Harold Moses
Faculty Member
Last active: 4/25/2016

Profile

Accumulating data indicate that the stroma can play a critical role in cancer initiation and progression. TGF-beta signaling in both epithelial and stromal cells appears to be a key regulator of the stromal microenvironment. There is now compelling evidence from transgenic mouse studies and analyses of mutations in human carcinomas indicating that the TGF-beta signal transduction pathway is tumor suppressive. Studies of human tumors have demonstrated inactivating mutations in human tumors of genes encoding proteins involved in TGF-beta signal transduction, including DPC4/Smad4, Smad2, and the type I and type II TGF-beta receptor (TßRI and TßRII, respectively). However, there is some evidence that TGF-beta signaling can promote tumor progression in the later stages. In order to examine the roles of TGF-beta signaling in cancer more closely, we have generated mice with loxP sites flanking exon 2 of the type II receptor gene, Tgfbr2, and crossed them with mice expressing Cre driven by different epithelial specific promoters. Loss of TGF-beta signaling in six different epithelial cells gave a minimal phenotype. However, when challenged with oncogene expression or tumor suppressor gene impairment, there was rapid development of invasive and metastatic carcinomas supporting the hypothesis that epithelial cell autonomous TGF-beta signaling is tumor suppressive in both early and late stages of carcinogenesis. One mechanism appears to be enhanced expression of chemokines by Tgfbr2 null carcinoma cells with resultant recruitment of bone marrow derived cells that express abundant TGF-beta and MMPs in the tumor microenvironment and promote invasion and metastasis. In contrast to the epithelial cell knockouts that gave a minimal phenotype, knockout of Tgfbr2 in stromal fibroblasts gave a striking epithelial phenotype in the mammary gland, prostate and forestomach, including epithelial pre-neoplasia and invasive carcinomas. One mechanism identified was paracrine stimulation of carcinoma cells by HGF, MSP and TGF-alpha. Another mechanism appeared to be over expression of chemokines by the knockout fibroblasts with recruitment of bone marrow derived cells. Thus, TGF-beta signaling in fibroblasts modulates the growth and oncogenic potential of adjacent epithelia in selected tissues. The data indicate that TGF-beta signaling is a major regulator of chemokine secretion and resultant bone marrow cell infiltration and that targeting pathways that inhibit bone marrow cell differentiation or chemokine receptors may be useful in both therapy and prevention of cancer.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors. Polosukhina D, Love HD, Correa H, Su Z, Dahlman KB, Pao W, Moses HL, Arteaga CL, Lovvorn HN, Zent R, Clark PE (2017) Mol Oncol 11(4): 405-421
    › Primary publication · 28188683 (PubMed) · PMC5378659 (PubMed Central)
  2. PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses. Sai J, Owens P, Novitskiy SV, Hawkins OE, Vilgelm AE, Yang J, Sobolik T, Lavender N, Johnson AC, McClain C, Ayers GD, Kelley MC, Sanders M, Mayer IA, Moses HL, Boothby M, Richmond A (2017) Clin Cancer Res 23(13): 3371-3384
    › Primary publication · 28003307 (PubMed) · PMC5479746 (PubMed Central)
  3. TβRIII Expression in Human Breast Cancer Stroma and the Role of Soluble TβRIII in Breast Cancer Associated Fibroblasts. Jovanović B, Pickup MW, Chytil A, Gorska AE, Johnson KC, Moses HL, Owens P (2016) Cancers (Basel) 8(11)
    › Primary publication · 27827906 (PubMed) · PMC5126760 (PubMed Central)
  4. Biomarker Tests for Molecularly Targeted Therapies--The Key to Unlocking Precision Medicine. Lyman GH, Moses HL (2016) N Engl J Med 375(1): 4-6
    › Primary publication · 27353537 (PubMed)
