Nelson BP, Raji A, Lu Y, Brakman A, et al. Hypoxia-inducible factor-1 {alpha} expression predicts superior survival in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2010 Feb 20;28(6):1017-24. Epub 2010 Jan 4. PubMed PMID: 20048181; PubMed Central PMCID: PMC2834428.

Farinha P, Al-Tourah A, Gill K, Klasa R, Connors JM, Gascoyne RD. The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation. Blood. 2010 Jan 14;115(2):289-95. Epub 2009 Nov 9. PubMed PMID: 19901260.

Gratzinger D, Advani R, Zhao S, Talreja N, Tibshirani RJ, Shyam R, et al. Lymphoma cell VEGFR2 expression detected by immunohistochemistry predicts poor overall survival in diffuse large B cell lymphoma treated with immunochemotherapy (R-CHOP). Br J Haematol. 2010 Jan;148(2):235-44. Epub 2009 Oct 11. PubMed PMID: 19821819; PubMed Central PMCID: PMC2809124.

Shustik J, Han G, Farinha P, Johnson NA, Ben Neriah S, Connors JM, et al. Correlations between BCL6 rearrangement and outcome in patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP. Haematologica. 2010 Jan;95(1):96-101. Epub 2009 Oct 1. PubMed PMID: 19797725; PubMed Central PMCID: PMC2805749.

Serpa J, Caiado F, Carvalho T, Torre C, Gonçalves LG, Casalou C, et al. Butyrate-rich colonic microenvironment is a relevant selection factor for metabolically adapted tumor cells. J Biol Chem. 2010 Dec 10;285(50):39211-23. Epub 2010 Oct 6. PubMed PMID: 20926374; PubMed Central PMCID: PMC2998102.

Cachaço AS, Carvalho T, Santos AC, Igreja C, Fragoso R, Osório C, et al. TNF-alpha regulates the effects of irradiation in the mouse bone marrow microenvironment. PLoS One. 2010 Feb 1;5(2):e8980. PubMed PMID: 20126546; PubMed Central PMCID: PMC2813873.

Gomes AL, Carvalho T, Serpa J, Torre C, Dias S. Hypercholesterolemia promotes bone marrow cell mobilization by perturbing the SDF-1:CXCR4 axis. Blood. 2010 May 13;115(19):3886-94. Epub 2009 Dec 15. PubMed PMID: 20009035.

Savage KJ, Johnson NA, Ben-Neriah S, Connors JM, Sehn LH, Farinha P, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009 Oct 22;114(17):3533-7. Epub 2009 Aug 24. PubMed PMID: 19704118.

Ci W, Polo JM, Cerchietti L, Shaknovich R, Wang L, Yang SN, et al. The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL. Blood. 2009 May 28;113(22):5536-48. Epub 2009 Mar 23. PubMed PMID:19307668; PubMed Central PMCID: PMC2689052.

Félix A, Nogales FF, Arias-Stella J. Polypoid endometriosis of the uterinecervix with Arias-Stella reaction in a patient taking phytoestrogens. Int JGynecol Pathol. 2010 Mar;29(2):185-8. PubMed PMID: 20173505.