OpenLB
Open Library of Bioscience
Advanced Search
Cell reports methods
09 27, 2021;1 (5):

functional cell phenotyping reveals microdomain networks in colorectal cancer recurrence.

Samantha A Furman, Andrew M Stern, Shikhar Uttam, D Lansing Taylor, Filippo Pullara, S Chakra Chennubhotla
Author Information
  1. Samantha A Furman: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  2. Andrew M Stern: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  3. Shikhar Uttam: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  4. D Lansing Taylor: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  5. Filippo Pullara: SpIntellx, Inc., 2425 Sidney Street, Pittsburgh, PA 15203, USA.
  6. S Chakra Chennubhotla: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
PMID: 34888541 DOI: 10.1016/j.crmeth.2021.100072

Abstract

Tumors are dynamic ecosystems comprising localized niches (microdomains), possessing distinct compositions and spatial configurations of cancer and non-cancer cell populations. Microdomain-specific network signaling coevolves with a continuum of cell states and functional plasticity associated with disease progression and therapeutic responses. We present LEAPH, an unsupervised machine learning algorithm for identifying cell phenotypes, which applies recursive steps of probabilistic clustering and spatial regularization to derive functional phenotypes (FPs) along a continuum. Combining LEAPH with pointwise mutual information and network biology analyses enables the discovery of outcome-associated microdomains visualized as distinct spatial configurations of heterogeneous FPs. Utilization of an immunofluorescence-based (51 biomarkers) image dataset of colorectal carcinoma primary tumors (n = 213) revealed microdomain-specific network dysregulation supporting cancer stem cell maintenance and immunosuppression that associated selectively with the recurrence phenotype. LEAPH enables an explainable artificial intelligence platform providing insights into pathophysiological mechanisms and novel drug targets to inform personalized therapeutic strategies.