  5. The Discovery and Early Days of TGF-β: A Historical Perspective. Moses HL, Roberts AB, Derynck R (2016) Cold Spring Harb Perspect Biol 8(7)
    › Primary publication · 27328871 (PubMed) · PMC4930926 (PubMed Central)
  6. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, Moses HL, Sanders ME, Pietenpol JA (2016) PLoS One 11(6): e0157368
    › Primary publication · 27310713 (PubMed) · PMC4911051 (PubMed Central)
  7. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Laklai H, Miroshnikova YA, Pickup MW, Collisson EA, Kim GE, Barrett AS, Hill RC, Lakins JN, Schlaepfer DD, Mouw JK, LeBleu VS, Roy N, Novitskiy SV, Johansen JS, Poli V, Kalluri R, Iacobuzio-Donahue CA, Wood LD, Hebrok M, Hansen K, Moses HL, Weaver VM (2016) Nat Med 22(5): 497-505
    › Primary publication · 27089513 (PubMed) · PMC4860133 (PubMed Central)
  8. Biomarker Tests for Molecularly Targeted Therapies: Laying the Foundation and Fulfilling the Dream. Lyman GH, Moses HL (2016) J Clin Oncol 34(17): 2061-6
    › Primary publication · 27069080 (PubMed)
  9. The impact of bone morphogenetic protein 4 (BMP4) on breast cancer metastasis in a mouse xenograft model. Ampuja M, Alarmo EL, Owens P, Havunen R, Gorska AE, Moses HL, Kallioniemi A (2016) Cancer Lett 375(2): 238-244
    › Primary publication · 26970275 (PubMed)
  10. Fibroblast-Mediated Collagen Remodeling Within the Tumor Microenvironment Facilitates Progression of Thyroid Cancers Driven by BrafV600E and Pten Loss. Jolly LA, Novitskiy S, Owens P, Massoll N, Cheng N, Fang W, Moses HL, Franco AT (2016) Cancer Res 76(7): 1804-13
    › Primary publication · 26818109 (PubMed) · PMC4873339 (PubMed Central)
  11. Bone morphogenetic protein signaling promotes tumorigenesis in a murine model of high-grade glioma. Hover LD, Owens P, Munden AL, Wang J, Chambless LB, Hopkins CR, Hong CC, Moses HL, Abel TW (2016) Neuro Oncol 18(7): 928-38
    › Primary publication · 26683138 (PubMed) · PMC4896540 (PubMed Central)
  12. Deletion of the BMP receptor BMPR1a impairs mammary tumor formation and metastasis. Pickup MW, Hover LD, Guo Y, Gorska AE, Chytil A, Novitskiy SV, Moses HL, Owens P (2015) Oncotarget 6(26): 22890-904
    › Primary publication · 26274893 (PubMed) · PMC4673207 (PubMed Central)
  13. Signal Transducer and Activator of Transcription 3, Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer. Nagathihalli NS, Castellanos JA, Shi C, Beesetty Y, Reyzer ML, Caprioli R, Chen X, Walsh AJ, Skala MC, Moses HL, Merchant NB (2015) Gastroenterology 149(7): 1932-1943.e9
    › Primary publication · 26255562 (PubMed) · PMC4863449 (PubMed Central)
  14. Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth. Hover LD, Young CD, Bhola NE, Wilson AJ, Khabele D, Hong CC, Moses HL, Owens P (2015) Cancer Lett 368(1): 79-87
    › Primary publication · 26235139 (PubMed) · PMC4554828 (PubMed Central)
  15. A Murine Model of K-RAS and β-Catenin Induced Renal Tumors Expresses High Levels of E2F1 and Resembles Human Wilms Tumor. Yi Y, Polosukhina D, Love HD, Hembd A, Pickup M, Moses HL, Lovvorn HN, Zent R, Clark PE (2015) J Urol 194(6): 1762-70
    › Primary publication · 25934441 (PubMed) · PMC4782590 (PubMed Central)
  16. TGFβ signaling in myeloid cells regulates mammary carcinoma cell invasion through fibroblast interactions. Shaw AK, Pickup MW, Chytil A, Aakre M, Owens P, Moses HL, Novitskiy SV (2015) PLoS One 10(1): e0117908
    › Primary publication · 25629162 (PubMed) · PMC4309578 (PubMed Central)
  17. Age- and pregnancy-associated DNA methylation changes in mammary epithelial cells. Huh SJ, Clement K, Jee D, Merlini A, Choudhury S, Maruyama R, Yoo R, Chytil A, Boyle P, Ran FA, Moses HL, Barcellos-Hoff MH, Jackson-Grusby L, Meissner A, Polyak K (2015) Stem Cell Reports 4(2): 297-311
    › Primary publication · 25619437 (PubMed) · PMC4325231 (PubMed Central)