References

  1. Nat Med. 2021 Feb;27(2):212-224 [PMID: 33574607]
  2. Cell. 2018 Aug 9;174(4):968-981.e15 [PMID: 30078711]
  3. Mol Oncol. 2017 Jan;11(1):97-119 [PMID: 28085225]
  4. Cell. 2020 Sep 3;182(5):1232-1251.e22 [PMID: 32822576]
  5. Nat Med. 2018 May;24(5):541-550 [PMID: 29686425]
  6. Curr Protoc Chem Biol. 2016 Dec 7;8(4):251-264 [PMID: 27925668]
  7. Trends Cancer. 2016 Sep;2(9):495-504 [PMID: 28741478]
  8. Nature. 2020 Feb;578(7796):615-620 [PMID: 31959985]
  9. Cancer Res. 2017 Nov 15;77(22):6065-6068 [PMID: 28754675]
  10. KDD. 2015 Aug;2015:387-396 [PMID: 27398260]
  11. Nat Commun. 2018 Dec 4;9(1):5150 [PMID: 30514914]
  12. Nat Rev Cancer. 2019 Jun;19(6):307-325 [PMID: 31092904]
  13. Nat Med. 2015 Nov;21(11):1350-6 [PMID: 26457759]
  14. Psychol Methods. 2018 Dec;23(4):617-634 [PMID: 29595293]
  15. Elife. 2018 Jul 11;7: [PMID: 29993362]
  16. Adv Anat Pathol. 2020 Jul;27(4):241-250 [PMID: 32541594]
  17. Nature. 2013 Sep 19;501(7467):346-54 [PMID: 24048067]
  18. Cell. 2011 Mar 4;144(5):646-74 [PMID: 21376230]
  19. Cancer Discov. 2020 Mar;10(3):406-421 [PMID: 31857391]
  20. Biol Open. 2013 Apr 18;2(5):439-47 [PMID: 23789091]
  21. Nat Methods. 2021 Jan;18(1):1 [PMID: 33408396]
  22. NPJ Breast Cancer. 2022 Jan 13;8(1):6 [PMID: 35027560]
  23. Neural Comput. 1999 Feb 15;11(2):443-82 [PMID: 9950739]
  24. Annu Rev Pathol. 2013 Jan 24;8:277-302 [PMID: 23092187]
  25. Cell. 2000 Oct 13;103(2):311-20 [PMID: 11057903]
  26. Cell. 2018 Aug 23;174(5):1293-1308.e36 [PMID: 29961579]
  27. Nat Methods. 2014 Apr;11(4):417-22 [PMID: 24584193]
  28. Ecology. 2012 Mar;93(3):477-89 [PMID: 22624203]
  29. J Hematol Oncol. 2017 May 5;10(1):101 [PMID: 28476164]
  30. BMC Med. 2017 Jul 18;15(1):133 [PMID: 28716075]
  31. Trends Cancer. 2019 Jul;5(7):411-425 [PMID: 31311656]
  32. Cancer Discov. 2018 Jun;8(6):730-749 [PMID: 29510987]
  33. Nat Rev Immunol. 2015 Nov;15(11):669-82 [PMID: 26471778]
  34. Nat Genet. 2015 Apr;47(4):320-9 [PMID: 25706628]
  35. Nat Methods. 2019 Dec;16(12):1289-1296 [PMID: 31740819]
  36. Cancer Discov. 2022 Jun 2;12(6):1518-1541 [PMID: 35404441]
  37. Trends Cancer. 2019 Nov;5(11):704-723 [PMID: 31735289]
  38. Nat Rev Cancer. 2017 Mar 23;17(4):268 [PMID: 28332502]
  39. Nat Commun. 2020 Jul 14;11(1):3515 [PMID: 32665557]
  40. Cell. 2015 Jul 2;162(1):184-97 [PMID: 26095251]
  41. Nat Rev Genet. 2019 Jun;20(6):317 [PMID: 30980030]
  42. Immunity. 2018 Apr 17;48(4):812-830.e14 [PMID: 29628290]
  43. Cell. 2018 Jun 14;173(7):1755-1769.e22 [PMID: 29754820]
  44. J Thorac Oncol. 2018 Oct;13(10):1496-1507 [PMID: 29933065]
  45. Nat Methods. 2020 Jan;17(1):101-106 [PMID: 31740815]
  46. Nat Biotechnol. 2021 Mar;39(3):313-319 [PMID: 33288904]
  47. Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):9956-9961 [PMID: 30224466]
  48. Cancer Res. 1998 Aug 15;58(16):3491-4 [PMID: 9721846]
  49. J Comput Biol. 2020 Aug;27(8):1204-1218 [PMID: 32243203]
  50. Mod Pathol. 2017 Apr;30(4):599-609 [PMID: 27982025]
  51. Cell. 2019 Aug 8;178(4):835-849.e21 [PMID: 31327527]
  52. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12258-62 [PMID: 9356436]
  53. Science. 2010 Nov 5;330(6005):827-30 [PMID: 21051638]
  54. Front Oncol. 2014 Dec 18;4:366 [PMID: 25566504]
  55. Trends Cell Biol. 2019 Jan;29(1):44-65 [PMID: 30220580]
  56. Nat Genet. 2015 Apr;47(4):312-9 [PMID: 25706627]
  57. J Immunother Cancer. 2015 Sep 15;3:43 [PMID: 26380088]
  58. Front Immunol. 2019 Feb 08;10:168 [PMID: 30800125]
  59. Sci Adv. 2018 Sep 12;4(9):eaat7828 [PMID: 30214939]
  60. Cell. 2020 Sep 3;182(5):1341-1359.e19 [PMID: 32763154]
  61. Front Immunol. 2019 Aug 20;10:1875 [PMID: 31481956]
  62. Nat Rev Cancer. 2018 Mar;18(3):139-147 [PMID: 29326431]
  63. Stem Cell Res. 2016 Nov;17(3):607-615 [PMID: 27838585]
  64. JCI Insight. 2017 Jun 2;2(11): [PMID: 28570279]
  65. Mol Syst Biol. 2020 Dec;16(12):e9798 [PMID: 33369114]
  66. Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):11982-7 [PMID: 23818604]
  67. Nat Med. 2018 Aug;24(8):1277-1289 [PMID: 29988129]
  68. Nature. 2018 Apr;556(7702):457-462 [PMID: 29643510]
  69. Cancer Cell. 2018 Jan 8;33(1):125-136.e3 [PMID: 29316426]
  70. Trends Cancer. 2017 Feb;3(2):79-88 [PMID: 28239669]
  71. J Pathol Inform. 2016 Nov 29;7:47 [PMID: 27994939]
  72. J Cell Sci. 2012 Dec 1;125(Pt 23):5591-6 [PMID: 23420197]
  73. J Immunother Cancer. 2019 Jul 23;7(1):194 [PMID: 31337426]
  74. Nat Methods. 2019 Oct;16(10):987-990 [PMID: 31501547]
  75. PLoS One. 2017 Nov 30;12(11):e0188878 [PMID: 29190747]
  76. Breast Cancer Res. 2016 Aug 11;18(1):84 [PMID: 27515302]

Grants

  1. U01 TR002383/NCATS NIH HHS
  2. P30 CA047904/NCI NIH HHS
  3. R21 CA204836/NCI NIH HHS
  4. F31 CA254332/NCI NIH HHS
  5. T32 EB009403/NIBIB NIH HHS
  6. U01 CA204826/NCI NIH HHS
  7. U54 HG008540/NHGRI NIH HHS

MeSH Term

Humans
Artificial Intelligence
Ecosystem
Algorithms
Biomarkers
Colorectal Neoplasms

Chemicals

Biomarkers
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural
Article has an altmetric score of 4

Word Cloud

Created with Highcharts 10.0.0cellspatialcancernetworkfunctionalLEAPHmicrodomainsdistinctconfigurationscontinuumassociatedtherapeuticphenotypesFPsenablescolorectalrecurrenceTumorsdynamicecosystemscomprisinglocalizednichespossessingcompositionsnon-cancerpopulationsMicrodomain-specificsignalingcoevolvesstatesplasticitydiseaseprogressionresponsespresentunsupervisedmachinelearningalgorithmidentifyingappliesrecursivestepsprobabilisticclusteringregularizationderivealongCombiningpointwisemutualinformationbiologyanalysesdiscoveryoutcome-associatedvisualizedheterogeneousUtilizationimmunofluorescence-based51biomarkersimagedatasetcarcinomaprimarytumorsn=213revealedmicrodomain-specificdysregulationsupportingstemmaintenanceimmunosuppressionselectivelyphenotypeexplainableartificialintelligenceplatformprovidinginsightspathophysiologicalmechanismsnoveldrugtargetsinformpersonalizedstrategiesphenotypingrevealsmicrodomainnetworks

Similar Articles

Cited By