  18. Attenuated transforming growth factor beta signaling promotes metastasis in a model of HER2 mammary carcinogenesis. Novitskiy SV, Forrester E, Pickup MW, Gorska AE, Chytil A, Aakre M, Polosukhina D, Owens P, Yusupova DR, Zhao Z, Ye F, Shyr Y, Moses HL (2014) Breast Cancer Res 16(5): 425
    › Primary publication · 25280532 (PubMed) · PMC4303109 (PubMed Central)
  19. Concerted loss of TGFβ-mediated proliferation control and E-cadherin disrupts epithelial homeostasis and causes oral squamous cell carcinoma. Andl T, Le Bras GF, Richards NF, Allison GL, Loomans HA, Washington MK, Revetta F, Lee RK, Taylor C, Moses HL, Andl CD (2014) Carcinogenesis 35(11): 2602-10
    › Primary publication · 25233932 (PubMed) · PMC4216061 (PubMed Central)
  20. BMPR2 loss in fibroblasts promotes mammary carcinoma metastasis via increased inflammation. Pickup MW, Hover LD, Polikowsky ER, Chytil A, Gorska AE, Novitskiy SV, Moses HL, Owens P (2015) Mol Oncol 9(1): 179-91
    › Primary publication · 25205038 (PubMed) · PMC4277920 (PubMed Central)
  21. Role of TGF-β signaling in generation of CD39+CD73+ myeloid cells in tumors. Ryzhov SV, Pickup MW, Chytil A, Gorska AE, Zhang Q, Owens P, Feoktistov I, Moses HL, Novitskiy SV (2014) J Immunol 193(6): 3155-64
    › Primary publication · 25127858 (PubMed) · PMC4157098 (PubMed Central)
  22. Inhibition of BMP signaling suppresses metastasis in mammary cancer. Owens P, Pickup MW, Novitskiy SV, Giltnane JM, Gorska AE, Hopkins CR, Hong CC, Moses HL (2015) Oncogene 34(19): 2437-49
    › Primary publication · 24998846 (PubMed) · PMC4689138 (PubMed Central)
  23. Transforming growth factor beta receptor type III is a tumor promoter in mesenchymal-stem like triple negative breast cancer. Jovanović B, Beeler JS, Pickup MW, Chytil A, Gorska AE, Ashby WJ, Lehmann BD, Zijlstra A, Pietenpol JA, Moses HL (2014) Breast Cancer Res 16(4): R69
    › Primary publication · 24985072 (PubMed) · PMC4095685 (PubMed Central)
  24. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R (2014) Cancer Cell 25(6): 719-34
    › Primary publication · 24856586 (PubMed) · PMC4180632 (PubMed Central)
  25. ALCAM/CD166 is a TGF-β-responsive marker and functional regulator of prostate cancer metastasis to bone. Hansen AG, Arnold SA, Jiang M, Palmer TD, Ketova T, Merkel A, Pickup M, Samaras S, Shyr Y, Moses HL, Hayward SW, Sterling JA, Zijlstra A (2014) Cancer Res 74(5): 1404-15
    › Primary publication · 24385212 (PubMed) · PMC4149913 (PubMed Central)
  26. The roles of TGFβ in the tumour microenvironment. Pickup M, Novitskiy S, Moses HL (2013) Nat Rev Cancer 13(11): 788-99
    › Primary publication · 24132110 (PubMed) · PMC4025940 (PubMed Central)
  27. Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas. Pickup MW, Laklai H, Acerbi I, Owens P, Gorska AE, Chytil A, Aakre M, Weaver VM, Moses HL (2013) Cancer Res 73(17): 5336-46
    › Primary publication · 23856251 (PubMed) · PMC3766496 (PubMed Central)
  28. Bone Morphogenetic Proteins stimulate mammary fibroblasts to promote mammary carcinoma cell invasion. Owens P, Polikowsky H, Pickup MW, Gorska AE, Jovanovic B, Shaw AK, Novitskiy SV, Hong CC, Moses HL (2013) PLoS One 8(6): e67533
    › Primary publication · 23840733 (PubMed) · PMC3695869 (PubMed Central)
  29. Turn off the IDO: will clinical trials be successful? Novitskiy SV, Moses HL (2012) Cancer Discov 2(8): 673-5
    › Primary publication · 22886661 (PubMed)
  30. Lack of transforming growth factor-β signaling promotes collective cancer cell invasion through tumor-stromal crosstalk. Matise LA, Palmer TD, Ashby WJ, Nashabi A, Chytil A, Aakre M, Pickup MW, Gorska AE, Zijlstra A, Moses HL (2012) Breast Cancer Res 14(4): R98
    › Primary publication · 22748014 (PubMed) · PMC3680921 (PubMed Central)
  31. Deletion of TGF-β signaling in myeloid cells enhances their anti-tumorigenic properties. Novitskiy SV, Pickup MW, Chytil A, Polosukhina D, Owens P, Moses HL (2012) J Leukoc Biol 92(3): 641-51
    › Primary publication · 22685318 (PubMed) · PMC3427612 (PubMed Central)
  32. Pathway analyses identify TGFBR2 as potential breast cancer susceptibility gene: results from a consortium study among Asians. Ma X, Beeghly-Fadiel A, Lu W, Shi J, Xiang YB, Cai Q, Shen H, Shen CY, Ren Z, Matsuo K, Khoo US, Iwasaki M, Long J, Zhang B, Ji BT, Zheng Y, Wang W, Hu Z, Liu Y, Wu PE, Shieh YL, Wang S, Xie X, Ito H, Kasuga Y, Chan KY, Iwata H, Tsugane S, Gao YT, Shu XO, Moses HL, Zheng W (2012) Cancer Epidemiol Biomarkers Prev 21(7): 1176-84
    › Primary publication · 22539603 (PubMed) · PMC3810157 (PubMed Central)
  33. p120-catenin is essential for terminal end bud function and mammary morphogenesis. Kurley SJ, Bierie B, Carnahan RH, Lobdell NA, Davis MA, Hofmann I, Moses HL, Muller WJ, Reynolds AB (2012) Development 139(10): 1754-64
    › Primary publication · 22461563 (PubMed) · PMC3328177 (PubMed Central)
  34. TGF-β receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms. Novitskiy SV, Pickup MW, Gorska AE, Owens P, Chytil A, Aakre M, Wu H, Shyr Y, Moses HL (2011) Cancer Discov 1(5): 430-41
    › Primary publication · 22408746 (PubMed) · PMC3297196 (PubMed Central)
  35. β-Catenin and K-RAS synergize to form primitive renal epithelial tumors with features of epithelial Wilms' tumors. Clark PE, Polosukhina D, Love H, Correa H, Coffin C, Perlman EJ, de Caestecker M, Moses HL, Zent R (2011) Am J Pathol 179(6): 3045-55
    › Primary publication · 21983638 (PubMed) · PMC3260797 (PubMed Central)
  36. Prostate cancer cells lose their sensitivity to TGFβI growth inhibition with tumor progression. Steiner MS, Anthony CT, Metts J, Moses HL (1995) Urol Oncol 1(6): 252-62
    › Primary publication · 21224127 (PubMed)
  37. Analysis of transforming growth factor β receptor expression and signaling in higher grade meningiomas. Johnson MD, Shaw AK, O'Connell MJ, Sim FJ, Moses HL (2011) J Neurooncol 103(2): 277-85
    › Primary publication · 20853018 (PubMed)
  38. TRAIL and interferon-alpha act synergistically to induce renal cell carcinoma apoptosis. Clark PE, Polosukhina DA, Gyabaah K, Moses HL, Thorburn A, Zent R (2010) J Urol 184(3): 1166-74
    › Primary publication · 20663526 (PubMed) · PMC2963111 (PubMed Central)
  39. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Yang L, Pang Y, Moses HL (2010) Trends Immunol 31(6): 220-7
    › Primary publication · 20538542 (PubMed) · PMC2891151 (PubMed Central)
  40. Quantitative analysis of the secretome of TGF-beta signaling-deficient mammary fibroblasts. Xu BJ, Yan W, Jovanovic B, An AQ, Cheng N, Aakre ME, Yi Y, Eng J, Link AJ, Moses HL (2010) Proteomics 10(13): 2458-70
    › Primary publication · 20405477 (PubMed) · PMC4156855 (PubMed Central)
  41. Meharry Medical College-Vanderbilt-Ingram Cancer Center partnership: its history and role in cancer health disparities research. Adunyah SE, Beech BM, Moses HL (2010) J Health Care Poor Underserved 21(1 Suppl): 1-4
    › Primary publication · 20173279 (PubMed) · PMC4826048 (PubMed Central)
  42. Transforming growth factor beta (TGF-beta) and inflammation in cancer. Bierie B, Moses HL (2010) Cytokine Growth Factor Rev 21(1): 49-59
    › Primary publication · 20018551 (PubMed) · PMC2834863 (PubMed Central)
  43. TGF-beta helps cells fly solo. Matise LA, Pickup MW, Moses HL (2009) Nat Cell Biol 11(11): 1281-4
    › Primary publication · 19838176 (PubMed)
  44. Gain or loss of TGFbeta signaling in mammary carcinoma cells can promote metastasis. Bierie B, Moses HL (2009) Cell Cycle 8(20): 3319-27
    › Primary publication · 19806012 (PubMed)
  45. Transforming growth factor beta: tumor suppressor or promoter? Are host immune cells the answer? Yang L, Moses HL (2008) Cancer Res 68(22): 9107-11
    › Primary publication · 19010878 (PubMed) · PMC2741321 (PubMed Central)
  46. Transforming growth factor-beta signaling-deficient fibroblasts enhance hepatocyte growth factor signaling in mammary carcinoma cells to promote scattering and invasion. Cheng N, Chytil A, Shyr Y, Joly A, Moses HL (2008) Mol Cancer Res 6(10): 1521-33
    › Primary publication · 18922968 (PubMed) · PMC2740918 (PubMed Central)
  47. Identification of novel Smad2 and Smad3 associated proteins in response to TGF-beta1. Brown KA, Ham AJ, Clark CN, Meller N, Law BK, Chytil A, Cheng N, Pietenpol JA, Moses HL (2008) J Cell Biochem 105(2): 596-611
    › Primary publication · 18729074 (PubMed) · PMC2700048 (PubMed Central)
  48. TGF-beta receptor II in epithelia versus mesenchyme plays distinct roles in the developing lung. Chen H, Zhuang F, Liu YH, Xu B, Del Moral P, Deng W, Chai Y, Kolb M, Gauldie J, Warburton D, Moses HL, Shi W (2008) Eur Respir J 32(2): 285-95
    › Primary publication · 18321928 (PubMed) · PMC2865234 (PubMed Central)
  49. Transcriptional cooperation between the transforming growth factor-beta and Wnt pathways in mammary and intestinal tumorigenesis. Labbé E, Lock L, Letamendia A, Gorska AE, Gryfe R, Gallinger S, Moses HL, Attisano L (2007) Cancer Res 67(1): 75-84
    › Primary publication · 17210685 (PubMed)
  50. Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-beta1 in adult mice. Ewan KB, Oketch-Rabah HA, Ravani SA, Shyamala G, Moses HL, Barcellos-Hoff MH (2005) Am J Pathol 167(2): 409-17
    › Primary publication · 16049327 (PubMed) · PMC1603552 (PubMed Central)
  51. Contributions by members of the TGFbeta superfamily to lens development. Beebe D, Garcia C, Wang X, Rajagopal R, Feldmeier M, Kim JY, Chytil A, Moses H, Ashery-Padan R, Rauchman M (2004) Int J Dev Biol 48(8-9): 845-56
    › Primary publication · 15558476 (PubMed)
  52. Conditional deletion of the TGF-beta type II receptor in Col2a expressing cells results in defects in the axial skeleton without alterations in chondrocyte differentiation or embryonic development of long bones. Baffi MO, Slattery E, Sohn P, Moses HL, Chytil A, Serra R (2004) Dev Biol 276(1): 124-42
    › Primary publication · 15531369 (PubMed)
  53. Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects. Ito Y, Yeo JY, Chytil A, Han J, Bringas P, Nakajima A, Shuler CF, Moses HL, Chai Y (2003) Development 130(21): 5269-80
    › Primary publication · 12975342 (PubMed)
  54. Transforming growth factor beta mimetics: discovery of 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid, a biaryl hydroxamate inhibitor of histone deacetylase. Glaser KB, Li J, Aakre ME, Morgan DW, Sheppard G, Stewart KD, Pollock J, Lee P, O'Connor CZ, Anderson SN, Mussatto DJ, Wegner CW, Moses HL (2002) Mol Cancer Ther 1(10): 759-68
    › Primary publication · 12492108 (PubMed)
  55. TGF-beta1 regulates the expression of multiple max-interacting transcription factors in Balb/MK cells: implications for understanding the mechanism of action of TGF-beta1. Satterwhite DJ, White RL, Aakre ME, Moses HL (2001) Pediatr Res 50(1): 67-75
    › Primary publication · 11420421 (PubMed)
  56. UICC Study Group on Basic and Clinical Cancer Research: mechanisms of growth factor and hormone insensitivity. Burger MM, Moses HL (1997) Int J Cancer 73(4): 461-3
    › Primary publication · 9389556 (PubMed)
  57. Stem cells in lung development, disease, and therapy. Mason RJ, Williams MC, Moses HL, Mohla S, Berberich MA (1997) Am J Respir Cell Mol Biol 16(4): 355-63
    › Primary publication · 9115744 (PubMed)
  58. Characterization of the interaction of FKBP12 with the transforming growth factor-beta type I receptor in vivo. Okadome T, Oeda E, Saitoh M, Ichijo H, Moses HL, Miyazono K, Kawabata M (1996) J Biol Chem 271(36): 21687-90
    › Primary publication · 8702959 (PubMed)